Pulmonary contusion in the pan-scan era.
Although pulmonary contusion (PC) is traditionally considered a major injury requiring intensive monitoring, more frequent detection by chest CT in blunt trauma evaluation may diagnose clinically irrelevant PC. We sought to determine (1) the frequency of PC diagnosis by chest CT versus chest X-ray (CXR), (2) the frequency of PC-associated thoracic injuries, and (3) PC patient clinical outcomes (mortality, length of stay [LOS], and need for mechanical ventilation), considering patients with PC seen on chest CT only (SOCTO) and isolated PC (PC without other thoracic injury). Focusing primarily on patients who had both CXR and chest CT, we conducted a pre-planned analysis of two prospectively enrolled cohorts with the following inclusion criteria: age >14 years, blunt trauma within 24h of emergency department presentation, and receiving CXR or chest CT during trauma evaluation. We defined PC and other thoracic injuries according to CT reports and followed patients through their hospital course to determine clinical outcomes. Of 21,382 enrolled subjects, 8661 (40.5%) had both CXR and chest CT and 1012 (11.7%) of these had PC, making it the second most common injury after rib fracture. PC was SOCTO in 739 (73.0%). Most (73.5%) PC patients had other thoracic injury. PC patients had higher admission rates (91.9% versus 61.7%; mean difference 30.2%; 95% confidence interval [CI] 28.1-32.1%) and mortality (4.7% versus 2.0%: mean difference 2.8%; 95% CI 1.6-4.3%) than non-PC patients, but mortality was restricted to patients with other injuries (injury severity scores>10). Patients with PC SOCTO had low rates of associated mechanical ventilation (4.6%) and patients with isolated PC SOCTO had low mortality (2.6%), comparable to that of patients without PC. PC is commonly diagnosed under current blunt trauma imaging protocols and most PC are SOCTO with other thoracic injury. Given that they are associated with low mortality and uncommon need for mechanical ventilation, isolated PC and PC SOCTO may be of limited clinical significance.


Assessment of AFLP marker behaviour in enriching STS radiation hybrid maps.
Radiation hybrid (RH) mapping provides a powerful tool to build high-resolution maps of genomes. Here, we demonstrate the use of the AFLP technique for high-throughput typing of RH cell lines. Cattle were used as the model species because an RH panel was available to investigate the behaviour of AFLP markers within the microsatellite- and STS-based maps of this species. A total of 747 AFLP markers were typed on the TM112 RH radiation panel and 651 of these were assigned by two-point analysis to the 29 bovine autosomes and sex chromosomes. AFLP markers were added to the 1222 microsatellite and STS markers that were included in earlier RH maps. Multipoint maps were constructed for seven example chromosomes, which retained 248 microsatellite and STS markers, and added 123 AFLP markers at LOD 4. The addition of the AFLP markers increased the number of markers by 42.1% and the map length by 10.4%. The AFLP markers showed lower retention frequency (RF) values than the STS markers. The comparison of RF values in AFLP markers and their corresponding AFLP-derived STSs demonstrated that the lower RF values were due to the lower detection sensitivity of the AFLP technique. Despite these differences, AFLP and AFLP-derived STS markers mapped to identical or similar positions. These results demonstrate that it is possible to merge AFLP and microsatellite markers in the same map. The application of AFLP technology could permit the rapid construction of RH maps in species for which extensive genome information and large numbers of SNP and microsatellite markers are not available.


Heart-rate responses by playing position during ball drills in basketball.
The physiological load experienced during basketball drills is crucial to understand players' adaptation to team-sport training and plan physical-conditioning programs. To compare mean heart-rate (HRmean) responses by playing position during 2-a-side (2v2) and 3-a-side (3v3) ball drills in male junior basketball players and explore the relationship between HRmean and repeated-sprint ability (RSA). Thirty- one players volunteered to participate in this study. On separate occasions, they performed 2v2 and 3v3 ball drills and 6 repetitions of shuttle-run sprints of 20 m (10+10 m), departing every 20 s (RSA). Ball drills took place on the full length but only half the width of the court and were three 4-min bouts separated by 1-min rest periods. An analysis of variance (ANOVA) assessed the effect of the number of players on court (2v2 vs 3v3) and playing position (guards vs forwards vs centers) on HRmean, and a Pearson correlation coefficient evaluated the relation between HRmean and RSA. The main results showed greater HRmean in 2v2 than in 3v3 ball drills (P < .001) in all playing positions (90.7% ± 1.3% vs 87.6% ± 3% of HRpeak in guards, 91.3% ± 2.1% vs 87.5% ± 3.7% of HRpeak for forwards, and 88.2% ± 3.5% vs 82.2% ± 5.6% of HRpeak in centers, respectively, for 2v2 and 3v3). In addition, centers were characterized by lower HRmean than guards and forwards in 3v3 only (P = .018). These results suggest that 2v2 drills should be preferred to 3v3 drills for aerobic conditioning, in particular for centers. Finally, RSA does not seem to influence players' acute responses to ball drills.


The performance of seven QPrediction risk scores in an independent external sample of patients from general practice: a validation study.
To validate the performance of a set of risk prediction algorithms developed using the QResearch database, in an independent sample from general practices contributing to the Clinical Research Data Link (CPRD). Prospective open cohort study using practices contributing to the CPRD database and practices contributing to the QResearch database. The CPRD validation cohort consisted of 3.3 million patients, aged 25-99 years registered at 357 general practices between 1 Jan 1998 and 31 July 2012. The validation statistics for QResearch were obtained from the original published papers which used a one-third sample of practices separate to those used to derive the score. A cohort from QResearch was used to compare incidence rates and baseline characteristics and consisted of 6.8 million patients from 753 practices registered between 1 Jan 1998 and until 31 July 2013. Incident events relating to seven different risk prediction scores: QRISK2 (cardiovascular disease); QStroke (ischaemic stroke); QDiabetes (type 2 diabetes); QFracture (osteoporotic fracture and hip fracture); QKidney (moderate and severe kidney failure); QThrombosis (venous thromboembolism); QBleed (intracranial bleed and upper gastrointestinal haemorrhage). Measures of discrimination and calibration were calculated. Overall, the baseline characteristics of the CPRD and QResearch cohorts were similar though QResearch had higher recording levels for ethnicity and family history. The validation statistics for each of the risk prediction scores were very similar in the CPRD cohort compared with the published results from QResearch validation cohorts. For example, in women, the QDiabetes algorithm explained 50% of the variation within CPRD compared with 51% on QResearch and the receiver operator curve value was 0.85 on both databases. The scores were well calibrated in CPRD. Each of the algorithms performed practically as well in the external independent CPRD validation cohorts as they had in the original published QResearch validation cohorts.


A three-genome phylogeny of malaria parasites (Plasmodium and closely related genera): evolution of life-history traits and host switches.
Phylogenetic analysis of genomic data allows insights into the evolutionary history of pathogens, especially the events leading to host switching and diversification, as well as alterations of the life cycle (life-history traits). Hundreds, perhaps thousands, of malaria parasite species exploit squamate reptiles, birds, and mammals as vertebrate hosts as well as many genera of dipteran vectors, but the evolutionary and ecological events that led to this diversification and success remain unresolved. For a century, systematic parasitologists classified malaria parasites into genera based on morphology, life cycle, and vertebrate and insect host taxa. Molecular systematic studies based on single genes challenged the phylogenetic significance of these characters, but several significant nodes were not well supported. We recovered the first well resolved large phylogeny of Plasmodium and related haemosporidian parasites using sequence data for four genes from the parasites' three genomes by combining all data, correcting for variable rates of substitution by gene and site, and using both Bayesian and maximum parsimony analyses. Major clades are associated with vector shifts into different dipteran families, with other characters used in traditional parasitological studies, such as morphology and life-history traits, having variable phylogenetic significance. The common parasites of birds now placed into the genus Haemoproteus are found in two divergent clades, and the genus Plasmodium is paraphyletic with respect to Hepatocystis, a group of species with very different life history and morphology. The Plasmodium of mammal hosts form a well supported clade (including Plasmodium falciparum, the most important human malaria parasite), and this clade is associated with specialization to Anopheles mosquito vectors. The Plasmodium of birds and squamate reptiles all fall within a single clade, with evidence for repeated switching between birds and squamate hosts.


Allergy skin testing of children.
Skin tests are important aids in the management of patients with inhalant allergy. Their usefulness will be increased if these basic principles are kept in mind: (1) Scratch test should be sufficiently deep, (2) Antigen extracts used for intradermal tests should be fresh enough to insure their activity, (3) Two control tests should be used each time tests are done, (4) Hydroxyzine and promethazine may diminish skin reactivity; therefore, negative skin tests should not be relied upon until repeated in the absence of such medication, and (5) Skin tests for food allergy are quite unreliable, whether positive or negative. Food allergy is best studied by means of elimination trial diets.


The search for equality: representations of the smoking act among adolescent women.
This study aimed to discover the representations of the smoking habit in both non-smoking and smoking female adolescents from a high school in Querétaro, Mexico. It is a qualitative research, carried out with 14 female adolescents in 2005. A semi-structured interview and a socioeconomic survey were used to collect data. Results evidenced adolescents know the biomedical discourse, which proposes that smoking causes serious consequences to health. However, there are other symbolic reasons that influence its use such as the search for equality and image, since they think men find smoking women more attractive and mature. Peer pressure represents an important factor for women to smoke by validating its practice and minimizing its effects to the body.


Orientational exchange approach to fluorescence anisotropy decay.
Fluorescence depolarization is a powerful technique in resolving dynamics of molecular systems. Data obtained in fluorescence depolarization experiments are highly complex. Mathematical models for analyzing data from depolarization due to rotational motion have been largely based on the rotational diffusion equation. These results have been verified by Monte Carlo simulations. It has been implicitly stated that a 90 degrees jump model between predefined orientations such as presented by G. Weber (1971. J. Chem. Phys. 55:2399-2411) should, for the specific case of fluorescence depolarization, give the same answer as the diffusion equation. Since the highly symmetric cases considered by G. Weber gave the same result as the diffusion equation, it has been desirable to use this method in cases where depolarization arises from both discrete processes and rotational diffusion. We have derived, in a compartmental formalism, the general result for excitation and emission dipoles not necessarily coincident with any of the principal rotational axes of the fluorophore from this exchange model, and have found it to be different from that of the diffusion equation approach. We have also verified this difference with a Monte Carlo simulation of our exchange model. This derivation allows us to define the limits of validity of the 90 degrees exchanges to model rotational diffusion. Also, for systems where movements may be jumps between a few preferred orientations, the actual physical mechanism of depolarization may not be accurately represented by continuous diffusion. The compartmental formalism developed here can be used to easily combine rotational motions with discrete position jumps or other level kinetics. While the difference between the diffusion equation and random walk of finite step size derivations has been presented for observations of different order properties for the compartmental formalism, we discuss the possibility of finding this difference by using the ratio of relaxation rates from a single experiment. Also,the temperature dependence of the exchange rates is calculated in relation to the Kramer's theory.


Assessment and management of pulmonary alveolar proteinosis in a reference center.
Pulmonary alveolar proteinosis (PAP) is a term defining an ultra-rare group of disorders characterised by a perturbation in surfactant homeostasis, resulting in its accumulation within airspaces and impaired gas transfer. In this report we provide data from a cohort of PAP patients (n=81) followed for more than two decades at the San Matteo University Hospital of Pavia, Italy. In agreement with other large series in PAP individuals, 90% of the study subjects were affected by autoimmune/idiopathic PAP, while the remaining subjects were divided as follow: congenital 1%, secondary 4% and PAP-like 5%. The disease affected males and females with a ratio of 2:1 and approximately one third of PAP patients were lifelong nonsmokers. Occupational exposure was reported in 35% of subjects in this series. With reference to the PAP clinical course, in 29 patients (7% with spontaneous remission) disease severity did not necessitate whole lung lavage (WLL) in the long-term follow up. On the other hand, 44 PAP patients underwent therapeutic WLL: in 31 subjects a single WLL was sufficient to provide long term, durable benefit, whereas 13 patients required multiple WLLs. The intra-patient mean interval between two consecutive WLLs was 15.7±13.6 months. When baseline data among never lavaged and PAP patients lavaged at least once were compared, the need for lavage was significantly associated with serum biomarkers (CEA, Cyfra, LDH), lung function parameters forced vital capacity (FVC), and lung diffusing capacity (Dlco). We conclude that patient cohorts with an ultra-rare disease, such as PAP, referred to a single reference center, can provide useful information on the natural history and clinical course of the disease.


Levobetaxolol-induced Up-regulation of retinal bFGF and CNTF mRNAs and preservation of retinal function against a photic-induced retinopathy.
Betaxolol (racemic), a beta-adrenoceptor antagonist that is used to lower intraocular pressure in the treatment of glaucoma, has been shown to protect inner retina cells from various insults. To determine if such protection could be afforded to retinal photoreceptors and retinal pigment epithelial cells (RPE), levobetaxolol (S-betaxolol) was evaluated in a photic-induced retinopathy model. Rats were dosed (IP) with vehicle or levobetaxolol (10 and 20 mg kg(-1)) 48, 24 and 0 hr prior to exposure for 6 hr to fluorescent blue light. The electroretinogram (ERG) and retinal morphology were assessed after a 3 week recovery period. Evaluation of the ERG demonstrated significant protection of retinal function in levobetaxolol (20 mg kg(-1))-dosed rats compared to vehicle-dosed rats. Similarly, the RPE and outer nuclear layer were significantly thicker in levobetaxolol (20 mg kg(-1))-dosed rats compared to vehicle-dosed rats. To elucidate potential mechanism(s) of the neuroprotective activity of levobetaxolol, bFGF and CNTF mRNA levels in normal rat retinas were evaluated 12 hr after a single i.p. injection. Northern blot analysis of levobetaxolol treated retinas demonstrated a 10-fold up-regulation of bFGF and a two-fold up-regulation of CNTF mRNA levels, trophic factors that have been shown to inhibit retinal degeneration in a number of species. These studies suggest that levobetaxolol can be used as a novel neuroprotective agent to ameliorate retinopathy.


Tetra-glucopyranosyl Diterpene ent-Kaur-16-en-19-oic Acid and ent-13(S)-Hydroxyatisenoic Acid Derivatives from a Commercial Extract of Stevia rebaudiana (Bertoni) Bertoni.
Stevia rebaudiana and its diterpene glycosides are one of the main focuses of food companies interested in developing novel zero calorie sugar substitutes since the recognition of steviol glycosides as Generally Recognized as Safe (GRAS) by the United States Food and Drug Administration. Rebaudioside A, one of the major steviol glycosides of the leaves is more than 200 times sweeter than sucrose. However, its lingering aftertaste makes it less attractive as a table-top sweetener, despite its human health benefits. Herein, we report the purification of two novel tetra-glucopyranosyl diterpene glycosides 1 and 3 (rebaudioside A isomers) from a commercial Stevia rebaudiana leaf extract compounds, their saponification products compounds 2 and 4, together with three known compounds isolated in gram quantities. Compound 1 was determined to be 13-[(2-O-β-d-glucopyranosyl-6-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]ent-kaur-16-en-19-oic acid-β-d-glucopyranosy ester (rebaudioside Z), whereas compound 3 was found to be 13-[(2-O-β-d-glucopyranosyl-3-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]ent-hydroxyatis-16-en-19-oic acid -β-d-glucopyranosy ester. Two new tetracyclic derivatives with no sugar at position C-19 were prepared from rebaudiosides 1 and 3 under mild alkaline hydrolysis to afford compounds 2 13-[(2-O-β-d-glucopyranosyl-6-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]ent-kaur-16-en-19-oic acid (rebaudioside Z₁) and 4 13-[(2-O-β-d-glucopyranosyl-3-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]ent-hydroxyatis-16-en-19-oic acid. Three known compounds were purified in gram quantities and identified as rebaudiosides A (5), H (6) and J (7). Chemical structures were unambiguously elucidated using different approaches, namely HRESIMS, HRESI-MS/MS, and 1D-and 2D-NMR spectroscopic data. Additionally, a high-quality crystal of iso-stevioside was grown in methanol and its structure confirmed by X-ray diffraction.


Bayesian modeling of perceived surface slant from actively-generated and passively-observed optic flow.
We measured perceived depth from the optic flow (a) when showing a stationary physical or virtual object to observers who moved their head at a normal or slower speed, and (b) when simulating the same optic flow on a computer and presenting it to stationary observers. Our results show that perceived surface slant is systematically distorted, for both the active and the passive viewing of physical or virtual surfaces. These distortions are modulated by head translation speed, with perceived slant increasing directly with the local velocity gradient of the optic flow. This empirical result allows us to determine the relative merits of two alternative approaches aimed at explaining perceived surface slant in active vision: an "inverse optics" model that takes head motion information into account, and a probabilistic model that ignores extra-retinal signals. We compare these two approaches within the framework of the bayesian theory. The "inverse optics" bayesian model produces veridical slant estimates if the optic flow and the head translation velocity are measured with no error; because of the influence of a "prior" for flatness, the slant estimates become systematically biased as the measurement errors increase. The bayesian model, which ignores the observer's motion, always produces distorted estimates of surface slant. Interestingly, the predictions of this second model, not those of the first one, are consistent with our empirical findings. The present results suggest that (a) in active vision perceived surface slant may be the product of probabilistic processes which do not guarantee the correct solution, and (b) extra-retinal signals may be mainly used for a better measurement of retinal information.


Winter color polymorphisms identify global hot spots for evolutionary rescue from climate change.
Maintenance of biodiversity in a rapidly changing climate will depend on the efficacy of evolutionary rescue, whereby population declines due to abrupt environmental change are reversed by shifts in genetically driven adaptive traits. However, a lack of traits known to be under direct selection by anthropogenic climate change has limited the incorporation of evolutionary processes into global conservation efforts. In 21 vertebrate species, some individuals undergo a seasonal color molt from summer brown to winter white as camouflage against snow, whereas other individuals remain brown. Seasonal snow duration is decreasing globally, and fitness is lower for winter white animals on snowless backgrounds. Based on 2713 georeferenced samples of known winter coat color-from eight species across trophic levels-we identify environmentally driven clinal gradients in winter coat color, including polymorphic zones where winter brown and white morphs co-occur. These polymorphic zones, underrepresented by existing global protected area networks, indicate hot spots for evolutionary rescue in a changing climate.


Cu2+-Regulated reversible coordination interaction of GQD@Tb/GMP ICP nanoparticles: towards directly monitoring cerebrospinal acetylcholinesterase as a biomarker for cholinic brain dysfunction.
This work demonstrates a new strategy for sensing cerebrospinal acetylcholinesterase (AChE) as a cholinergic biomarker for brain dysfunction based on graphene quantum dot (GQD)-functionalized lanthanide infinite coordination polymer (Ln-ICP) nanoparticles. The ICPs used in this work were comprised of two components, i.e. a supramolecular Ln-ICP host formed by the coordination between the GMP ligand and central metal ion Tb3+, and guest GQDs with abundant functional groups, which were utilized as antenna ligands to further sensitize the fluorescence of Tb/GMP. Upon excitation at 300 nm, the obtained GQD@Tb/GMP ICP nanoparticles exhibited enhanced green fluorescence from Tb/GMP. With the addition of Cu2+, the competitive coordination between Cu2+ and GQDs weakened the antenna effect, leading to a decrease in the fluorescence of GQD@Tb/GMP ICPs. However, in the presence of thiocholine (TCh), a thiol-containing compound hydrolyzed from acetylthiocholine (ATCh) by AChE, a stronger coordination interaction between Cu2+ and TCh occurred, resulting in the restoration of the fluorescence of GQD@Tb/GMP ICPs. Using the method established herein, the cerebrospinal AChE fluctuation of rats with acute organophosphorus pesticide (OP) poisoning or chronic Alzheimer's disease (AD) could be monitored. This study essentially provides a novel approach to realize the direct monitoring of a biomarker for brain dysfunction by regulating the competitive coordination interaction reversibly, which is critical in the early diagnosis and therapy of brain diseases.


Elucidating the early stages of keratin filament assembly.
Because of extraordinarily tight coiled-coil associations of type I and type II keratins, the composition and structure of keratin subunits has been difficult to determine. We report here the use of novel genetic and biochemical methods to explore the early stages of keratin filament assembly. Using bacterially expressed humans K5 and K14, we show that remarkably, these keratins behave as 1:1 complexes even in 9 M urea and in the presence of a reducing agent. Gel filtration chromatography and chemical cross-linking were used to identify heterodimers and heterotetramers as the most stable building blocks of keratin filament assembly. EM suggested that the dimer consists of a coiled-coil of K5 and K14 aligned in register and in parallel fashion, and the tetramer consists of two dimers in antiparallel fashion, without polarity. In 4 M urea, both end-to-end and lateral packing of tetramers occurred, leading to a variety of larger heteromeric complexes. The coexistence of multiple, higher-ordered associations under strongly denaturing conditions suggests that there may not be a serial sequence of events leading to the assembly of keratin intermediate filaments, but rather a number of associations may take place in parallel.


Aldosterone infusion into the rat and dose-dependent changes in blood pressure and arterial ionic transport.
Induction of hypertension by implantation or injection of deoxycorticosterone acetate (DOCA) requires a dose well above the physiological range. The objective of this study was to produce hypertension in rats by chronic infusion of d-aldosterone, a more potent mineralocorticoid. Aldosterone infused at a dose of 1 microgram/hr for 4 weeks gave maximal rise in systolic blood pressure (132 +/- 3 vs 203 +/- 7 mm Hg). A significant rise in blood pressure was achieved at 0.1 microgram/hr (170 +/- 6 mm Hg) which was associated with a 2.3-fold rise in plasma aldosterone levels (7.6 +/- 0.4 vs 17.7 +/- 2.2 ng/dl). A series of isotope flux studies on the aorta and femoral artery from hypertensive animals demonstrated increases in 42K and 36Cl turnover. In both vessels the largest changes in ion turnover were observed in vessels from animals infused with aldosterone at 0.25 micrograms/hr. Increases in 42K and 36Cl turnover were detected as early as 1 week after the start of aldosterone infusion, well before a significant rise in blood pressure had occurred.


Adiponectin and its receptors in the ovary: further evidence for a link between obesity and hyperandrogenism in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS), characterized by ovarian androgen excess, is the commonest endocrine disorder in women. Obesity increases androgen synthesis, a phenomenon attributed to the accompanying hyperinsulinemia. Our hypothesis was that adipokines, fat cell-derived hormones, play a direct role in modulating ovarian androgen secretion. Therefore, the aims of this study were to explore the effects of adipokines (in particular, adiponectin) on ovarian steroidogenesis and compare the expression of adiponectin receptors in ovaries from women with and without PCO. Sections of archived human ovaries (nine from women with normal ovaries and 16 with PCOS, classified histologically, with reference to menstrual history and ultrasound) were analysed by quantitative morphometry and the proportion of positive-labelling cells compared. In addition, studies of androgen production in relation to adipokine function in primary bovine theca cell culture were also performed. A significantly lower proportion of theca cells expressed adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) in polycystic ovaries than in normal ovaries. In cultured theca cells, adiponectin suppressed androstenedione production and gene expression of LH receptor and key enzymes in the androgen synthesis pathway. Moreover, knockdown of genes for AdipoR1 and AdipoR2 was associated with increased androstenedione secretion by bovine theca cells. These results provide evidence for a direct link between fat cell metabolism and ovarian steroidogenesis, suggesting that disruption of adiponectin and/or its receptors plays a key role in pathogenesis of hyperandrogenism in PCOS.


[Results of a study on the under-detection of meningococcus in vaccinated subjects in Galicia].
On the basis of active surveillance and the monitoring of Meningococcal Disease (MD) following the vaccination campaign carried out in Galicia, it was observed that the proportion of isolations of the serogroups responsible for the disease among individuals suspected of Meningococcal Disease (SMD) who had been vaccinated was lower than among unvaccinated individuals. In view of this situation, a study was made in order to determine whether in the origin of those SMDs that were not isolated, we would find N. Meningitidis serogroup C, and to quantify the significance of the sub-detection of same. For this purpose, and during the period under study (from the 26th week of 1997 to the 14th week of 1999), blood and cephalorachidian fluid samples were taken from the SMDs without isolation for their study with C protein reagent for type and serogroup. The analysis of the samples was performed by the microbiology laboratory of the Clinical Hospital of Santiago de Compostela. Of the 120 cases notified during the period under study, 65 were analysed by C protein reagent (38 vaccinated and 27 unvaccinated), with a positive reading for N. meningitidis in 65% (42 samples) 74% in vaccinated individuals and 52% in unvaccinated. By estimating, on the basis of the cases studied, the results for the total, and excluding the C protein reagent negative cases, we find that, for serogroup C, in only 27% of the cases occurring in vaccinated individuals was it possible to isolate it, in comparison with 80% in the case of unvaccinated subjects (p < 0.0001). These percentages are, in the case of serogroup B, 59% and 71%, respectively, a difference which is not statistically significant. The vaccine brought about an true sub-detection of serogroup C meningococci in the vaccinated cases.


Structural Modeling of γ-Secretase Aβ n Complex Formation and Substrate Processing.
The intramembrane aspartyl protease γ-secretase (GSEC) cleaves single-span transmembrane helices including the C-terminal fragment of the amyloid precursor protein (APP). This substrate is initially cleaved at the ϵ-site followed by successive processing (trimming) events mostly in steps of three amino acids. GSEC is responsible for the formation of N-terminal APP amyloid-β (Aβ) peptides of different length (e.g., Aβ42) that can form aggregates involved in Alzheimer's disease pathogenesis. The molecular mechanism of GSEC-APP substrate recognition is key for understanding how different peptide products are formed and could help in designing APP-selective modulators. Based on the known structure of apo GSEC and the APP-C99 fragment we have generated putative structural models of the initial binding in three different possible modes using extensive molecular dynamics (MD) simulations. The binding mode with the substrate helix located in a cleft between the transmembrane helices 2 and 3 of the presenilin subunit was identified as a most likely binding mode. Based on this arrangement, the processing steps were investigated using restraint MD simulations to pull the scissile bond (for each processing step) into a transition like (cleavable) state. This allowed us to analyze in detail the motions and energetic contributions of participating residues. The structural model agrees qualitatively well with the influence of many mutations in GSEC and C99. It also explains the effects of inhibitors, cross-linking, as well as spectroscopic data on GSEC substrate binding and can serve as working model for the future planning of structural and biochemical studies.


Age-related changes in the metabolism and excretion of allyl isothiocyanate. A model compound for glutathione conjugation.
The objective of this study was to evaluate age-related changes in the in vivo metabolism and excretion of allyl isothiocyanate (AITC), which is used as a model compound to assess glutathione conjugation. AITC is a constituent of oil of mustard and a food additive that has been shown to induce transitional cell papillomas in the urinary bladder of male Fischer rats. Male Fischer rats, ages 3, 16, and 27 months, were dosed orally with 14C-AITC (25 mg/kg). Urine, feces, volatiles, and expired air were collected for 72 hr. Biliary excretion was also examined after iv administration of 10 mg/kg of 14C-AITC. There was no significant difference between these age groups in the percentage of the total dose of AITC eliminated in urine, which is the major route of excretion. The percentage of the dose excreted as volatiles increased in the 27-month animals. These animals also showed a decrease in the production of 14CO2. An age-related decrease in fecal excretion of AITC-derived radioactivity was observed. However, the percentage of the dose excreted in bile increased at 16 months and then decreased in the senescent rats as compared to the 3-month age group. The age-related decrease in 14CO2 production suggests a change in the oxidative metabolism of AITC in senescent animals. However, there was no change in the relative amounts of mercapturic acid excreted in urine, suggesting that glutathione conjugation was unchanged with age.(ABSTRACT TRUNCATED AT 250 WORDS)


Erasing Bisexual Identity: The Visibility and Invisibility of Bisexuality as a Sexual Identity in the Dutch Homosexual Movement, 1946-1972.
Scholars of bisexuality commonly agree that bisexuality as a distinct sexual identity remained invisible for epistemic reasons until the 1970s. This article examines this dominant explanation for the late invention of bisexual identity by discussing how bisexuality functioned in the homosexual movement in the Netherlands from 1946 to the early 1970s. This historical case study shows that in the Netherlands bisexuality as an identity existed in the movement in the first postwar decades and was erased in the late 1960s, not only for epistemic reasons but also for tactical ones. The article aims to contribute to a better insight into the history of bisexuality and the politics in the Dutch postwar homosexual movement.


A New Enzyme Immunoassay for the Quantitative Determination of Classical Autotaxins (ATXα, ATXβ, and ATXγ) and Novel Autotaxins (ATXδ and ATXε).
Autotaxin (ATX) is a secreted enzyme that converts lysophosphatidylcholine to lysophosphatidic acid, a potent bioactive lipid mediator, through its lysophospholipase D activity. Although five alternative splicing isoforms of ATX have been identified as ATXα, ATXβ, ATXγ, ATXδ, and ATXε and the expression patterns of each isoform differ among several tissues, the clinical significance of each isoform remains to be elucidated. Anti-ATXβ and anti-ATXδ monoclonal antibodies were produced by immunization with recombinant human ATXβ and ATXδ expressed using a baculovirus system, respectively. We then developed enzyme immunoassays to measure the serum concentrations of "classical ATX" (ATXα, ATXβ, and ATXγ) and "novel ATX" (ATXδ and ATXε) antigens and evaluated the usefulness of these assays using human serum samples. The with-run and between-run precision, interference, detection limit, and linearity studies for the present assay were well validated. In healthy subjects, the serum concentrations of classical ATX and novel ATX were significantly (P < 0.01) higher in women than in men, while the ratios of classical ATX or novel ATX to total ATX were not different between women and men. The concentrations of both classical ATX and novel ATX in normal pregnant subjects and patients with chronic liver diseases or follicular lymphoma were significantly higher than those in healthy subjects, while the ratio of both ATX isoforms to total ATX did not vary among these groups. We have developed a new enzyme immunoassay to determine the concentrations of classical ATX and novel ATX in human serum. These assays may be helpful for elucidating the distinct functional roles of each ATX isoform, which are largely unknown at present.


[Comparative study of room-temperature phosphorescence of 1-bromonaphthalene induced by synergetic effect of nonionic surfactants and beta-cyclodextrin].
Room-temperature phosphorescence of 1-BrN induced by a combination of OPE-10 and Triton X-100 with beta-CD was comparatively studied. In terms of molecular size and dimensions of beta-CD, the octyl group and phenyl group of OPE-10 and Triton X-100 were incorporated into the cavity of beta-CD and the complexes with the stoichiometry of 1:1 were formed. The removal of water molecules inside the cavity results in a greater apolar interior. By enhanced hydrophobic interaction, the cavity occupied by OPE-10 and Triton X-100 is able to further capture another 1-BrN and form close packing 1:1:1 ternary inclusion complexes with apparent stability constant of 1.09 x 10(5) and 4.47 x 10(5) L2 x mol(-2), respectively. 1-BrN shows bright phosphorescence at room temperature due to the greater rigidity in the limited space and the favorable microenvironment shielding from external quenchers and quenching effect on the fluorescence of the phenyl group of OPE-10 and Triton X-100 within the same cavity. In the case of Triton X-100, the larger tert-octyl group better shields off external quenchers such as dissolved oxygen and iodide ion. Energy transfer from the excited phenyl group of Triton X-100 to adjacent 1-BrN acceptor was observed.


The case for xenotransplantation.
The availability of organs and cells from deceased humans for transplantation is not meeting the demand. Xenotransplantation, specifically the transplantation of organs and cells from genetically engineered pigs, could resolve this problem. Diabetic monkeys have remained normoglycemic and insulin-independent after pig islet transplantation for >one yr, and a pig heterotopic (non-life-supporting) heart transplant recently reached the one-yr milestone in a baboon. With these encouraging results, why is it that, with some notable exceptions, research into xenotransplantation has received relatively little support by industry, government funding agencies, and medical charitable foundations? Industry appears reluctant to support research that will take more than two to three yr to come to clinical trial, and the funding agencies appear to have been "distracted" by the current appeal of stem cell technology and regenerative medicine. It has only been the willingness of living donors to provide organs that has significantly increased the number of transplants being performed worldwide. These altruistic donations are not without risk of morbidity and even mortality to the donor. Although with the best of intentions, we are therefore traversing the Hippocratic Oath of doctors to "do no harm." This should be a stimulus to fund exploration of alternative approaches, including xenotransplantation.


Characterization of fungal keratitis in alpacas: 11 cases (2003-2012).
To describe clinical, microbiological, in vivo confocal microscopic, and histopathologic features of fungal keratitis in alpacas and to estimate prevalence of the disease in a population of alpacas from the northeastern United States. Retrospective case series. Animals-11 alpacas. Medical records of alpacas evaluated by the ophthalmology service of a veterinary teaching hospital were searched to identify animals with a clinical diagnosis of fungal keratitis and positive results for fungal culture of a corneal sample between 2003 and 2012. Signalment and historical, clinical, and microbiological details were recorded. Results of cytologic, histopathologic, and in vivo confocal microscopic corneal examinations were collected when available. Fungal keratitis was diagnosed in 11 of 169 (6.5%) alpacas that underwent ophthalmologic examination by the ophthalmology service during the study period. Ten of the 11 alpacas were evaluated in the summer or fall months. Corneal lesions included stromal ulcer, stromal abscess, corneal perforation, and nonulcerative keratitis. Aspergillus fumigatus and Fusarium solani were the most frequently cultured fungi. Fungi were also identified through corneal cytologic examination, histologic examination, or in vivo confocal microscopy in 9 alpacas. Historically, 2 alpacas were evaluated following external ocular trauma and 1 following corneal foreign body removal. Nine alpacas had received topical treatment with antimicrobials and 2 had antimicrobial-corticosteroid combinations administered topically prior to referral. Nine of 10 alpacas for which follow-up information was available were successfully treated, with globe and vision retention. Fungal keratitis was a relatively common ocular disease in this population of alpacas and appeared to share several clinical features with keratomycosis in horses.


Alveolar macrophages are a major determinant of early responses to viral lung infection but do not influence subsequent disease development.
Macrophages are abundant in the lower respiratory tract. They play a central role in the innate response to infection but may also modulate excessive inflammation. Both macrophages and ciliated epithelial cells respond to infection by releasing soluble mediators, leading to the recruitment of innate and adaptive effector cells. To study the role of lung macrophages in acute respiratory viral infection, we depleted them by the inhalation of clodronate liposomes in an established mouse model of respiratory syncytial virus (RSV) disease. Infection caused an immediate local release of inflammatory cytokines and chemokines, peaking on day 1, which was virtually abolished by clodronate liposome treatment. Macrophage depletion inhibited the activation (days 1 to 2) and recruitment (day 4) of natural killer (NK) cells and enhanced peak viral load in the lung (day 4). However, macrophage depletion did not affect the recruitment of activated CD4 or CD8 T cells, weight loss, or virus-induced changes in lung function. Therefore, lung macrophages play a central role in the early responses to viral infection but have remarkably little effect on the adaptive response occurring at the time of peak disease severity.


Trends in water level and flooding in Dhaka, Bangladesh and their impact on mortality.
Climate change is expected to impact flooding in many highly populated coastal regions, including Dhaka (Bangladesh), which is currently among the fastest growing cities in the world. In the past, high mortality counts have been associated with extreme flood events. We first analyzed daily water levels of the past 100 years in order to detect potential shifts in extremes. A distributed lag non-linear model was then used to examine the connection between water levels and mortality. Results indicate that for the period of 2003-2007, which entails two major flood events in 2004 and 2007, high water levels do not lead to a significant increase in relative mortality, which indicates a good level of adaptation and capacity to cope with flooding. However, following low water levels, an increase in mortality could be found. As our trend analysis of past water levels shows that minimum water levels have decreased during the past 100 years, action should be taken to ensure that the exposed population is also well-adapted to drought.


Histological localization of messenger RNAs for rat acetyltransferases that acetylate serotonin and genotoxic arylamines.
Rat acetyltransferases (ATs) can acetylate the endogenous arylalkylamines tryptamine, 5-hydroxytryptamine (serotonin), and 5-methoxytryptamine, the immediate precursor of melatonin. The same enzymes also acetylate and activate exogenous, carcinogenic arylamines, thereby being immediately responsible for the generation of DNA adducts. Localization of AT transcripts in the pineal gland and in specific cells of the intestine, cerebral cortex, pituitary, and lung identifies cells that may be important to the neurotransmitter and hormonal roles of the tryptamine derivatives. Transcript localization i liver, mammary gland, Zymbal gland, kidney, forestomach, and bladder, as well as intestine and lung, identifies cells that may be at increased carcinogenic risk because they can convert N-hydroxylated arylamines to genotoxic metabolites. Highly specific expression is also observed in the reproductive organs of both the male and female, including the testes, epididymis, uterus, ovary, and fallopian tube. In addition to these diverse organs, which are consistent with possible roles of the enzyme in carcinogen metabolism, neurotransmission, or hormonal regulation, specific cells of the cornea, cilliary process of the eye, olfactory process, adrenal gland, exorbital lacrimal gland, and skin also exhibit highly specific expression of AT mRNAs for which one can only speculate as to their function. In virtually every case, the extent of labeling suggested that AT1 was expressed at levels that were orders of magnitude higher than those of AT2. Qualitative differences in the sites of mRNA of these two enzymes were seen only in the olfactory process, in which AT1 was expressed in both respiratory and olfactory epithelia as well as Bowman's cells, and AT2 was detected only in the latter cells. The available data support the conclusion that the ATs are likely to be involved both in the metabolic activation of exogenous carcinogenic amines as well as the metabolism of endogenous arylalkylamines that play important hormonal and neurotransmitter roles.


Effect of substance P on C1 and other bulbospinal cells of the RVLM in neonatal rats.
Sixty-two bulbospinal neurons were recorded in the rostral ventrolateral medulla (RVLM) of neonatal rats using patch electrodes. Sixty-one percent of the recorded neurons identified by histology contained tyrosine-hydroxylase (C1 cells). Substance P increased the spontaneous firing rate of all recorded cells but had no effect on spike configuration. The peptide depolarized neurons that were silenced by injection of hyperpolarizing current and increased their input resistance. All cells (n = 12) were activated by a neurokinin (NK)1 receptor agonist but most were unaffected by an NK2- or an NK2-selective compound. In voltage clamp, substance P produced a current that was linearly related to the membrane voltage. This current reversed polarity close to the potassium equilibrium potential in 11 of 23 cells. It reversed at more hyperpolarized potentials or not at all in the rest of the cells. In conclusion, substance P upregulates the intrinsic discharge rate of C1 and other putative sympathoexcitatory cells in neonatal rats. This effect is mediated via NK1 receptors. The depolarization is mediated by a reduction in resting potassium conductance and possibly by an additional cationic conductance. These results support the possibility that substance P could play a role "in vivo" in setting the basal level of discharge of the vasomotor cells of RVLM and therefore in regulating sympathetic vasomotor tone.


Limited-treatment policies in long-term care facilities.
Two-thirds of the long-term care facilities in Minnesota accept do-not-resuscitate (DNR) orders and 73% accept care plans to limit medical treatment. The major objectives for limited-treatment plans cited by the 16.3% of facilities with administrative protocols for such plans was to provide for the resident's physical and emotional comfort and dignity. Nearly half of the protocols said limited treatment plans were intended to limit emergency care or hospitalization or to allow death to occur. Protocols advocated the alleviation of physical discomfort, anxiety, and social isolation. Tube feedings were not recommended when oral feeding became impossible. Airway suctioning, oxygen, or antibiotic treatment was suggested only as needed to alleviate suffering. Only a fourth of the protocols described a primary role for the resident in these decisions. This study demonstrates that nursing homes are developing administrative protocols for the formulation of limited-treatment plans and suggests that model policy statements describing key decision-making principles, issues, and procedural safeguards could play a constructive role in this process.


Inhibition of NFE2L2-Antioxidant Response Element Pathway by Mitochondrial Reactive Oxygen Species Contributes to Development of Cardiomyopathy and Left Ventricular Dysfunction in Chagas Disease.
We investigated the effects of mitochondrial reactive oxygen species (mtROS) on nuclear factor (erythroid 2)-like 2 (NFE2L2) transcription factor activity during Trypanosoma cruzi (Tc) infection and determined whether enhancing the mtROS scavenging capacity preserved the heart function in Chagas disease. C57BL/6 wild type (WT, female) mice infected with Tc exhibited myocardial loss of mitochondrial membrane potential, complex II (CII)-driven coupled respiration, and ninefold increase in mtROS production. In vitro and in vivo studies showed that Tc infection resulted in an ROS-dependent decline in the expression, nuclear translocation, antioxidant response element (ARE) binding, and activity of NFE2L2, and 35-99% decline in antioxidants' (gamma-glutamyl cysteine synthase [γGCS], heme oxygenase-1 [HO1], glutamate-cysteine ligase modifier subunit [GCLM], thioredoxin (Trx), glutathione S transferase [GST], and NAD(P)H dehydrogenase, quinone 1 [NQO1]) expression. An increase in myocardial and mitochondrial oxidative adducts, myocardial interventricular septum thickness, and left ventricle (LV) mass, a decline in LV posterior wall thickness, and disproportionate synthesis of collagens (COLI/COLIII), αSMA, and SM22α were noted in WT.Tc mice. Overexpression of manganese superoxide dismutase (MnSOD) in cultured cells (HeLa or cardiomyocytes) and MnSODtg mice preserved the NFE2L2 transcriptional activity and antioxidant/oxidant balance, and cardiac oxidative and fibrotic pathology were significantly decreased in MnSODtg.Tc mice. Importantly, echocardiography finding of a decline in LV systolic (stroke volume, cardiac output, ejection fraction) and diastolic (early/late peak filling ratio, myocardial performance index) function in WT.Tc mice was abolished in MnSODtg.Tc mice. Innovation and Conclusion: The mtROS inhibition of NFE2L2/ARE pathway constitutes a key mechanism in signaling the fibrotic gene expression and evolution of chronic cardiomyopathy. Preserving the NFE2L2 activity arrested the mitochondrial and cardiac oxidative stress, cardiac fibrosis, and heart failure in Chagas disease. Antioxid. Redox Signal. 27, 550-566.


Liver Bioreactor Design Issues of Fluid Flow and Zonation, Fibrosis, and Mechanics: A Computational Perspective.
Tissue engineering, with the goal of repairing or replacing damaged tissue and organs, has continued to make dramatic science-based advances since its origins in the late 1980's and early 1990's. Such advances are always multi-disciplinary in nature, from basic biology and chemistry through physics and mathematics to various engineering and computer fields. This review will focus its attention on two topics critical for tissue engineering liver development: (a) fluid flow, zonation, and drug screening, and (b) biomechanics, tissue stiffness, and fibrosis, all within the context of 3D structures. First, a general overview of various bioreactor designs developed to investigate fluid transport and tissue biomechanics is given. This includes a mention of computational fluid dynamic methods used to optimize and validate these designs. Thereafter, the perspective provided by computer simulations of flow, reactive transport, and biomechanics responses at the scale of the liver lobule and liver tissue is outlined, in addition to how bioreactor-measured properties can be utilized in these models. Here, the fundamental issues of tortuosity and upscaling are highlighted, as well as the role of disease and fibrosis in these issues. Some idealized simulations of the effects of fibrosis on lobule drug transport and mechanics responses are provided to further illustrate these concepts. This review concludes with an outline of some practical applications of tissue engineering advances and how efficient computational upscaling techniques, such as dual continuum modeling, might be used to quantify the transition of bioreactor results to the full liver scale.


Low Solids Emulsion Gels Based on Nanocellulose for 3D-Printing.
Multiphase (emulsion) gels with internal phase fractions between 0.1 and 0.5 were formulated at low loadings of cellulose nanofibrils (CNF), alginate, and polylactide (PLA). Their properties (rheology and morphology) fitted those of inks used for direct ink writing (DIW). The effect of formulation and composition variables were elucidated after printing cubic scaffolds and other solid designs. The distinctive microstructures that were developed allowed high printing fidelity and displayed limited shrinkage after room temperature and freeze-drying (0 and 5% shrinkage in the out-of-plane and in-plane directions upon freeze-drying, respectively). The CNF added in the continuous phase was shown to be critical to achieve rheology control as an effective interfacial stabilizer and to ensure the printability of the ink toward high structural reliability. We found that the extent of shape retention of the dried scaffolds resulted from the tightly locked internal structure. The PLA that was initially added in the nonpolar or organic phase (0 to 12%) was randomly embedded in the entire scaffold, providing a strong resistance to shrinkage during the slow water evaporation at ambient temperature. No surface collapse or lateral deformation of the dried scaffolds occurred, indicating that the incorporation of PLA limited drying-induced shape failure. It also reduced compression strain by providing better CNF skeletal support, improving the mechanical strength. Upon rewetting, the combination of the hydrophilicity imparted by CNF and alginate together with the highly porous structure of the 3D material and the internal microchannels contributed to high water absorption via capillary and other phenomena (swelling % between ∼400 and 900%). However, no shape changes occurred compared to the initial 3D-printed shape. The swelling of the scaffolds correlated inversely with the PLA content in the precursor emulsion gel, providing a means to regulate the interaction with water given its low surface energy. Overall, the results demonstrate that by compatibilization of the CNF-based hydrophilic and the PLA-based hydrophobic components, it is possible to achieve shape control and retention upon 3D printing, opening the possibility of adopting low-solids inks for DIW into dry objects. The dryable CNF-based 3D structural materials absorb water while being able to support load (high elastic modulus) and maintain the shape upon hydration.


Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis.
Cannabidiol (CBD), a constituent of cannabis with few psychoactive effects, has been reported in some studies to attenuate certain aspects of Δ(9)-tetrahydrocannabinol (THC) intoxication. However, most studies have tested only one dose of CBD in combination with one dose of oral THC, making it difficult to assess the nature of this interaction. Further, the effect of oral CBD on smoked cannabis administration is unknown. The objective of this multi-site, randomized, double-blind, within-subject laboratory study was to assess the influence of CBD (0, 200, 400, 800 mg, p.o.) pretreatment on the reinforcing, subjective, cognitive, and physiological effects of smoked cannabis (0.01 (inactive), 5.30-5.80% THC). Non-treatment-seeking, healthy cannabis smokers (n=31; 17M, 14 F) completed eight outpatient sessions. CBD was administered 90 min prior to cannabis administration. The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session. A subset of participants (n=8) completed an additional session to measure plasma CBD concentrations after administration of the highest CBD dose (800 mg). Under placebo CBD conditions, active cannabis (1) was self-administered by significantly more participants than placebo cannabis and (2) produced significant, time-dependent increases in ratings of 'High', 'Good Effect', ratings of the cannabis cigarette (eg, strength, liking), and heart rate relative to inactive cannabis. CBD, which alone produced no significant psychoactive or cardiovascular effects, did not significantly alter any of these outcomes. Cannabis self-administration, subjective effects, and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules. These findings suggest that oral CBD does not reduce the reinforcing, physiological, or positive subjective effects of smoked cannabis.


Electroglottographic contact quotient in different phonation types using different amplitude threshold levels.
Contact quotient (CQ), measured by electroglottogram (EGG), is a ratio which illustrates the duration of vocal fold contact during one vocal fold period. In the present study CQ(EGG) was calculated from a sustained vowel phonation in three different phonation types (breathy, normal, pressed) at three amplitude threshold levels (25%, 35%, 50%). CQ(EGG) values were compared with experts' perceptual evaluation of the firmness of phonation. The contact time of the vocal folds differed significantly between the different phonation types at all threshold levels (P < 0.01). Perceptual evaluation correlated best with CQ(EGG) at threshold levels 25% and 35%. The results of the linear regression model suggested that by using threshold level 25% the effect of F0 and SPL on CQ(EGG) were not significant.


The impact of assisted reproductive technologies on the genome and epigenome of the newborn.
The question of genetic alterations resulting from assisted reproductive technologies (ART) in humans is examined within the organization of the human genome. Increased rates of birth defects have been reported among children conceived using ART; however, questions remain and controversy exists regarding how "infertility" predisposes to birth defects. ART has been shown to be associated with an increased number of chromosomal alterations especially in the X chromosome. There is increased risk for embryonal tumors among ART conceived children, as well as, imprinting disorders (Beckwith-Wiedemann and Angelman Syndromes). Genetic studies of children conceived using ART reveal a larger (genome-wide) scale of methylation defects that encompass hundreds of genes. Genes involved in carcinogenesis and developmental pathways appear altered and may impact on later development of chronic illness, although these data are very preliminary. ART may create novel mutations by different chromosomal and molecular mechanisms; however, these techniques also enable propagation of pre-existing mutations that are associated with impaired fertility. While older maternal age is often associated with female infertility and chromosomal aneuploidy, sperm from older men have more new gene mutations. The prevalence of birth defects is increased when ART is used for conception. These data are summarized by large meta-analyses or from multi-year national registries. Whether the increased number of birth defects is due to ART procedures themselves or are a consequence of the impaired fertility of the parents is discussed. Long-term evaluation of children conceived using ART and/or ovarian hyper-stimulation is needed to determine whether alterations during embryonic development may increase the prevalence of chronic diseases in adulthood.


CQL4NLP: Development and Integration of FHIR NLP Extensions in Clinical Quality Language for EHR-driven Phenotyping.
Lack of standardized representation of natural language processing (NLP) components in phenotyping algorithms hinders portability of the phenotyping algorithms and their execution in a high-throughput and reproducible manner. The objective of the study is to develop and evaluate a standard-driven approach - CQL4NLP - that integrates a collection of NLP extensions represented in the HL7 Fast Healthcare Interoperability Resources (FHIR) standard into the clinical quality language (CQL). A minimal NLP data model with 11 NLP-specific data elements was created, including six FHIR NLP extensions. All 11 data elements were identified from their usage in real-world phenotyping algorithms. An NLP ruleset generation mechanism was integrated into the NLP2FHIR pipeline and the NLP rulesets enabled comparable performance for a case study with the identification of obesity comorbidities. The NLP ruleset generation mechanism created a reproducible process for defining the NLP components of a phenotyping algorithm and its execution.


New water-soluble chitin derivative with high antibacterial properties for potential application in active food coatings.
The synthesis of new chitin derivatives through ultrasound-assisted treatment of the chitin with 1-azido-3-chloropropan-2-ol under Green Chemistry conditions is described. This is the first example of ultrasound-assisted polymer analogues transformation of chitin unaccompanied by noticeable backbone degradation or deacetylation. The obtained water-soluble azido chitin derivatives are characterized by high antibacterial activity, which is comparable with that of commercial antibiotics ampicillin and gentamicin. At the same time, they were demonstrated almost identical in vitro toxicity as unmodified chitin and chitosan. The antibacterial activity of the obtained polymers is mainly provided by azido moiety in their macromolecules. The conjugation of azido moiety to chitin backbone strongly diminishes the toxicity of the azido pharmacophore, but preserves its antibacterial properties. The most potent chitin derivative was used for the film coating of Ricotta cheese samples. This food coating proved to be efficient for the prolongation of shelf life of Ricotta cheese.


Exploring the proteome of an echinoderm nervous system: 2-DE of the sea star radial nerve cord and the synaptosomal membranes subproteome.
We describe the first proteomic characterization of the radial nerve cord (RNC) of an echinoderm, the sea star Marthasterias glacialis. The combination of 2-DE with MS (MALDI-TOF/TOF) resulted in the identification of 286 proteins in the RNC. Additionally, 158 proteins were identified in the synaptosomal membranes enriched fraction after 1-DE separation. The 2-DE RNC reference map is available via the WORLD-2DPAGE Portal (http://www.expasy.ch/world-2dpage/) along with the associated protein identification data which are also available in the PRIDE database. The identified proteins constitute the first high-throughput evidence that seems to indicate that echinoderms nervous transmission relies primarily on chemical synapses which is similar to the synaptic activity in adult mammal's spinal cord. Furthermore, several homologous proteins known to participate in the regeneration events of other organisms were also identified, and thus can be used as targets for future studies aiming to understand the poorly uncharacterized regeneration capability of echinoderms. This "echinoderm missing link" is also a contribution to unravel the mystery of deuterostomian CNS evolution.


Plant peptide deformylase: a novel selectable marker and herbicide target based on essential cotranslational chloroplast protein processing.
Transgenic tobacco plants expressing three different forms of Arabidopsis plant peptide deformylase (AtDEF1.1, AtDEF1.2 and AtDEF2; EC 184.108.40.206) were evaluated for resistance to actinonin, a naturally occurring peptide deformylase inhibitor. Over-expression of either AtDEF1.2 or AtDEF2 resulted in resistance to actinonin, but over-expression of AtDEF1.1 did not. Immunological analyses demonstrated that AtDEF1.2 and AtDEF2 enzymes were present in both stromal and thylakoid fractions in chloroplasts, but AtDEF1.1 was localized to mitochondria. The highest enzyme activity was associated with stromal AtDEF2, which was approximately 180-fold greater than the level of endogenous activity in the host plant. Resistance to actinonin cosegregated with kanamycin resistance in Atdef1.2-D and Atdef2-D transgenic plants. Here, we demonstrate that the combination of plant peptide deformylase and peptide deformylase inhibitors may represent a native gene selectable marker system for chloroplast and nuclear transformation vectors, and also suggest plant peptide deformylase as a potential broad-spectrum herbicide target.


Attribution of nosocomial seeding to long-term care facility COVID-19 outbreaks.
Residents of long-term care facilities (LTCFs) were disproportionately affected by the COVID-19 pandemic. We assessed the extent to which hospital-associated infections contributed to COVID-19 LTCF outbreaks in England. We matched addresses of cases between March 2020 and June 2021 to reference databases to identify LTCF residents. Linkage to health service records identified hospital-associated infections, with the number of days spent in hospital before positive specimen date used to classify these as definite or probable. Of 149,129 cases in LTCF residents during the study period, 3,748 (2.5%) were definite or probable hospital-associated and discharged to an LTCF. Overall, 431 (0.3%) were identified as index cases of potentially nosocomial-seeded outbreaks (2.7% (431/15,797) of all identified LTCF outbreaks). These outbreaks involved 4,521 resident cases and 1,335 deaths, representing 3.0% and 3.6% of all cases and deaths in LTCF residents, respectively. The proportion of outbreaks that were potentially nosocomial-seeded peaked in late June 2020, early December 2020, mid-January 2021, and mid-April 2021. Nosocomial seeding contributed to COVID-19 LTCF outbreaks but is unlikely to have accounted for a substantial proportion. The continued identification of such outbreaks after the implementation of preventative policies highlights the challenges of preventing their occurrence.


Abnormal retention of 99mTc-TF in a hamster model of cardiomyopathy analyzed by 99mTc-TF and 125I-BMIPP autoradiography.
Enhanced washout of 99mTc-tetrofosmin (TF) has been reported in patients with hypertrophic cardiomyopathy (HCM). Here, using quantitative dual-autoradiography, the relationship between TF retention abnormality and metabolism depicted by 125I-BMIPP uptake was investigated quantitatively in a hamster model of cardiomyopathy. Early and delayed TF images were obtained at 5 min (7 cardiomyopathic and 5 normal hamsters) and 60 min (8 cardiomyopathic and 5 normal hamsters) after injection, respectively. BMIPP image was obtained 5 min after injection. Five cardiomyopathic and 5 normal hamsters were evaluated histologically. Percent uptake of TF and BMIPP in the heart was measured by an auto-well counter. The left ventricular wall was divided into 12 segments, and the relative regional uptake of TF and BMIPP was measured for each segment. Heterogeneity of radioactive distribution was determined by the standard deviation (SD) of radioactive counts in the left ventricular wall on autoradiogram. The uptake of early TF, delayed TF, and BMIPP in cardiomyopathic hamsters was 8.8%, 20.3%, and 25.3% lower than that in normal hamsters, p < 0.05, p < 0.01, and p < 0.001, respectively. In normal hamsters, distribution of radioactivity in all images was homogeneous, and the SD values were about 13. In cardiomyopathic hamsters, heterogeneous distribution was observed on all images, and the degree of heterogeneity was marked on delayed TF and BMIPP images. The SD was 19.7 +/- 1.2 for early TF image, 25.5 +/- 1.4 for delayed TF image, and 31.7 +/- 2.4 for BMIPP image, respectively. A weak linear correlation was observed between the relative regional uptake of the delayed TF and BMIPP in cardiomyopathic hamsters (r = 0.57). Electron microscopy demonstrated ultra-structural changes in mitochondria of cardiomyopathic hamsters. Degree of retention abnormality on delayed TF image corresponded to the metabolic abnormality, probably due to mitochondrial dysfunction, depicted on BMIPP imaging.


Metabolic risk with second-generation antipsychotic treatment: a double-blind randomized 8-week trial of risperidone and olanzapine.
The second-generation antipsychotics are effective for treating psychotic disorders and incur fewer motor side effects than are commonly experienced with the use of first-generation antipsychotics. However, their use is commonly associated with weight gain and metabolic disturbances. This study examined weight and metabolic changes with two widely used antipsychotics, risperidone and olanzapine; addressing the issue of early monitoring for metabolic side effects. This 8-week double blind randomized trial included patients with schizophrenia or schizoaffective disorder (N = 377) randomly assigned to risperidone (2-6 mg/day) or olanzapine (5-20 mg/day). Weight, BMI, HbA1C, total cholesterol (TC), LDL-C, HDL-C and triglycerides (TG) were monitored. Mean BMI increases were higher in the olanzapine group as compared to risperidone (1.3 kg/m(2)(SD = 0.13) vs. 0.7 kg/m(2) (SD = 0.13)(p < 0.001). Increases in mean TC (13.5 mg/dl (SD 2.4), LDL-C (11.0 mg/dl (SD 2.2)) and TG (14.8 mg/dl (SD = 7.6)) occurred in the olanzapine group while significant changes in TC (-3.9 mg/dl (SD = 2.5)) and TG (-32.8 mg/dl (SD = 7.8)) were noted in the risperidone group. Men (not women) on olanzapine had higher than expected increases in lipids given the amount of weight gain. Baseline values and prior therapy did not contribute to the significant differences, however BMI increases (p = 0.0002) were linked to study discontinuation in both drug groups. The fact that significant metabolic changes occurred (both positive and negative) in eight weeks is important to clinical care. Monitoring for metabolic changes may be important within the first eight weeks of treatment, as changes can be determined very early in antipsychotic treatment.


The effect of depression on heart rate variability during pregnancy. A naturalistic study.
Depression during pregnancy has been associated with a number of adverse outcomes, but the underlying physiological mechanisms involved remain unclear. The purpose of this study was to examine the effects of maternal depression during pregnancy on the autonomic modulation of heart rate, in a naturalistic setting. Eighty-one pregnant women were studied between 25 and 31 weeks of gestation and were identified as either Depressed (n = 46), or healthy, Control (n = 35), based on depression scores and lifetime psychiatric history. Subjects wore a 24-h Holter recorder to measure time-domain and frequency-domain of heart rate variability (HRV). Pregnant women in the Depressed Group had significantly reduced time-domain measures: standard deviation of all 24-h NN intervals (SDNN) and the standard deviation of the averages of NN intervals in all 5-min segments of the entire recording (SDANN) (P = 0.013, 0.016, respectively), as well as higher heart rates while asleep (P = 0.028), compared to Controls, after controlling for age, smoking, and antidepressant (AD) medication. The low frequency/high frequency (LF/HF) ratio during the sleeping hours was associated with higher depression scores (R = 0.24; P = 0.041). HRV measures improved in women taking AD medication. The autonomic nervous system may be affected in women experiencing depression during pregnancy, indicating a possible decreased parasympathetic (vagal) influence. Women taking AD medication showed some improvement in HRV measures. These data suggest that psychophysiological changes occur in women experiencing depression during pregnancy.


Dental utilization by low-income mothers.
This study examines the influence of predisposing, enabling, and need variables on whether low-income mothers sought dental care during the past year. This report is a substudy of mothers and children on their self-reported health status, utilization, access, and satisfaction with health care in general. A convenience sample of 502 mothers and youngest child younger than 6 years old was administered a face-to-face questionnaire in four Ohio counties. Information was collected at county human services offices and WIC clinics between November 1995 and July 1996. Using whether or not the mother sought dental care as the dependent variable, logistic regression models were created for the variables within the predisposing, enabling, and need characteristics separately and together. Fewer than one-half of the mothers sought dental care during the past year. Variables associated with the predisposing characteristic explained little about who sought care. Those mothers who have Medicaid coverage are 2.7 times more likely to have a dental visit than those without insurance. Moreover, those mothers who perceive any dental need are several times less likely to have received dental care than those who have no perceived need. Even among a somewhat homogeneous population of low-income women, source of payment for dental services and perceived need for dental care are discriminating variables in determining who seeks dental care.


Discrepancies in death certificates, public health registries, and judicial determinations in Italy.
The death certificate is mandated by civil law and serves as a medical-scientific document useful for biostatistics and epidemiological research. For a variety of reasons, death certificates can be misclassified. We reviewed data from self-inflicted deaths collected over an 8-year period by the Forensic Institute of the University Sacro Cuore of Rome (Italy). Four hundred and thirty-five of 2904 were classified as self-inflicted deaths (15%). The comparison with death certificates processed by the local public health authority (ASL) and by the Italian National Census Bureau (Istat) and with the judicial investigation results available in the Italian Penal Court archive shows some discrepancies. One-hundred and twenty-four of 435 deaths were not considered to be self-inflicted but due to a crime (29% overrecording suicide) with a higher reduction for women, suggesting that it is easier to confuse a murder for suicide in female cases. Any discrepancies between the mortality and crime data are discussed in details.


Evaluating limiting steps of anaerobic degradation of food waste based on methane production tests.
This research adapted a batch test for biochemical methane production (BMP) to follow the degradation of complex compounds such as proteins and vegetable oils. The test measured the transformation of albumin and olive oil into methane under mesophilic and thermophilic conditions and assess limiting step in the overall degradation process. The thermophilic sludge used for the BMP tests was adapted during ten month from mesophilic sludge while being fed food waste. As compared to acetic acid, the specific rate of transformation of albumin and olive oil into methane reached 22 and 51%, respectively, under mesophilic conditions. Acetoclastic methanogenesis was not the limiting step in the presence of albumin or olive oil (and its monomer-like molecules such as amino acids, glycerol and oleic acid). Rather, the degradation of albumin was restricted by the presence of proteins. The thermophilically adapted sludge showed good proteolytic activity, but its acetoclastic methanogens were unable to degrade olive oil, because of the inhibitory effect of oleic acid.


Selective Detection of Penicillin G Antibiotic in Milk by Molecularly Imprinted Polymer-Based Plasmonic SPR Sensor.
Molecularly imprinted polymer-based surface plasmon resonance sensor prepared using silver nanoparticles was designed for the selective recognition of Penicillin G (PEN-G) antibiotic from both aqueous solution and milk sample. PEN-G imprinted sensors (NpMIPs) SPR sensor was fabricated using poly (2-hydroxyethyl methacrylate-N-methacroyl-(L)-cysteine methyl ester)-silver nanoparticles-N-methacryloyl-L-phenylalanine methyl ester polymer by embedding silver nanoparticles (AgNPs) into the polymeric film structure. In addition, a non-imprinted (NpNIPs) SPR sensor was prepared by utilizing the same polymerization recipe without addition of the PEN-G template molecule to evaluate the imprinting effect. FTIR-ATR spectrophotometer, ellipsometer, contact angle measurements were used for the characterization of NpMIPs SPR sensors. The linear concentration range of 0.01-10 ng/mL PEN-G was studied for kinetic analyses. The augmenting effect of AgNPs used to increase the surface plasmon resonance signal response was examined using polymer-based PEN-G imprinted (MIPs) sensor without the addition of AgNPs. The antibiotic amount present in milk chosen as a real sample was measured by spiking PEN-G into the milk. According to the Scatchard, Langmuir, Freundlich and Langmuir-Freundlich adsorption models, the interaction mechanism was estimated to be compatible with the Langmuir model.


Liposomes loaded with bioactive lipids enhance antibacterial innate immunity irrespective of drug resistance.
Phagocytosis is a key mechanism of innate immunity, and promotion of phagosome maturation may represent a therapeutic target to enhance antibacterial host response. Phagosome maturation is favored by the timely and coordinated intervention of lipids and may be altered in infections. Here we used apoptotic body-like liposomes (ABL) to selectively deliver bioactive lipids to innate cells, and then tested their function in models of pathogen-inhibited and host-impaired phagosome maturation. Stimulation of macrophages with ABLs carrying phosphatidic acid (PA), phosphatidylinositol 3-phosphate (PI3P) or PI5P increased intracellular killing of BCG, by inducing phagosome acidification and ROS generation. Moreover, ABLs carrying PA or PI5P enhanced ROS-mediated intracellular killing of Pseudomonas aeruginosa, in macrophages expressing a pharmacologically-inhibited or a naturally-mutated cystic fibrosis transmembrane conductance regulator. Finally, we show that bronchoalveolar lavage cells from patients with drug-resistant pulmonary infections increased significantly their capacity to kill in vivo acquired bacterial pathogens when ex vivo stimulated with PA- or PI5P-loaded ABLs. Altogether, these results provide the proof of concept of the efficacy of bioactive lipids delivered by ABL to enhance phagosome maturation dependent antimicrobial response, as an additional host-directed strategy aimed at the control of chronic, recurrent or drug-resistant infections.


A micropatterned conductive electrospun nanofiber mesh combined with electrical stimulation for synergistically enhancing differentiation of rat neural stem cells.
An effective treatment for spinal cord injury (SCI) remains a severe clinical challenge due to the intrinsically limited regenerative capacity and complex anatomical structure of the spinal cord. The combination of biomaterials, which serve as scaffolds for axonal growth, cells and neurotrophic factors, is an excellent candidate for spinal cord regeneration. Herein, a new micropatterned conductive electrospun nanofiber mesh was constructed with poly{[aniline tetramer methacrylamide]-co-[dopamine methacrylamide]-co-[poly(ethylene glycol) methyl ether methacrylate]}/PCL (PCAT) using a rotation electrospinning technology. The aim was to study the synergistic effects of electrical stimulation (ES) and a micropatterned conductive electrospun nanofiber mesh incorporated with nerve growth factor (NGF) on the differentiation of rat nerve stem cells (NSCs). The hydrophilicity of the conductive nanofiber mesh could be tailored by changing the dopamine (DA) and aniline tetramer (AT) content from 19° to 79°. A favorable electroactivity and conductivity was achieved by the AT segment of PCAT. The as-fabricated micropatterned electrospun nanofiber mesh possessed a regularly aligned valley and ridge structure, and the diameter of the nanofiber was 312 ± 58 nm, while the width of the valley and ridge was measured to be 210 ± 17 μm and 200 ± 16 μm, respectively. The growth and neurite outgrowth of differentiated NSCs were observed along the valley of the micropatterned nanofiber mesh. In addition, the NGF loaded micropatterned conductive electrospun nanofiber mesh combined with ES exhibited the highest cell viability, and effectively facilitated the differentiation of NSCs into neurons and suppressed the formation of astrocytes, thus exhibiting a great application potential for nerve tissue engineering.


Child-Reported Family Violence: A Systematic Review of Available Instruments.
The impact of family violence (FV) on children is a significant global public policy issue. Earliest identification of FV among children is critical for preventing escalating sequelae. While practitioners routinely ask adults about FV, there are relatively few measures that enable children to reliably self-report on their own safety. This review sought to systematically identify and appraise all available child self-report measures for screening and assessment of FV in both clinical and research settings. Database searching was conducted in January 2022. Articles were eligible for review if they included a validated child (5-18 years) self-report measure of FV (including victimization, perpetration, and/or exposure to inter-parental violence). Screening of an initial 4,714 records identified a total of 85 articles, representing 32 unique validated instruments. Results provide an up-to-date catalog of child self-report measures of FV, intended to benefit practitioners, services and researchers in selecting appropriate tools, and in understanding their suitability and limitations for different cohorts and practice goals. While just under half of the measures captured both exposure to inter-parental violence and direct victimization, none captured all three domains of exposure, victimization and perpetration together. Instruments with provision for input from multiple respondents (e.g., both child and parent report) and with assessment of contextual risk factors were few. Findings point to the need for developmentally appropriate, whole-of-family screening and assessment frameworks to support children in the early identification of family safety concerns.


Detection of Early Ischemic Changes with Virtual Noncontrast Dual-Energy CT in Acute Ischemic Stroke: A Noninferiority Analysis.
Dual-energy virtual NCCT has the potential to replace conventional NCCT to detect early ischemic changes in acute ischemic stroke. In this study, we evaluated whether virtual NCCT is noninferior compared with standard linearly blended NCCT, a surrogate of conventional NCCT, regarding the detection of early ischemic changes with ASPECTS. Adult patients who presented with suspected acute ischemic stroke and who underwent dual-energy NCCT and CTA and brain MR imaging within 48 hours were included. Standard linearly blended images were reconstructed to match a conventional NCCT. Virtual NCCT images were reconstructed from CTA. ASPECTS was evaluated on conventional NCCT, virtual NCCT, and DWI, which served as the reference standard. Agreement between CT assessments and the reference standard was evaluated with the Lin concordance correlation coefficient. Noninferiority was assessed with bootstrapped estimates of the differences in ASPECTS between conventional and virtual NCCT with 95% CIs. Of the 193 included patients, 100 patients (52%) had ischemia on DWI. Compared with the reference standard, the ASPECTS concordance correlation coefficient for conventional and virtual NCCT was 0.23 (95% CI, 0.15-0.32) and 0.44 (95% CI, 0.33-0.53), respectively. The difference in the concordance correlation coefficient between virtual and conventional NCCT was 0.20 (95% CI, 0.01-0.39) and did not cross the prespecified noninferiority margin of -0.10. Dual-energy virtual NCCT is noninferior compared with conventional NCCT for the detection of early ischemic changes with ASPECTS.


Song practice as a rewarding form of play in songbirds.
In adult songbirds, the primary functions of song are mate attraction and territory defense; yet, many songbirds sing at high rates as juveniles and outside these primary contexts as adults. Singing outside primary contexts is critical for song learning and maintenance, and ultimately necessary for breeding success. However, this type of singing (i.e., song "practice") occurs even in the absence of immediate or obvious extrinsic reinforcement; that is, it does not attract mates or repel competitors. Here we review studies that support the hypothesis that song practice is stimulated and maintained by intrinsic reward mechanisms (i.e., that it is associated with a positive affective state). Additionally, we propose that song practice can be considered a rewarding form of play behavior similar to forms of play observed in multiple young animals as they practice sequences of motor events that are used later in primary adult reproductive contexts. This review highlights research suggesting at least partially overlapping roles for neural reward systems in birdsong and mammalian play and evidence that steroid hormones modify these systems to shift animals from periods of intrinsically rewarded motor exploration (i.e., singing in birds and play in mammals) to the use of similar motor patterns in primary reproductive contexts.


Responses of Mytilus galloprovincialis hemocytes to environmental strains of Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio vulnificus.
Marine bivalves are exposed to different types of bacteria in the surrounding waters, in particular of the Vibrio genus. In the hemocytes of the mussel Mytilus spp. immune responses to different vibrios have been largely characterized. However, little information is available on the hemocyte responses to human pathogenic vibrios commonly detected in coastal waters and bivalve tissues that are involved in seafood-borne diseases. In this work, functional parameters of the hemocytes from the Mediterranean mussel M. galloprovincialis were evaluated in response to in vitro challenge with different vibrios isolated from environmental samples of the Adriatic sea (Italy): V. parahaemolyticus Conero, V. alginolyticus 1513 and V. vulnificus 509. V. parahaemolyticus ATCC 43996 was used for comparison. At the 50:1 bacteria hemocyte ratio, only V. parahaemolyticus strains induced significant lysosomal membrane destabilisation. Stimulation of extracellular lysozyme release, total ROS, O2- and NO production were observed, although to different extents and with distinct time courses for different vibrios, V. vulnificus 509 in particular. Further comparisons between V. parahaemolyticus Conero and V. vulnificus 509 showed that only the latter induced dysregulation of the phosphorylation state of p38 MAP Kinase and apoptotic processes. The results indicate that mussel hemocytes can mount an efficient immune response towards V. parahaemolyticus and V. alginolyticus strains, whereas V. vulnificus 509 may affect the hemocyte function. This is the first report on immune responses of mussels to local environmental isolates of human pathogenic vibrios. These data reinforce the hypothesis that Mytilus hemocytes show specific responses to different vibrio species and strains.


The Cambridge Experience with Lower Limb Long Bone Non-union Following Fixation and the Treatment Algorithm.
Non-unions have been traditionally classified as atrophic, oligotrophic and hypertrophic and their management was primarily dictated by that. In our Unit, we have based our treatment rationale mainly on the stability of the metalwork and the presence of symptoms rather than the radiologic appearance of the non-union or the presence of infection. The aim was to present the treatment algorithm for lower limb long bone non-union following operative fixation. All patients treated for a femoral or tibial non-union following fixation between 2014 and 2020 in our unit and with a minimum follow-up of 2 years were included. Non-union was defined as having no evidence of fracture healing in any cortices six months after the index procedure. Union was defined as bridging callus in at least three cortices visualized on at least two orthogonal radiographs. Information retrieved included demographic and fracture characteristics, presence of infection, evidence of metalwork stability and treatment. Outcome measures included union rate, time to union and complications. Data were analysed with the Statistical Program for Social Sciences (SPSS) using contingency tables and linear regression. A p-value of less than 0.05 was considered statistically significant. Seventy-seven consecutive patients were included in the study. Union was achieved in 91% of the cases, while union was noted in all the patients treated non-operatively. The mean time to union was 14.49 months (9.98). Complications were encountered in 20 of the patients and the most common were docking site non-union and metalwork breakage. Infection was the only factor that affected time to union in a statistically significant manner (p = 0.006). The results of our study suggest that in cases of long bone non-union following operative fixation using signs of metalwork instability and the presence of clinical symptoms as the main indication for surgical intervention provides a satisfactory outcome. This approach prevented operative management in a large proportion of patients. This article presents an algorithmic approach that could aid clinicians in their decision-making in long-bone non-union management. Therapeutic level III. Poutoglidou F, Krkovic M. The Cambridge Experience with Lower Limb Long Bone Non-union Following Fixation and the Treatment Algorithm. Strategies Trauma Limb Reconstr 2023;18(2):100-105.


Chronic obstructive pulmonary disease and comorbidities.
Results of epidemiological studies have shown that chronic obstructive pulmonary disease (COPD) is frequently associated with comorbidities, the most serious and prevalent being cardiovascular disease, lung cancer, osteoporosis, muscle weakness, and cachexia. Mechanistically, environmental risk factors such as smoking, unhealthy diet, exacerbations, and physical inactivity or inherent factors such as genetic background and ageing contribute to this association. No convincing evidence has been provided to suggest that treatment of COPD would reduce comorbidities, although some indirect indications are available. Clear evidence that treatment of comorbidities improves COPD is also lacking, although observational studies would suggest such an effect for statins, β blockers, and angiotensin-converting enzyme blockers and receptor antagonists. Large-scale prospective studies are needed. Reduction of common risk factors seems to be the most powerful approach to reduce comorbidities. Whether reduction of so-called spill-over of local inflammation from the lungs or systemic inflammation with inhaled or systemic anti-inflammatory drugs, respectively, would also reduce COPD-related comorbidities is doubtful.


State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases.
Using the Southern blot technique and cloned hepatitis B virus (HBV) DNA as a probe, we studied the state of HBV DNA in the liver of 13 patients with hepatocellular carcinoma, 17 patients with chronic hepatitis, and 2 patients with acute hepatitis. The hybridization results were compared with the serological and immunohistological data. Integration of HBV DNA in cellular DNA of the liver from patients with hepatocellular carcinoma was demonstrated. In two patients from which tumorous and nontumorous liver tissue samples were available the integration patterns were different. In one patient with hepatitis B e antigen (HBeAg)-positive early hepatocellular carcinoma, free viral DNA was present in the liver. In some patients with HBeAg-negative chronic hepatitis, without tumor, integration of HBV DNA in cellular DNA was also demonstrated. This suggests that HBV is not the only factor involved in the development of a tumor. In patients with HBeAg-positive chronic hepatitis, free viral DNA was detected in the liver. In the two acute hepatitis patients analyzed, the restriction endonuclease patterns strongly suggested HBV DNA integration. Therefore, viral DNA integration seems to occur early in infection. Whatever the form of the disease, discrete bands were observed, suggesting the existence of limited and specific integration sites in host cellular DNA. The presence of integrated or free DNA sequences has implications for antiviral therapy. In addition, detection of HBV DNA in the liver is another sensitive viral marker that could be useful for diagnostic purposes.


Intraoperative periprosthetic fractures associated with metacarpophalangeal joint arthroplasty.
To assess the incidence of and identify risk factors for intraoperative periprosthetic fractures during primary and revision metacarpophalangeal (MCP) joint arthroplasty. Through our institutional Joint Registry Database, we identified 818 MCP joint arthroplasties performed in 285 patients from 1998 to 2012, including 690 primary arthroplasties and 128 revision arthroplasties. Primary diagnoses included inflammatory arthritis (667), osteoarthritis (75), and posttraumatic arthritis (76). Periprosthetic fractures were identified through review of medical records. Intraoperative periprosthetic fractures occurred in 23 (3%) fingers (21 patients), including 19 primary and 4 revision arthroplasties. Twelve fractures required stabilization, 4 required only bone grafting, and 1 required both. The fractures occurred during broaching (12), implantation (10), or prior implant removal (1). Diabetes mellitus (DM), younger age, pyrocarbon implant insertion, and cementless fixation increased risk for intraoperative fracture. In particular, DM and the use of pyrocarbon implants significantly increased fracture risk. At 4 years (range, 1.3-10.2 y) average follow-up, no patient with intraoperative fracture had developed a subsequent fracture compared with 3 postoperative fractures in patients without intraoperative fractures. All fractures had healed by the time of the last follow-up. The 2- and 5-year implant survival rates were 96% and 80% in those with intraoperative fractures, respectively, which was not significantly different from those without an intraoperative fracture. When comparing patients with an intraoperative fracture with those without, there was an increased risk of postoperative MCP joint instability defined as implant dislocation. Patients with intraoperative fractures still had noteworthy improvements in their postoperative pain levels and pinch strengths. Intraoperative fractures occurred in 3% of MCP joint arthroplasties, including 3% of primary and 3% of revision arthroplasties. Increased risk for fracture was associated with the use of pyrocarbon implants, cementless fixation, and DM. Although these fractures did not appear to adversely affect implant survival, they were associated with increased risk of postoperative instability. Prognostic III.


[Biliary tract tumors].
Biliary tract cancers are rare neoplasms including gallbladder cancer (the commonest), extrahepatic biliary tract cancer and cancer of the ampulla of Vater. Descriptive epidemiology of biliary tract cancers as a whole has two peculiarities: incidence and mortality rates are higher for women than men, and in some specific populations. Mortality rates are highest among New Mexico American Indian women, in Chile and Japan, lowest in Great Britain and Greece. Mortality trends vary widely: the largest increases have been observed in Japan, Hong-Kong and Spain and the largest decreases in the Anglo-Saxon populations. Our knowledge of biliary tract cancer etiology is limited. Defined risks include genetic factors (family history of biliary tract cancers, ethnicity), history of gallbladder disease, and cholelithiasis. Risk factors reported in some studies, on which, however, information is not consistent and which need further study, include overweight, some menstrual and reproductive factors (multiparity, young age at first birth, late menopause), low education, cigarette smoking, selected bacterial infections, some intestinal diseases and diabetes.


[Pathology of the reproductive apparatus of cells under the action of remantadine and deitiforin].
The antiviral effect of chemical agents remantadine and deutephorine on the reproductive apparatus of MDCK-cells was studied. It was established that the action of the chemical agents during 3-4 days induced enhancement in pathologically transformed mitoses. This enhancement was in direct proportion to the doses used and to the cultivation time. Dose dependent enhancement of the total pathological mitoses number was simultaneous with the redistribution of mitoses into groups: the relative number of pathologies connected with chromosome damage became lower and the number of degenerating mitoses grew. Computer regression analysis showed the linear dependence between the chemical agent dose and the number of mitoses in the metaphase, that gives an indirect evidence of statmokinetic action of the agents under study.


Personality traits and the classification of mental disorders: toward a more complete integration in DSM-5 and an empirical model of psychopathology.
Personality trait dimensions are related to a wide variety of important life outcomes, such as mortality, physical and mental health, and interpersonal relationships. Nevertheless, the diagnostic system with arguably the most influence in mental health settings (Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-IV]) formally includes personality primarily in the form of 10 putatively categorical personality disorders. We advocate a more complete and extensive integration of personality in future DSMs, via the explicit inclusion of an empirically based, dimensional personality trait model. To justify this position, we provide a broad review of the ways in which personality traits have proven useful in the description and conceptualization of personality disorders and other mental disorders, as well as in the prediction of key clinical phenomena. We also discuss the importance of constructing a comprehensive quantitative model of psychopathology based on data, an endeavor that is motivated and informed by the close conceptual and empirical parallels between personality and psychopathology.