Liver transplantation for cryptogenic cirrhosis.
End-stage liver disease secondary to cryptogenic cirrhosis is the indication for orthotopic liver transplantation (OLT) in 7% to 14% of recipients. However, there are no reports documenting the outcome of OLT for this indication. The aim of this study was to determine (1) survival and (2) the incidence of histological recurrence of cryptogenic cirrhosis after OLT. Between March 1985 and December 1994, 560 OLTs were performed at our institution. Of these, 39 transplants for cryptogenic cirrhosis were in patients who met the following criteria: antinuclear antibody < 1:40; negative anti-smooth muscle antibody, antimitochondrial antibody, polymerase chain reaction for hepatitis C virus, and hepatitis B surface antigen results; normal ceruloplasmin and alpha-1 antitrypsin phenotype; transferrin saturation < 65%; and liver biopsy specimen not suggestive of hemochromatosis or other known disorders. Histological recurrence was assessed with protocol liver biopsies in all patients who survived longer than 6 months. The mean age of cryptogenic recipients at the time of transplantation was significantly lower (40.6 years; range, 3 to 63 years) than that of noncryptogenic recipients (48.5 years; range, 1-70; P < .03). Median modified Child's-Pugh score was slightly higher for cryptogenic recipients at the time of transplantation (10.0 + 0.08 standard error of mean [SEM]), than for the noncryptogenic recipients (9.0 + 0.03 SEM; P < .02). Actuarial survival was 72% (+ 0.07 SEM) at 1 and 58% (+ 0.08 SEM) at 5 years for cryptogenic recipients compared with 89% at 1 and 80% at 5 years for noncryptogenic recipients. The difference in survival was significant (P < .001) at both 1 and 5 years. Among the 27 cryptogenic recipients surviving more than 6 months (mean follow-up, 5.5 years), 6 have persistent hepatitis histologically without apparent infectious, vascular, biliary, or drug origins. Four patients (15%) had chronic active hepatitis, and 2 (7%) had steatohepatitis. No cases of recurrent cryptogenic cirrhosis were seen. OLT for cryptogenic cirrhosis is associated with a poor outcome compared with other indications, hepatitis of uncertain origin occurred in 22% of cryptogenic recipients surviving longer than 6 months, and no evidence of recurrence of cryptogenic cirrhosis was seen thus far in follow-up.


Public health impact of antiviral therapy for hepatitis C in the United States.
Despite dramatic improvements in antiviral therapy for hepatitis C, there is reason to believe that the uptake of antiviral therapy remains limited. The aims of this study were to determine the number of patients being treated with antiviral therapy in the U.S., to estimate the public health impact of these treatment patterns, and to identify barriers to treatment for patients with hepatitis C. Data on the number of new patient pegylated interferon prescriptions each year, from 2002-2007, was obtained from Wolters Kluwer Inc., which maintains an electronic audit of pharmacies nationwide. A Markov model was created of the population with chronic hepatitis C in the U.S. from 2002 to 2030, and was used to estimate the number of liver-related deaths caused by hepatitis C that will be prevented by current treatment patterns. The National Health and Nutrition Evaluation Survey (NHANES) Hepatitis C Follow-Up Questionnaire was used to investigate reasons for lack of treatment and to identify strategies for improving access. Approximately 663,000 patients received antiviral therapy between 2002 and 2007, and treatment rates appear to be declining. If this trend continues, only 14.5% of liver-related deaths caused by hepatitis C from 2002-2030 will be prevented by antiviral therapy. Results from the NHANES questionnaire suggest that the primary barrier to treatment is lack of diagnosis, with 69/133 (adjusted proportion 49%) of respondents previously unaware that they had hepatitis C. Efforts to improve rates of diagnosis and treatment will be required if the future public health burden of hepatitis C is to be ameliorated.


The Human Centrosomal Protein CCDC146 Binds Chlamydia trachomatis Inclusion Membrane Protein CT288 and Is Recruited to the Periphery of the Chlamydia-Containing Vacuole.
Chlamydia trachomatis is an obligate intracellular human pathogen causing mainly ocular and genital infections of significant clinical and public health impact. C. trachomatis multiplies intracellularly in a membrane bound vacuole, known as inclusion. Both extracellularly and from within the inclusion, C. trachomatis uses a type III secretion system to deliver several effector proteins into the cytoplasm of host cells. A large proportion of these effectors, the inclusion membrane (Inc) proteins, are exposed to the host cell cytosol but possess a characteristic hydrophobic domain mediating their insertion in the inclusion membrane. By yeast two-hybrid, we found that C. trachomatis Inc CT288 interacts with the human centrosomal protein CCDC146 (coiled-coil domain-containing protein 146). The interaction was also detected by co-immunoprecipitation in mammalian cells either ectopically expressing CCDC146 and CT288 or ectopically expressing CCDC146 and infected by a C. trachomatis strain expressing epitope-tagged and inclusion membrane-localized CT288. In uninfected mammalian cells, ectopically expressed full-length CCDC146 (955 amino acid residues) localized at the centrosome; but in cells infected by wild-type C. trachomatis, its centrosomal localization was less evident and CCDC146 accumulated around the inclusion. Recruitment of CCDC146 to the inclusion periphery did not require intact host Golgi, microtubules or microfilaments, but was dependent on chlamydial protein synthesis. Full-length CCDC146 also accumulated at the periphery of the inclusion in cells infected by a C. trachomatis ct288 mutant; however, a C-terminal fragment of CCDC146 (residues 692-955), which interacts with CT288, showed differences in localization at the periphery of the inclusion in cells infected by wild-type or ct288 mutant C. trachomatis. This suggests a model in which chlamydial proteins other than CT288 recruit CCDC146 to the periphery of the inclusion, where the CT288-CCDC146 interaction might contribute to modulate the function of this host protein.


High-repetition-rate combustion thermometry with two-line atomic fluorescence excited by diode lasers.
We report on kilohertz-repetition-rate flame temperature measurements performed using blue diode lasers. Two-line atomic fluorescence was performed by using diode lasers emitting at around 410 and 451 nm to probe seeded atomic indium. At a repetition rate of 3.5 kHz our technique offers a precision of 1.5% at 2000 K in laminar methane/air flames. The spatial resolution is better than 150 microm, while the setup is compact and easy to operate, at much lower cost than alternative techniques. By modeling the spectral overlap between the locked laser and the probed indium lines we avoid the need for any calibration of the measurements. We demonstrate the capability of the technique for time-resolved measurements in an acoustically perturbed flame. The technique is applicable in flames with a wide range of compositions including sooting flames.


Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock.
Maintenance of circadian alignment between an organism and its environment is essential to ensure metabolic homeostasis. Synchrony is achieved by cell autonomous circadian clocks. Despite a growing appreciation of the integral relation between clocks and metabolism, little is known regarding the direct influence of a peripheral clock on cellular responses to fatty acids. To address this important issue, we utilized a genetic model of disrupted clock function specifically in cardiomyocytes in vivo (termed cardiomyocyte clock mutant (CCM)). CCM mice exhibited altered myocardial response to chronic high fat feeding at the levels of the transcriptome and lipidome as well as metabolic fluxes, providing evidence that the cardiomyocyte clock regulates myocardial triglyceride metabolism. Time-of-day-dependent oscillations in myocardial triglyceride levels, net triglyceride synthesis, and lipolysis were markedly attenuated in CCM hearts. Analysis of key proteins influencing triglyceride turnover suggest that the cardiomyocyte clock inactivates hormone-sensitive lipase during the active/awake phase both at transcriptional and post-translational (via AMP-activated protein kinase) levels. Consistent with increased net triglyceride synthesis during the end of the active/awake phase, high fat feeding at this time resulted in marked cardiac steatosis. These data provide evidence for direct regulation of triglyceride turnover by a peripheral clock and reveal a potential mechanistic explanation for accelerated metabolic pathologies after prevalent circadian misalignment in Western society.


Efficacy and Safety of EMLA Cream for Pain Control Due to Venipuncture in Infants: A Meta-analysis.
: media-1vid110.1542/5852339542001PEDS-VA_2018-1173Video Abstract CONTEXT: The eutectic mixture of lidocaine (EMLA) cream has been used to reduce the pain during venipuncture in infants. To determine the efficacy and safety of EMLA in infants <3 months of age requiring venipuncture in comparison with nonpharmacological interventions in terms of pain reduction, change in physiologic variables, and methemoglobinemia. Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Web of Science, and gray literature were searched from inception to August 2017, without language restrictions. We selected randomized controlled trials in which researchers compared EMLA with nonpharmacological interventions. Two reviewers independently performed abstract screening and full-text review, and extracted the data and assessed the risk of bias. Ten randomized controlled trials (907 infants) were included. EMLA revealed little or no effect in reduction of pain (standardized mean difference: 0.14; 95% confidence interval [CI]: -0.17 to 0.45; 6 trials, n = 742; moderate-quality evidence) when EMLA was compared with sucrose, breastfeeding, or placebo. In comparison with placebo, EMLA revealed a small-to-moderate effect on increasing methemoglobin levels (mean difference: 0.35; 95% CI: 0.04 to 0.66; 2 trials, n = 134; low-quality evidence). There was an increased risk of blanching of the skin in the EMLA group (relative risk: 2.63; 95% CI: 1.58 to 4.38; 2 trials, n = 123; I2 = 84%, very low-quality evidence). Our results may not be applicable to older infants. EMLA reveals minimal benefits in terms of reduction of pain due to venipuncture procedure in comparison with placebo and no benefit in comparison with sucrose and/or breastfeeding. Moreover, it produced an elevation in methemoglobin levels and skin blanching.


Alkaline direct transesterification of different species of Stichococcus for bio-oil production.
The cost of bio-oil refining from microalgal biomass can be significantly reduced by combining extraction and transesterification. The characterisation and optimisation of the combined steps have been carried out on strains of Stichococcus bacillaris, focusing on catalyst type and concentration, reaction time and temperature, methanol/biomass ratio, pre-mixing time and water content in the biomass. The bio-oil yield has been referenced as production of fatty acid methyl esters (FAMEs). The maximum yield (∼17%) was achieved using dried biomass with alkaline catalyst at 60°C and methanol/biomass weight ratio of 79:1. Alkaline catalyst conditions gave faster reaction rates and higher bio-oil yields than acid catalyst. Yield was also strongly affected by water content in the biomass. A mechanistic interpretation has been proposed to elucidate the effect of the different operating conditions. However, the structural characteristics of the Chlorophyta cell wall can be very different, leading to different bio-oil yields when the same protocol is applied. Therefore, the optimised protocol of direct transesterification for Stichococcus bacillaris strains was tested on other Stichococcus strains and several other Chlorophyta species characterised by a different cell wall structure. It was clearly demonstrated that different results for bio-oil yield were obtained within the same microalgal species and much more within different microalgal genera.


Prehospital cricothyrotomies in a helicopter emergency medical service: analysis of 19,382 dispatches.
Creating a patent airway by cricothyrotomy is the ultimate maneuver to allow oxygenation (and ventilation) of the patient. Given the rarity of airway management catastrophes necessitating cricothyrotomy, sufficiently sized prospective randomized trials are difficult to perform. Our Helicopter Emergency Medical Service (HEMS) documents all cases electronically, allowing a retrospective analysis of a larger database for all cases of prehospital cricothyrotomy. We analyzed all 19,382 dispatches of our HEMS 'Lifeliner 1', since set-up of a searchable digital database. This HEMS operates 24/7, covering ~ 4.5 million inhabitants of The Netherlands. The potential cases were searched and cross-checked in two independent databases. We recorded n = 18 cases of prehospital cricothyrotomy. In all 18 cases, less invasive airway techniques, e.g., supraglottic devices, were attempted before cricothyrotomy. With exception of 2 cases, at least one attempt of orotracheal intubation had been performed before cricothyrotomy. Out of the 18 cases, 4 were performed by puncture-based technique (Melker), the remaining 14 cases by surgical technique. Indications for cricothyrotomy were diverse, dividable into 9 trauma cases and 9 medical cases. The procedure was successful in all but one case (17/18, i.e., 94%; with a 95% confidence interval of 72.7-99.9%). Outcome was such that 6/18 patients arrived at the hospital alive. Long term outcome was poor, with only 2/18 patients discharged from hospital alive. Cricothyrotomy remains, although rare, a regularly occurring requirement in (H)EMS. Our finding of a convincingly high success rate of 94% in trained hands encourages training and a timely performance of cricothyrotomy.


Violence against women in video games: a prequel or sequel to rape myth acceptance?
Current research suggests a link between negative attitudes toward women and violence against women, and it also suggests that media may condition such negative attitudes. When considering the tremendous and continued growth of video game sales, and the resulting proliferation of sexual objectification and violence against women in some video games, it is lamentable that there is a dearth of research exploring the effect of such imagery on attitudes toward women. This study is the first study to use actual video game playing and control for causal order, when exploring the effect of sexual exploitation and violence against women in video games on attitudes toward women. By employing a Solomon Four-Group experimental research design, this exploratory study found that a video game depicting sexual objectification of women and violence against women resulted in statistically significant increased rape myths acceptance (rape-supportive attitudes) for male study participants but not for female participants.


Reconstitution and characterization of eukaryotic N6-threonylcarbamoylation of tRNA using a minimal enzyme system.
The universally conserved Kae1/Qri7/YgjD and Sua5/YrdC protein families have been implicated in growth, telomere homeostasis, transcription and the N6-threonylcarbamoylation (t(6)A) of tRNA, an essential modification required for translational fidelity by the ribosome. In bacteria, YgjD orthologues operate in concert with the bacterial-specific proteins YeaZ and YjeE, whereas in archaeal and eukaryotic systems, Kae1 operates as part of a larger macromolecular assembly called KEOPS with Bud32, Cgi121, Gon7 and Pcc1 subunits. Qri7 orthologues function in the mitochondria and may represent the most primitive member of the Kae1/Qri7/YgjD protein family. In accordance with previous findings, we confirm that Qri7 complements Kae1 function and uncover that Qri7 complements the function of all KEOPS subunits in growth, t(6)A biosynthesis and, to a partial degree, telomere maintenance. These observations suggest that Kae1 provides a core essential function that other subunits within KEOPS have evolved to support. Consistent with this inference, Qri7 alone is sufficient for t(6)A biosynthesis with Sua5 in vitro. In addition, the 2.9 Å crystal structure of Qri7 reveals a simple homodimer arrangement that is supplanted by the heterodimerization of YgjD with YeaZ in bacteria and heterodimerization of Kae1 with Pcc1 in KEOPS. The partial complementation of telomere maintenance by Qri7 hints that KEOPS has evolved novel functions in higher organisms.


Pathophysiological Functions of Rnd3/RhoE.
Rnd3, also known as RhoE, belongs to the Rnd subclass of the Rho family of small guanosine triphosphate (GTP)-binding proteins. Rnd proteins are unique due to their inability to switch from a GTP-bound to GDP-bound conformation. Even though studies of the biological function of Rnd3 are far from being concluded, information is available regarding its expression pattern, cellular localization, and its activity, which can be altered depending on the conditions. The compiled data from these studies implies that Rnd3 may not be a traditional small GTPase. The basic role of Rnd3 is to report as an endogenous antagonist of RhoA signaling-mediated actin cytoskeleton dynamics, which specifically contributes to cell migration and neuron polarity. In addition, Rnd3 also plays a critical role in arresting cell cycle distribution, inhibiting cell growth, and inducing apoptosis and differentiation. Increasing data have shown that aberrant Rnd3 expression may be the leading cause of some systemic diseases; particularly highlighted in apoptotic cardiomyopathy, developmental arrhythmogenesis and heart failure, hydrocephalus, as well as tumor metastasis and chemotherapy resistance. Therefore, a better understanding of the function of Rnd3 under different physiological and pathological conditions, through the use of suitable models, would provide a novel insight into the origin and treatment of multiple human diseases.


Serial agonistic attacks by greylag goose families, Anser anser, against the same opponent.
It is known from primates that alliance partners may support each other's interests in competition with others, for example, through repeated agonistic attacks against a particular individual. We examined serial aggressive interactions between greylag goose families and other flock members. We found that repeated attacks towards the same individual were common and that up to five serial attacks by family members followed an initial attack. Family size did not affect the frequency of such serial attacks. Juvenile geese evidently benefited most from active social support through serial attacks. About 60% of the juveniles' lost primary interactions were subsequently reversed by another family member. This may be one of the reasons why juveniles rank higher in the social hierarchy than would be expected from their age and size alone. Losses in serial attacks predominantly occurred against other, presumably higher-ranking, family geese and ganders. We propose three major functions/consequences of serial attacks. Analogous to primates, serial attacks in greylag geese may serve to reinforce a losing experience of an opponent defeated in a preceding attack. On the side of the winning family, serial attacks may reinforce the experience of winning. Both winning and losing experiences are linked with physiological consequences in higher vertebrates, affecting the future social performance of winners or losers. Finally, serial attacks may signal the agonistic potential of a family to other flock members. This is supported by heart rate data, which indicate that greylags are competent to interpret third-party relationships.


Deep brain stimulation for phantom limb pain.
Phantom limb pain is an often severe and debilitating phenomenon that has been reported in up to 85% of amputees. Its pathophysiology is poorly understood. Peripheral and spinal mechanisms are thought to play a role in pain modulation in affected individuals; however central mechanisms are also likely to be of importance. The neuromatrix theory postulates a genetically determined representation of body image, which is modified by sensory input to create a neurosignature. Persistence of the neurosignature may be responsible for painless phantom limb sensations, whereas phantom limb pain may be due to abnormal reorganisation within the neuromatrix. This study assessed the clinical outcome of deep brain stimulation of the periventricular grey matter and somatosensory thalamus for the relief of chronic neuropathic pain associated with phantom limb in three patients. These patients were assessed preoperatively and at 3 month intervals postoperatively. Self-rated visual analogue scale pain scores assessed pain intensity, and the McGill Pain Questionnaire assessed the quality of the pain. Quality of life was assessed using the EUROQOL EQ-5D scale. Periventricular gray stimulation alone was optimal in two patients, whilst a combination of periventricular gray and thalamic stimulation produced the greatest degree of relief in one patient. At follow-up (mean 13.3 months) the intensity of pain was reduced by 62% (range 55-70%). In all three patients, the burning component of the pain was completely alleviated. Opiate intake was reduced in the two patients requiring morphine sulphate pre-operatively. Quality of life measures indicated a statistically significant improvement. This data supports the role for deep brain stimulation in patients with phantom limb pain. The medical literature relating to the epidemiology, pathogenesis, and treatment of this clinical entity is reviewed in detail.


A tetrahedron beam computed tomography benchtop system with a multiple pixel field emission x-ray tube.
To demonstrate the feasibility of Tetrahedron Beam Computed Tomography (TBCT) using a carbon nanotube (CNT) multiple pixel field emission x-ray (MPFEX) tube. A multiple pixel x-ray source facilitates the creation of novel x-ray imaging modalities. In a previous publication, the authors proposed a Tetrahedron Beam Computed Tomography (TBCT) imaging system which comprises a linear source array and a linear detector array that are orthogonal to each other. TBCT is expected to reduce scatter compared with Cone Beam Computed Tomography (CBCT) and to have better detector performance. Therefore, it may produce improved image quality for image guided radiotherapy. In this study, a TBCT benchtop system has been developed with an MPFEX tube. The tube has 75 CNT cold cathodes, which generate 75 x-ray focal spots on an elongated anode, and has 4 mm pixel spacing. An in-house-developed, 5-row CT detector array using silicon photodiodes and CdWO(4) scintillators was employed in the system. Hardware and software were developed for tube control and detector data acquisition. The raw data were preprocessed for beam hardening and detector response linearity and were reconstructed with an FDK-based image reconstruction algorithm. The focal spots were measured at about 1 × 2 mm(2) using a star phantom. Each cathode generates around 3 mA cathode current with 2190 V gate voltage. The benchtop system is able to perform TBCT scans with a prolonged scanning time. Images of a commercial CT phantom were successfully acquired. A prototype system was developed, and preliminary phantom images were successfully acquired. MPFEX is a promising x-ray source for TBCT. Further improvement of tube output is needed in order for it to be used in clinical TBCT systems.


Cooperative breeding influences the number and type of vocalizations in avian lineages.
Although communicative complexity is often predicted to correlate with social complexity in animal societies, few studies have employed large-scale comparative analyses to test whether socially complex species have more complex systems of communication. I tested this social complexity hypothesis in birds (Class: Aves) using the large amount of natural history information that describes both vocal repertoire and social system in these species. To do so, I marshalled data from primary and secondary records of avian vocal repertoires (n = 253), and for each of the species in the dataset I recorded the reported repertoire size and associated species information. Using phylogenetic comparative methods, I found that cooperative breeding was a strong and repeatable predictor of vocal repertoire size, while other social variables, e.g. group size and group stability, had little or no influence on repertoire size. Importantly, repertoire sizes expanded concurrently with the evolution of cooperative breeding, suggesting a direct link between these two traits. Cooperatively breeding species devoted significantly more of their repertoire to contact calls and alarm calls. Overall, these results therefore lend support to the hypothesis that social complexity via behavioural coordination leads to increases in vocal complexity.


Bone imaging in hypoparathyroidism.
Hypoparathyroidism (HypoPT) is an uncommon endocrine disorder characterized by chronic deficiency or absence of parathyroid hormone (PTH), which leads to a profound reduction in bone remodeling. Subjects with HypoPT typically have bone mineral densities (BMDs) by dual-energy X-ray absorptiometry (DXA) above average at all skeletal sites, with greatest scores observed at the lumbar spine. Trabecular bone score (TBS), an indirect measure of bone microarchitecture, also appears to be normal in HypoPT. By peripheral quantitative computed tomography (pQCT) of the radius, volumetric BMD at cancellous and cortical compartments, as well as cortical area and thickness, are greater in hypoparathyroid subjects than in controls. The use of high-resolution pQCT (HRpQCT) confirmed the increase in cortical volumetric BMD but demonstrated reduced cortical thickness, associated with lower cortical porosity in HypoPT. Trabeculae tend to be more numerous but thinner in hypoparathyroid subjects. It is not clear whether these structural and the dynamic skeletal abnormalities in HypoPT affect bone strength or fracture risk. Treatment of HypoPT with PTH leads to improvement in bone remodeling rate, variable changes in bone density, and a transient increase in estimated bone strength. The effect of PTH therapy on fracture risk remains unknown. This article reviews skeletal involvement and the effect of PTH treatment in patients with HypoPT, as assessed by DXA, TBS, QCT, and HRpQCT. Data on bone strength and fracture risk in HypoPT are also reviewed here.


Identification, functional and structural characterization of novel aminoglycoside phosphotransferase APH(3″)-Id from Streptomyces rimosus subsp. rimosus ATCC 10970.
In this study, we identified a new gene (aph(3″)-Id) coding for a streptomycin phosphotransferase by using phylogenetic comparative analysis of the genome of the oxytetracycline-producing strain Streptomyces rimosus ATCC 10970. Cloning the aph(3″)-Id gene in E.coli and inducing its expression led to an increase in the minimum inhibitory concentration of the recombinant E.coli strain to streptomycin reaching 350 μg/ml. To evaluate the phosphotransferase activity of the recombinant protein APH(3″)-Id we carried out thin-layer chromatography of the putative 32P-labeled streptomycin phosphate. We also performed a spectrophotometric analysis to determine the production of ADP coupled to NADH oxidation. Here are the kinetic parameters of the streptomycin phosphotransferase APH(3″)-Id: Km 80.4 μM, Vmax 6.45 μmol/min/mg and kcat 1.73 s-1. We demonstrated for the first time the ability of the aminoglycoside phototransferase (APH(3″)-Id) to undergo autophosphorylation in vitro. The 3D structures of APH(3″)-Id in its unliganded state and in ternary complex with streptomycin and ADP were obtained. The structure of the ternary complex is the first example of this class of enzymes with bound streptomycin. Comparison of the obtained structures with those of other aminoglycoside phosphotransferases revealed peculiar structure of the substrate-binding pocket reflecting its specificity to a particular antibiotic.


Exploring the fate of liposomes in the intestine by dynamic in vitro lipolysis.
Liposomes are generally well tolerated drug delivery systems with a potential use for the oral route. However, little is known about the fate of liposomes during exposure to the conditions in the gastro-intestinal tract (GIT). To gain a better understanding of liposome stability in the intestine, a dynamic in vitro lipolysis model, which so far has only been used for the in vitro characterisation of other lipid-based drug delivery systems, was applied to different liposomal formulations. Liposome size and phospholipid (PL) digestion were determined as two markers for liposome stability. In addition, the effect of PL degradation on the ability to maintain liposomally incorporated danazol in solution during lipolysis was evaluated in order to address the feasibility of liposomes designed for oral administration. Rate and extend of hydrolysis of PLs mediated by pancreatic enzymes was determined by titration and HPLC. Size of liposomes was determined by dynamic light scattering during incubation in lipolysis medium (LM) and during lipolysis. SPC-based (soy phosphatidylcholine) liposomes were stable in LM, whereas for EPC-3-based (hydrated egg phosphatidylcholine) formulations the formation of aggregates of around 1 μm in diameter was observed over time. After 60 min lipolysis more than 80% of PLs of the SPC-liposomes were digested, but dependent on the liposome concentration only a slight change in size and size distribution could be observed. Although EPC-3 formulations did form aggregates during lipolysis, the lipids exhibited a higher stability compared to SPC and only 30% of the PLs were digested. No direct correlation between liposome integrity assessed by vesicle size and PL digestion was observed. Danazol content in the liposomes was around 5% (mol/mol danazol/total lipid) and hardly any precipitation was detected during the lipolysis assay, despite pronounced lipolytic degradation and change in vesicle size. In conclusion, the tested dynamic in vitro lipolysis model is suitable for the assessment of liposome stability in the intestine. Furthermore, liposomes might be a useful alternative to other lipid based delivery systems for the oral delivery of poorly soluble drugs.


Hybrid histidine kinases in pathogenic fungi.
Histidine kinases (HK) sense and transduce via phosphorylation events many intra- and extracellular signals in bacteria, archaea, slime moulds and plants. HK are also widespread in the fungal kingdom, but their precise roles in the regulation of physiological processes remain largely obscure. Expanding genomic resources have recently given the opportunity to identify uncharacterised HK family members in yeasts and moulds and now allow proposing a complex classification of Basidiomycota, Ascomycota and lower fungi HK. A growing number of genetic approaches have progressively provided new insight into the role of several groups of HK in prominent fungal pathogens. In particular, a series of studies have revealed that members of group III HK, which occur in the highest number of fungal species and contain a unique N-terminus region consisting of multiple HAMP domain repeats, regulate morphogenesis and virulence in various human, plant and insect pathogenic fungi. This research field is further supported by recent shape-function studies providing clear correlation between structural properties and signalling states in group III HK. Since HK are absent in mammals, these represent interesting fungal target for the discovery of new antifungal drugs.


Revealing mammalian evolutionary relationships by comparative analysis of gene clusters.
Many software tools for comparative analysis of genomic sequence data have been released in recent decades. Despite this, it remains challenging to determine evolutionary relationships in gene clusters due to their complex histories involving duplications, deletions, inversions, and conversions. One concept describing these relationships is orthology. Orthologs derive from a common ancestor by speciation, in contrast to paralogs, which derive from duplication. Discriminating orthologs from paralogs is a necessary step in most multispecies sequence analyses, but doing so accurately is impeded by the occurrence of gene conversion events. We propose a refined method of orthology assignment based on two paradigms for interpreting its definition: by genomic context or by sequence content. X-orthology (based on context) traces orthology resulting from speciation and duplication only, while N-orthology (based on content) includes the influence of conversion events. We developed a computational method for automatically mapping both types of orthology on a per-nucleotide basis in gene cluster regions studied by comparative sequencing, and we make this mapping accessible by visualizing the output. All of these steps are incorporated into our newly extended CHAP 2 package. We evaluate our method using both simulated data and real gene clusters (including the well-characterized α-globin and β-globin clusters). We also illustrate use of CHAP 2 by analyzing four more loci: CCL (chemokine ligand), IFN (interferon), CYP2abf (part of cytochrome P450 family 2), and KIR (killer cell immunoglobulin-like receptors). These new methods facilitate and extend our understanding of evolution at these and other loci by adding automated accurate evolutionary inference to the biologist's toolkit. The CHAP 2 package is freely available from http://www.bx.psu.edu/miller_lab.


Reducing central line infections in pediatric and neonatal patients.
The stakes for the prevention of central line associated bloodstream infections (CLABSIs) have increased dramatically over the past decade. Over the past 10 years, the rate of CLABSI in the pediatric population has dropped markedly due to the significant investment in this initiative. Although there has been a substantial increase in studies on CLABSIs, difficulties in studying CLABSIs have limited the quality of the evidence produced. These difficulties include challenges in the sample size required to complete trials, pressure from external regulatory forces to reduce CLABSI rates, and challenges in defining CLABSIs. The definition of CLABSI is continuously being updated to improve the misclassification bias inherent in defining CLABSI. This is especially relevant given the stress placed on decreasing health-care-associated infections and the negative consequences associated if unsuccessful. In order to prevent CLABSIs, pediatric and neonatal intensive care units have formed bundles of basic evidenced-based strategies leading to effective reduction of CLABSIs. These basic bundles have been modified for spread to other nonintensive care areas, also yielding great results. However, additional therapies above the basic bundle have yielded mixed results, and more research is needed to understand the cost effectiveness of these therapies in the setting of decreasing CLABSI rates. As a goal, a "getting to zero" CLABSI rate should be set, but it may not be possible without significant resource allocation.


Predictors of diaphragm use as a potential sexually transmitted disease/HIV prevention method in Zimbabwe.
Women who are the most vulnerable to sexually transmitted diseases/HIV are often unable to consistently use condoms. One potential alternative method currently under investigation is the diaphragm. The goals of this study were to assess diaphragm uptake and use over time in Zimbabwe and to identify factors associated with self-reported consistent diaphragm use. Women attending family planning clinics who were inconsistent condom users received a diaphragm intervention and were followed for 6 months. Of the 186 participants, 99% ever reported using the diaphragm, and, at study exit, 96% had used it in the previous 2 months. Consistent diaphragm use since the previous visit was reported by 13% to 16% of the women, and in multivariate regression analysis, it was significantly associated with never using condoms (adjusted odds ratio, 24.08; 95% confidence interval, 6.71-86.34). Other factors included discreet use, preferring diaphragms to condoms, timing of insertion, domestic violence, and contraception. Diaphragms were well accepted among women at risk for sexually transmitted diseases/HIV.


Activation of AMPKα2 is not crucial for mitochondrial uncoupling-induced metabolic effects but required to maintain skeletal muscle integrity.
Transgenic (UCP1-TG) mice with ectopic expression of UCP1 in skeletal muscle (SM) show a phenotype of increased energy expenditure, improved glucose tolerance and increase substrate metabolism in SM. To investigate the potential role of skeletal muscle AMPKα2 activation in the metabolic phenotype of UCP1-TG mice we generated double transgenic (DTG) mice, by crossing of UCP1-TG mice with DN-AMPKα2 mice overexpressing a dominant negative α2 subunit of AMPK in SM which resulted in an impaired AMPKα2 activity by 90±9% in SM of DTG mice. Biometric analysis of young male mice showed decreased body weight, lean and fat mass for both UCP1-TG and DTG compared to WT and DN-AMPKα2 mice. Energy intake and weight-specific total energy expenditure were increased, both in UCP1-TG and DTG mice. Moreover, glucose tolerance, insulin sensitivity and fatty acid oxidation were not altered in DTG compared to UCP1-TG. Also uncoupling induced induction and secretion of fibroblast growth factor 21 (FGF21) from SM was preserved in DTG mice. However, voluntary physical cage activity as well as ad libitum running wheel access during night uncovered a severe activity intolerance of DTG mice. Histological analysis showed a progressive degenerative morphology in SM of DTG mice which was not observed in SM of UCP1-TG mice. Moreover, ATP-depletion related cellular stress response via heat shock protein 70 was highly induced, whereas capillarization regulator VEGF was suppressed in DTG muscle. In addition, AMPKα2-mediated induction of mitophagy regulator ULK1 was suppressed in DTG mice, as well as mitochondrial respiratory capacity and content. In conclusion, we demonstrate that AMPKα2 is dispensable for SM mitochondrial uncoupling induced metabolic effects on whole body energy balance, glucose homeostasis and insulin sensitivity. But strikingly, activation of AMPKα2 seems crucial for maintaining SM function, integrity and the ability to compensate chronic metabolic stress induced by SM mitochondrial uncoupling.


Characterization of IS900 loci in Mycobacterium avium subsp. paratuberculosis and development of multiplex PCR typing.
Mycobacterium avium subsp. paratuberculosis is a pathogen that causes chronic inflammation of the intestine in many animals, including primates, and is implicated in Crohn's disease in humans. It differs from other members of the M. avium complex in having 14-18 copies of IS900 inserted into conserved loci in its genome. In the present study, genomic DNA flanking 14 of these insertions was characterized and homologues in the Mycobacterium tuberculosis and M. avium subsp. avium genomes were identified. These included regions encoding a sigma factor (sigJ) at locus 3, a nitrate reductase (nirA) at locus 4, a transcription regulator (tetR) and polyketide synthase at locus 6, and a 6-O-methylguanine methyltransferase at locus 9. In addition, locus numbers were assigned to 9 of 15 RFLP bands previously described. IS900 insertion at 7 of the 14 characterized loci was into the RBS of a gene substituting an RBS encoded by IS900 sited two bases closer to the initiation codon. IS900 insertion at five loci interrupted an ORF at the target site, one of which encoded a homologue of the immunodominant mycobacterial DesA1 protein. Eleven of eighty-one M. avium subsp. paratuberculosis isolates lacked the insertion site at locus 6 together with flanking genomic DNA. This region was also absent from seven reference strains of M. avium subsp. avium, from one M. avium subsp. silvaticum and from six other mycobacterial species. A multiplex PCR of IS900 loci (MPIL) typing method was developed which was able to discriminate 10 different types of M. avium subsp. paratuberculosis from the panel of 81 isolates with consistent differences between those of bovine and ovine origin. Nine MPIL types corresponded with a single PstI/Bst:EII RFLP type, suggesting that this method may be applicable to typing of M. avium subsp. paratuberculosis directly from a sample without the need for culture. The remaining MPIL type corresponded with seven PstI/BstEII RFLP types. Further resolution of these may come from sequencing the remaining four uncharacterized IS900 loci.


Cognitive function and mood in MDMA/THC users, THC users and non-drug using controls.
Repeated ecstasy (MDMA) use is reported to impair cognition and cause increased feelings of depression and anxiety. Yet, many relevant studies have failed to control for use of drugs other than MDMA, especially marijuana (THC). To address these confounding effects we compared behavioural performance of 11 MDMA/THC users, 15 THC users and 15 non-drug users matched for age and intellect. We tested the hypothesis that reported feelings of depression and anxiety and cognitive impairment (memory, executive function and decision making) are more severe in MDMA/THC users than in THC users. MDMA/THC users reported more intense feelings of depression and anxiety than THC users and non-drug users. Memory function was impaired in both groups of drug users. MDMA/THC users showed slower psychomotor speed and less mental flexibility than non-drug users. THC users exhibited less mental flexibility and performed worse on the decision making task compared to non-drug users but these functions were similar to those in MDMA/THC users. It was concluded that MDMA use is associated with increased feelings of depression and anxiety compared to THC users and non-drug users. THC users were impaired in some cognitive abilities to the same degree as MDMA/THC users, suggesting that some cognitive impairment attributed to MDMA is more likely due to concurrent THC use.


Comparing spatial maps of human population-genetic variation using Procrustes analysis.
Recent applications of principal components analysis (PCA) and multidimensional scaling (MDS) in human population genetics have found that "statistical maps" based on the genotypes in population-genetic samples often resemble geographic maps of the underlying sampling locations. To provide formal tests of these qualitative observations, we describe a Procrustes analysis approach for quantitatively assessing the similarity of population-genetic and geographic maps. We confirm in two scenarios, one using single-nucleotide polymorphism (SNP) data from Europe and one using SNP data worldwide, that a measurably high level of concordance exists between statistical maps of population-genetic variation and geographic maps of sampling locations. Two other examples illustrate the versatility of the Procrustes approach in population-genetic applications, verifying the concordance of SNP analyses using PCA and MDS, and showing that statistical maps of worldwide copy-number variants (CNVs) accord with statistical maps of SNP variation, especially when CNV analysis is limited to samples with the highest-quality data. As statistical maps with PCA and MDS have become increasingly common for use in summarizing population relationships, our examples highlight the potential of Procrustes-based quantitative comparisons for interpreting the results in these maps.


Unconscious relational encoding depends on hippocampus.
Textbooks divide between human memory systems based on consciousness. Hippocampus is thought to support only conscious encoding, while neocortex supports both conscious and unconscious encoding. We tested whether processing modes, not consciousness, divide between memory systems in three neuroimaging experiments with 11 amnesic patients (mean age=45.55 years, standard deviation=8.74, range=23-60) and 11 matched healthy control subjects. Examined processing modes were single item versus relational encoding with only relational encoding hypothesized to depend on hippocampus. Participants encoded and later retrieved either single words or new relations between words. Consciousness of encoding was excluded by subliminal (invisible) word presentation. Amnesic patients and controls performed equally well on the single item task activating prefrontal cortex. But only the controls succeeded on the relational task activating the hippocampus, while amnesic patients failed as a group. Hence, unconscious relational encoding, but not unconscious single item encoding, depended on hippocampus. Yet, three patients performed normally on unconscious relational encoding in spite of amnesia capitalizing on spared hippocampal tissue and connections to language cortex. This pattern of results suggests that processing modes divide between memory systems, while consciousness divides between levels of function within a memory system.


Social Inequalities in Cancer Survival in Belgium: A Population-Based Cohort Study.
Socioeconomic status (SES) is an important factor in cancer survival; however, results are heterogeneous and linked to characteristics of the study population and health care system. This population-based cohort study evaluates the association between individual-level socioeconomic and demographic factors and cancer survival for the first time in Belgium. From the Belgian Cancer Registry, we identified 109,591 patients diagnosed between 2006 and 2013 with one of eight common cancer types. Information on treatment, socioeconomic parameters, and vital status were retrieved from multiple data sources and linked using a unique personal identification number. The outcome was 5-year observed survival. Associations between survival and socioeconomic and demographic factors were assessed using multivariable Cox proportional-hazard regression models. Lower income, unemployment, and living alone were all associated with worse cancer survival. These associations were most pronounced for certain lifestyle-related cancer types (e.g., head and neck cancers) and those with good to moderate prognosis (e.g., colorectal and female breast cancer). These results indicate that, despite a comprehensive and nationwide health insurance program in which equity in rights and access to health care are pursued, SES is associated with disparities in cancer survival in Belgium. This population-based study with individual-level socioeconomic information of more than 100,000 patients with cancer identifies patient groups that may be at highest risk for socioeconomic disparities in cancer survival. Reasons behind the observed disparities are multiple and complex and should be further examined. Health policy interventions should consider the observed deprivation gap to plan targeted actions.


Outcome of catheter ablation for ventricular tachycardia in patients with ischemic cardiomyopathy: A systematic review and meta-analysis of randomized clinical trials.
Current ventricular tachycardia (VT) management in patients with ischemic cardiomyopathy (ICM) includes optimal medical therapy, ICDs device therapy, and antiarrhythmic medications. Data about outcomes of catheter ablation (CA) in these patients is scarce. We aimed to perform a meta-analysis of RCTs to compare outcomes of CA vs conventional management of VT in ICM patients who had ICD. A systematic review and meta-analysis of published RCTs between January 1970 and December 2016 were performed. Random effects DerSimonian-Laird risk ratios (RR) were calculated. Sensitivity analyses using fixed-effects summary odds ratios (OR) were performed using Peto model. Outcomes of interest were: all-cause mortality (ACM), cardiovascular death (CVD), CV disease-related hospitalization, VT storms, and ICD shocks. 4 RCTs were identified (521 patients (261 had CA), mean age: 66.4 ± 1.7 years, 91.5% male, mean follow-up: 19 months). No difference observed between VT ablation and conventional management regarding ACM (RR 0.94, 95% CI, 0.66-1.32, p = 0.70) or CVD (RR 0.82, 95% CI, 0.52-1.29, p = 0.39). VT ablation was associated with less CV disease-related hospitalization (RR 0.72, 95% CI, 0.54-0.96, p = 0.02), VT storms (RR 0.71, 95% CI, 0.52-0.97, p = 0.03), and trend towards reducing ICD shocks (RR 0.59, 95% CI, 0.34-1.05, p = 0.07). In sensitivity analysis using fixed-effects OR, CA was associated with significant reduction in ICD shocks. In patients with ICM, VT ablation reduced CV disease-related hospitalization, VT storms, and ICD shocks when compared to conventional management with no mortality benefit over a relatively short mean follow-up period.


Surveillance of healthcare-associated infections in a neonatal intensive care unit in Italy during 2006-2010.
Healthcare-associated infections (HAIs) are a frequent complication associated with hospitalization of infants in neonatal intensive care units (NICUs). The aim of this study was to evaluate and describe the results of surveillance of HAIs in a III level NICU in Naples, Italy during 2006-2010. The surveillance covered 1,699 neonates of all birth weight (BW) classes with >2 days NICU stay. Infections were defined using standard Centers for Disease Control and Prevention definitions adapted to neonatal pathology and were considered to be healthcare-associated if they developed >2 days after NICU admission. One hundred-fifty-three HAIs were diagnosed with a frequency of 9% and an incidence density of 3.5 per 1000 days of hospital stay. HAIs developed in all BW classes, but patients weighing≤1000 g at birth were more affected with a decreasing trend from the lowest to the highest BW classes. Sepsis proved to be the most frequent infection (44.4%), followed by urinary tract infection (UTI) (28.8%), pneumonia (25.5%) and meningitis (1.3%). Device associated infections (i.e. central line-associated bloodstream infections (BSIs), umbilical catheter-associated BSI and ventilator associated pneumonias (VAPs) represented 64.1% of all HAIs. Most frequent pathogens responsible for all types of infections were: P. aeruginosa (17%), C. parapsilosis (16.3%), E. coli (13.1%), C. albicans (10.5%), non- extended spectrum beta-lactamase (ESBL) K. pneumoniae (7.8%), and coagulase-negative Staphylococci (5.2%). No microbiological diagnosis was achieved for 6.5% of infections. HAIs developed in all BW classes but low BW neonates were at major risk to acquire HAIs in our NICU. Use of central line-, umbilical-catheter and mechanical ventilation was associated with higher risk of infection. Our findings highlight the importance of an extensive surveillance approach in the NICU setting, which includes all BW classes of neonates and monitors infections associated with the use of medical devices.


Association of Body Mass Index with Injuries: A Systematic Review and Meta-Analyses Comparing Healthy Weight Military Service Members with Underweight, Overweight, and Obese.
Obesity is a worldwide health problem that has reached pandemic proportions. In the military, obesity and overweight are associated with health problems, attrition from military service, and reduced job performance. National and international organizations suggest body mass index (BMI) as a population screening tool to define overweight and obesity. BMI is calculated as weight/height2 (kg/m2). Four categories of adult BMI are underweight (<18.5 kg/m2), healthy weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (=30.0 kg/m2). This article reports on a systematic review and meta-analysis examining the association between BMI and injury risk among military service members (SMs). Studies were selected for review if they involved military personnel, were prospective or retrospective observational studies, and contained original quantitative data on injury risk at all four BMI levels. Nine studies met the review criteria. Pooled data from these investigations indicated that underweight, overweight, and obese individuals were at 1.17 (95% confidence interval [95%CI]=1.07-1.28), 1.03 (95%CI=1.01-1.06), and 1.15 (95%CI=1.11-1.20) times higher risk of injury than healthy weight individuals, respectively. Compared with healthy weight SMs, military personnel with both low and high BMI are at higher injury risk.


Empirical analysis of RNA robustness and evolution using high-throughput sequencing of ribozyme reactions.
RNA molecules provide a realistic but tractable model of a genotype to phenotype relationship. This relationship has been extensively investigated computationally using secondary structure prediction algorithms. Enzymatic RNA molecules, or ribozymes, offer access to genotypic and phenotypic information in the laboratory. Advancements in high-throughput sequencing technologies have enabled the analysis of sequences in the lab that now rivals what can be accomplished computationally. This has motivated a resurgence of in vitro selection experiments and opened new doors for the analysis of the distribution of RNA functions in genotype space. A body of computational experiments has investigated the persistence of specific RNA structures despite changes in the primary sequence, and how this mutational robustness can promote adaptations. This article summarizes recent approaches that were designed to investigate the role of mutational robustness during the evolution of RNA molecules in the laboratory, and presents theoretical motivations, experimental methods and approaches to data analysis.


Results of heavy metals and other water quality levels in tap water from Çan sourced from Ağı Dağı (Mt. Ağı) (Çanakkale, Turkey).
In this study, the concentrations of heavy metals Pb, Cu, Zn, Cd, Ni, Fe, Mn and Cr were determined using an inductively coupled plasma and optical emission spectrophotometer (ICP-OES), and water quality parameters pH, temperature, and conductivity were measured using the YSI 556 MPS water probe. The water samples were collected monthly from five different street tap water points sourced from Mt. Agi (Ağı Dağı in Turkish) spring waters between May 2012 and February 2013 in Çan (Canakkale, Turkey). All results were compared with the drinking water standards of the Turkish Standards Institute (TSE 266), World Health Organization, European Union and US Environmental Protection Agency. While concentrations of Cu, Zn, Fe, and Mn were within limit values, Pb, Cd, Ni, and Cr were at undetectable limits. The highest concentrations of Cu, Zn, Fe, and Mn were 0.010 ppm, 0.018 ppm, 0.058 ppm, and 0.014 ppm, respectively. The findings revealed that although there was no public health risk in view of heavy metal concentrations, there was an acidity problem due to lower pH levels correlated with some heavy metals such as Cu (R = 0.419), Fe (R = -0.421) and Mn (R = -0.687).


Validity and public health implications of maternal perception of the onset of lactation: an international analytical overview.
The main objective of this analytical overview is to assess the validity of maternal perception of the onset of lactation (OL) as an indicator of lactogenesis stage II (LS-II). Prospective studies that assessed OL and/or LS-II [based on test-weighing milk volume (MV) and/or breast milk biomarkers (BMB)] were identified. OL is a clearly defined and easily identified event across cultures, with the overwhelming majority of women being able to report when they experience it. Mean OL ranges from 50 to 73 h postpartum across studies and from 1 to 148 h postpartum within studies. The wide range detected within samples is fully consistent with the wide within sample LS-II variability as determined by BMB or MV. Studies have identified similar risk factors for delayed LS-II, such as labor and delivery stress, primiparity and insulin-dependent diabetes mellitus, regardless of marker used (i.e., OL, MV or BMB). The correlation between OL and MV (r = -0.60) is of similar magnitude to that between OL and BMB (r = 0.50) and that between BMB and MV (r = 0.47-0.69). In conclusion, OL is a valid clinical indicator of LS-II. This has public health relevance because studies have identified delayed OL (i.e., >72 h postpartum) as a risk factor for shorter breastfeeding duration and for greater infant weight loss by d 3 postpartum. Multidisciplinary studies are needed to standardize the definition of OL and to confirm its validity in different sociocultural contexts.


Factors that influence engagement in collaborative practice: how 8 health professionals became advocates.
To generate hypotheses regarding factors that might influence engagement in collaborative practice. Qualitative study using in-depth interviews. Participants interviewed each other in dyads. The pairing was based upon geographical location and proximity to each other. Eight professionals from the disciplines of medicine, nursing, occupational therapy, physical therapy, and massage therapy. Semistructured interviews, lasting 30 to 45 minutes each, were recorded and transcribed verbatim. The transcripts were read by all research team members using independent content analysis for common words, phrases, statements, or units of text for key themes. At a subsequent face-to-face meeting, the team used an iterative process of comparing and contrasting key themes until consensus was reached. The transcripts were then analyzed further for subthemes using NVivo software. Initial findings suggest that some common characteristics grounded in family history, school experiences, social interactions, and professional training might influence collaborative practice choices. The narrative form of the interview broke down interpersonal and interprofessional barriers, creating a new level of trust and respect that could improve professional collaboration. This study suggests that life experiences from childhood into later adulthood can and do influence professional choices.


Computational characterisation of dried and hydrated graphene oxide membranes.
A multi-step molecular dynamics procedure was developed to construct fully flexible atomistic models of graphene oxide (GO) membranes. The method of preparation replicates the experimental synthesis of the material; i.e. the flow-directed self-assembly of individual flakes onto a substrate or filter. A total of 180 GO membrane models were prepared with water contents varying between 0 and 20%, providing an insight into changes in the membrane's interlayer distance with swelling. Membranes with 15% water content have an average interlayer distance (0.80 nm), bulk density (1.77 g cm-3) and tensile modulus (18.1 GPa) in excellent agreement with the experimental literature, demonstrating that air-dried membranes have 15% water content. The models reveal the intrinsic structural heterogeneity and complex morphology of GO membranes. This feature has previously been unaccounted for in both experimental interpretations and GO nanopore models, which often use pre-defined and idealised 2D geometries. Completely dried membranes have considerable free pore volume. This observation explains the modest change in interlayer distance (0.02 nm) as the membrane's water content is increased from 0% to 10% compared to a much more significant change (0.12 nm) as the water content is increased from 10% to 20%. Combined with this new understanding of membrane swelling, the availability of such representative models opens the possibility of the molecular-level design of GO membranes for a variety of applications, such as gaseous and aqueous separations.


Description of the healthy eating indices-based diet quality in Turkish adults: a cross-sectional study.
This study aims to describe the dietary status of Turkish adults using two different versions of the Healthy Eating Index (HEI). In this cross sectional study, 494 healthy participants (311 females) with randomly selected and living in Ankara were included between September 2013 and March 2014. A questionnaire was completed and anthropometric measurements (weight and height) were performed. The 24-h dietary recall of individuals was collected. Diet quality was measured through HEI-2005 and HEI-2010 scores. The mean age, body mass index (BMI), HEI-2005 and HEI-2010 scores of individuals were 32.9 ± 10.8 years; 25.0 ± 4.8 kg/m2; 56.1 ± 13.9 and 41.5 ± 13.7 points, respectively. Significant differences were found between mean HEI-2005 and HEI-2010 scores (p < 0.05). The individual's whose diet quality needs to be improved according to mean HEI-2005 score, had poorer diet based on mean HEI-2010 scores. The highest mean HEI-2005 and HEI-2010 scores were stated in female, in subjects had low education levels, aged 51 years or older and in overweight groups (p <0.05). Both versions of healthy eating indices were correlated positively with BMI and age CONCLUSION: Diet qualities of the individuals are associated with age, gender, education and BMI. Although the components and scores in HEI-2010 version were changed from the version of HEI-2005, the changes may encourage healthy choices of some food group. HEI-2010 gives more attention to food quality than HEI-2005. Thus, in the present study it was concluded that HEI-2010 provided more precise results about diet quality.


Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia.
This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.


Delivery of mengovirus-derived RNA replicons into tumoural liver enhances the anti-tumour efficacy of a peripheral peptide-based vaccine.
Hepatocellular carcinoma is a deadly cancer with growing incidence for which immunotherapy is one of the most promising therapeutic approach. Peptide-based vaccines designed to induce strong, sustained CD8+ T cell responses are effective in animal models and cancer patients. We demonstrated the efficacy of curative peptide-based immunisation against a unique epitope of SV40 tumour antigen, through the induction of a strong CD8+ T cell-specific response, in our liver tumour model. However, as in human clinical trials, most tumour antigen epitopes did not induce a therapeutic effect, despite inducing strong CD8+ T cell responses. We therefore modified the tumour environment to enhance peptide-based vaccine efficacy by delivering mengovirus (MV)-derived RNA autoreplicating sequences (MV-RNA replicons) into the liver. The injection of replication-competent RNA replicons into the liver converted partial tumour regression into tumour eradication, whereas non-replicating RNA had no such effect. Replicating RNA replicon injection induced local recruitment of innate immunity effectors (NK and NKT) to the tumour and did not affect specific CD8+ T cell populations or other myelolymphoid subsets. The local delivery of such RNA replicons into tumour stroma is therefore a promising strategy complementary to the use of peripheral peptide-based vaccines for treating liver tumours.


Results of the prospective evaluation of radial keratotomy (PERK) study 10 years after surgery.
To determine the long-term effects and stability of refraction following a standardized technique of radial keratotomy for myopia in the nine-center Prospective Evaluation of Radial Keratotomy (PERK) Study 10 years after surgery. Radial keratotomy using eight centripetal incisions was performed to reduce myopia of -2.00 to -8.75 diopters in 1982 and 1983. A mean of 10 years later, patients underwent a standardized ophthalmic examination similar to previous study examinations. Of 427 patients (793 eyes that underwent radial keratotomy), 374 patients (88%) (693 eyes) returned for the 10-year examination. Of 675 eyes with refractive data, 38% had a refractive error within 0.50 D and 60% within 1.00 D. For 310 first-operated eyes, the mean refractive error was -0.36 D at 6 months and changed in a hyperopic direction to + 0.51 D at 10 years. The average rate of change was +0.21 D/y between 6 months and 2 years and +0.06 D/y between 2 and 10 years. Between 6 months and 10 years, the refractive error of 43% of eyes changed in the hyperopic direction by 1.00 D or more. The hyperopic shift was statistically associated with the diameter of the clear zone. Uncorrected visual acuity was 20/20 or better in 53% of 681 eyes and 20/40 or better in 85%. Loss of spectacle-corrected visual acuity of 2 lines or more on a Snellen chart occurred in 3% of all 793 eyes that underwent surgery. Among 310 patients with bilateral radial keratotomy, 70% reported not wearing spectacles or contact lenses for distance vision at 10 years. The PERK technique of radial keratotomy eliminated distance optical correction in 70% of patients, with a reasonable level of safety. A shift of the refractive error in the hyperopic direction continued during the entire 10 years after surgery.


Membrane effects of the n-3 fish oil fatty acids, which prevent fatal ventricular arrhythmias.
Fish oil fatty acids are known to exert beneficial effects on the heart and vascular systems. We have studied the membrane effects on ion channel conductance by the n-3 fish oil fatty acids that account for these beneficial effects. We have confirmed that these fatty acids prevent fatal cardiac arrhythmias in a reliable dog model of sudden cardiac death. This finding was followed by experiments indicating that the n-3 fatty acids electrically stabilize heart cells and do so largely through modulation of the fast voltage-dependent Na(+) currents and the L-type Ca(2+) channels in a manner, which makes the heart cells resistant to arrhythmias. Others and we have demonstrated that these membrane effects on the heart can prevent fatal cardiac arrhythmias in humans.


Wound ballistics of military rifle bullets: An update on controversial issues and associated misconceptions.
The wound ballistics literature contains several misconceptions about the physical effects of penetrating projectiles in tissue and tissue simulants. These can adversely affect the proper management of gunshot injuries, particularly in view of the ongoing threat of terrorist and criminal acts using assault rifles against civilians. The understanding of the wounding effects by military rifle bullets can be founded on the concept of energy transfer to the wound as applied to high-energy missile trauma. A substantial component of high-energy transfer in assault rifle injuries is manifested by the dynamic phenomenon of temporary cavitation, which is extensively reviewed with respect to its impact on the wound production and the associated controversy surrounding its consequences in soft tissue wounds. Part of this controversy emanates from misinterpretation of experimental data regarding the magnitude of the temporary cavity induced by high-velocity projectiles and the different conceptions of the tissue response to cavitation. The interaction between the projectile and tissue can lead to tumbling and possibly to deformation and fragmentation of the bullet, all of which strongly influence the energy transfer characteristics affecting both the temporary cavitation and the size of the permanent wound channel. Awareness of these effects can enhance perception of clinical and radiological findings suggestive of the wounding mechanism by various projectiles. LEVEL OF EVIDENCE: Review/therapeutic, level V.


A Genetically Tractable, Natural Mouse Model of Cryptosporidiosis Offers Insights into Host Protective Immunity.
Cryptosporidium is a leading cause of diarrheal disease and an important contributor to early childhood mortality, malnutrition, and growth faltering. Older children in high endemicity regions appear resistant to infection, while previously unexposed adults remain susceptible. Experimental studies in humans and animals support the development of disease resistance, but we do not understand the mechanisms that underlie protective immunity to Cryptosporidium. Here, we derive an in vivo model of Cryptosporidium infection in immunocompetent C57BL/6 mice by isolating parasites from naturally infected wild mice. Similar to human cryptosporidiosis, this infection causes intestinal pathology, and interferon-γ controls early infection while T cells are critical for clearance. Importantly, mice that controlled a live infection were resistant to secondary challenge and vaccination with attenuated parasites provided protection equal to live infection. Both parasite and host are genetically tractable and this in vivo model will facilitate mechanistic investigation and rational vaccine design.


The antitumorigenic response of neural precursors depends on subventricular proliferation and age.
Glioblastomas, the most aggressive primary brain tumors, occur almost exclusively in adult patients. Neural precursor cells (NPCs) are antitumorigenic in mice, as they can migrate to glioblastomas and induce tumor cell death. Here, we show that the antitumor effect of NPCs is age-dependently controlled by cell proliferation in the subventricular zone (SVZ) and that NPCs accumulating at a glioblastoma are diverted from their normal migratory path to the olfactory bulb. Experimentally induced cortical glioblastomas resulted in decreased subventricular proliferation in adult (postnatal day 90) but not in young (postnatal day 30) mice. Adult mice supplied fewer NPCs to glioblastomas and had larger tumors than young mice. Apart from the difference in proliferation, there was neither a change in cell number and death rate in the SVZ nor a change in angiogenesis and immune cell density in the tumors. The ability to kill glioblastomas was similar in NPCs isolated from young and adult mice. The proliferative response of NPCs to glioblastomas depended on the expression of D-type cyclins. In young mice, NPCs express the cyclins D1 and D2, but the expression of cyclin D1 is lost during aging, and in adult NPCs only cyclin D2 remains. In young and adult cyclin D2-deficient mice we observed a reduced supply of NPCs to glioblastomas and the generation of larger tumors compared with wild-type mice. We conclude that cyclin D1 and D2 are nonredundant for the antitumor response of subventricular NPCs. Loss of a single D-type cyclin results in a smaller pool of proliferating NPCs, lower number of NPCs migrating to the tumor, and reduced antitumor activity. Disclosure of potential conflicts of interest is found at the end of this article.


Embryonic exposure to an aqueous coal dust extract results in gene expression alterations associated with the development and function of connective tissue and the hematological system, immunological and inflammatory disease, and cancer in zebrafish.
Coal mining is one of the economic activities with the greatest impact on environmental quality. At all stages contaminants are released as particulates such as coal dust. The first aim of this study was to obtain an aqueous coal dust extract and characterize its composition in terms of trace elements by ICP-MS. In addition, the developmental toxicity of the aqueous coal extract was evaluated using zebrafish (Danio rerio) after exposure to different concentrations (0-1000 ppm; μg mL-1) to establish acute toxicity, morphology and transcriptome changes. Trace elements within the aqueous coal dust extract present at the highest concentrations (>10 ppb) included Sr, Zn, Ba, As, Cu and Se. In addition, Cd and Pb were found in lower concentrations. No significant difference in mortality was observed (p > 0.05), but a delay in hatching was found at 0.1 and 1000 ppm (p < 0.05). No significant differences in morphological characteristics were observed in any of the treatment groups (p > 0.05). Transcriptomic results of zebrafish larvae revealed alterations in 77, 61 and 1376 genes in the 1, 10, and 100 ppm groups, respectively. Gene ontology analysis identified gene alterations associated with the development and function of connective tissue and the hematological system, as well as pathways associated with apoptosis, the cell cycle, transcription, and oxidative stress including the MAPK signaling pathway. In addition, altered genes were associated with cancer; connective tissue, muscular, and skeletal disorders; and immunological and inflammatory diseases. Overall, this is the first study to characterize gene expression alterations in response to developmental exposure to aqueous coal dust residue from coal mining with transcriptome results signifying functions and systems to target in future studies.


The utility and cost of Chlamydia trachomatis and Neisseria gonorrhoeae screening of a male infertility population.
To determine the utility and cost of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) screening in infertile males. Cohort study. Canadian tertiary-level male infertility clinic and university-affiliated laboratories. 5,588 male infertility patients. CT and NG testing on 8,972 urine and semen samples. Prevalence of CT and NG infection in infertile males versus general male population in Canada over 8 years (2003-2010) and the reagent cost to detect one case of CT or NG. In infertile males, the prevalence rate for CT and NG was 0.304% and 0.0537%, which was statistically significantly lower (3.4- and 8.1-fold lower, respectively) than the age-adjusted general population prevalence. With the reagents costing $86.20 per patient tested, the reagent cost alone to diagnose one case of CT or NG was $38,669. The prevalence of CT and NG in this study are among the lowest reported in the male infertility literature. These findings question the utility of CT/NG screening in this low-risk population and emphasize that decisions about the utility of screening must be based on the prevalence rates of the disease in the studied population.


Size-specific tree mortality varies with neighbourhood crowding and disturbance in a Montane Nothofagus forest.
Tree mortality is a fundamental process governing forest dynamics, but understanding tree mortality patterns is challenging because large, long-term datasets are required. Describing size-specific mortality patterns can be especially difficult, due to few trees in larger size classes. We used permanent plot data from Nothofagus solandri var. cliffortioides (mountain beech) forest on the eastern slopes of the Southern Alps, New Zealand, where the fates of trees on 250 plots of 0.04 ha were followed, to examine: (1) patterns of size-specific mortality over three consecutive periods spanning 30 years, each characterised by different disturbance, and (2) the strength and direction of neighbourhood crowding effects on size-specific mortality rates. We found that the size-specific mortality function was U-shaped over the 30-year period as well as within two shorter periods characterised by small-scale pinhole beetle and windthrow disturbance. During a third period, characterised by earthquake disturbance, tree mortality was less size dependent. Small trees (<20 cm in diameter) were more likely to die, in all three periods, if surrounded by a high basal area of larger neighbours, suggesting that size-asymmetric competition for light was a major cause of mortality. In contrast, large trees (≥ 20 cm in diameter) were more likely to die in the first period if they had few neighbours, indicating that positive crowding effects were sometimes important for survival of large trees. Overall our results suggest that temporal variability in size-specific mortality patterns, and positive interactions between large trees, may sometimes need to be incorporated into models of forest dynamics.


Self-inflicted cosmetic tongue split: a case report.
The objective of this case study was to obtain some first-hand information about the functional consequences of a cosmetic tongue split operation for speech and tongue motility. One male patient who had performed the operation on himself was interviewed and underwent a tongue motility assessment, as well as an ultrasound examination. Tongue motility was mildly reduced as a result of tissue scarring. Speech was rated to be fully intelligible and highly acceptable by 4 raters, although 2 raters noticed slight distortions of the sibilants /s/ and /z/. The 3-dimensional ultrasound demonstrated that the synergy of the 2 sides of the tongue was preserved. A notably deep posterior genioglossus furrow indicated compensation for the reduced length of the tongue blade. It is concluded that the tongue split procedure did not significantly affect the participant's speech intelligibility and tongue motility.


Cloning and characterization of the glucosidase II alpha subunit gene of Trichoderma reesei: a frameshift mutation results in the aberrant glycosylation profile of the hypercellulolytic strain Rut-C30.
We describe isolation and characterization of the gene encoding the glucosidase II alpha subunit (GIIalpha) of the industrially important fungus Trichoderma reesei. This subunit is the catalytic part of the glucosidase II heterodimeric enzyme involved in the structural modification within the endoplasmic reticulum (ER) of N-linked oligosaccharides present on glycoproteins. The gene encoding GIIalpha (gls2alpha) in the hypercellulolytic strain Rut-C30 contains a frameshift mutation resulting in a truncated gene product. Based on the peculiar monoglucosylated N-glycan pattern on proteins produced by the strain, we concluded that the truncated protein can still hydrolyze the first alpha-1,3-linked glucose residue but not the innermost alpha-1,3-linked glucose residue from the Glc2Man9GlcNAc2 N-glycan ER structure. Transformation of the Rut-C30 strain with a repaired T. reesei gls2alpha gene changed the glycosylation profile significantly, decreasing the amount of monoglucosylated structures and increasing the amount of high-mannose N-glycans. Full conversion to high-mannose carbohydrates was not obtained, and this was probably due to competition between the endogenous mutant subunit and the introduced wild-type GIIalpha protein. Since glucosidase II is also involved in the ER quality control of nascent polypeptide chains, its transcriptional regulation was studied in a strain producing recombinant tissue plasminogen activator (tPA) and in cultures treated with the stress agents dithiothreitol (DTT) and brefeldin A (BFA), which are known to block protein transport and to induce the unfolded protein response. While the mRNA levels were clearly upregulated upon tPA production or BFA treatment, no such enhancement was observed after DTT addition.


HyperDense-Net: A Hyper-Densely Connected CNN for Multi-Modal Image Segmentation.
Recently, dense connections have attracted substantial attention in computer vision because they facilitate gradient flow and implicit deep supervision during training. Particularly, DenseNet that connects each layer to every other layer in a feed-forward fashion and has shown impressive performances in natural image classification tasks. We propose HyperDenseNet, a 3-D fully convolutional neural network that extends the definition of dense connectivity to multi-modal segmentation problems. Each imaging modality has a path, and dense connections occur not only between the pairs of layers within the same path but also between those across different paths. This contrasts with the existing multi-modal CNN approaches, in which modeling several modalities relies entirely on a single joint layer (or level of abstraction) for fusion, typically either at the input or at the output of the network. Therefore, the proposed network has total freedom to learn more complex combinations between the modalities, within and in-between all the levels of abstraction, which increases significantly the learning representation. We report extensive evaluations over two different and highly competitive multi-modal brain tissue segmentation challenges, iSEG 2017 and MRBrainS 2013, with the former focusing on six month infant data and the latter on adult images. HyperDenseNet yielded significant improvements over many state-of-the-art segmentation networks, ranking at the top on both benchmarks. We further provide a comprehensive experimental analysis of features re-use, which confirms the importance of hyper-dense connections in multi-modal representation learning. Our code is publicly available.


Assessment of landfill leachate toxicity reduction after biological treatment.
In the present article, the efficiency of biological treatment of landfill leachates was evaluated by implementation of physicochemical characterisation and a complex toxicity assessment. An array of toxicity tests using bacterium Vibrio fischeri, alga Desmodesmus subspicatus, crustacean Daphnia magna, and embryo of fish Danio rerio, as well as unconventional methods using biochemical biomarkers (protein content, enzymes cholinesterase, and glutathione-S-transferase), were employed. Toxicity of leachates varied depending on the season of collection in relation to their different physicochemical characteristics. Uncommon effects of leachates on organisms, such as hormetic-like increases of algal growth and reproduction of daphnids, were identified. New approaches using the activities of enzymes were found unsuitable for routine hazard assessment of leachates. Although physicochemical parameters and toxicity decreased significantly after biological treatment, the effluents did not meet the demands of the current Slovenian legislation; thus, the existing biological treatment was found inappropriate. The development of advanced treatment techniques for landfill leachates is thus encouraged.


Invasive lobular carcinoma of the breast: mammographic characteristics and computer-aided detection.
To characterize the mammographic appearance of invasive lobular carcinoma in a large series of screening-detected consecutive breast cancers and to evaluate the ability of a computer-aided detection system to mark these carcinomas. Investigators used the Breast Imaging Reporting and Data System lexicon to characterize lesions as part of a retrospective review of 90 screening mammographic examinations that led to biopsy-proved diagnosis of 94 invasive lobular carcinoma lesions. The 40 available prior mammographic examinations (obtained 9-24 months earlier) were also reviewed to characterize any visible findings. The results of a computer-aided detection analysis were compared with the images, and the sensitivity of the algorithm was calculated for correct detection of the lesions. Fifty-six (60%) of 94 lesions manifested as masses, of which 40 (71%) were described as irregular and spiculated; 20 (21%) of 94, as architectural distortions; and the remainder, 18 (20%), as either asymmetric densities or calcifications. On the screening mammograms showing biopsy-proved cancers, the sensitivity of the computer-aided detection system was 86 (91%) of 94 lesions. Thirty-one of the 40 prior mammograms showed retrospectively visible findings, and 24 (77%) of 31 were marked by the computer-aided detection system. Spiculated masses and architectural distortions are the predominant appearances of invasive lobular carcinoma, and a computer-aided detection system correctly marked a high percentage of invasive lobular carcinoma lesions.


Creasing in evaporation-driven cavity collapse.
We report on crease morphology and evolution at the surface of contracting cavities embedded within elastomeric solids of varying composition (Sylgard 184: pre-polymer to crosslinker mixing ratios of 10 : 1, 12 : 1, 17.5 : 1, and 25 : 1). Cavity contraction is achieved through evaporation of an embedded 10 μL liquid droplet. In validation of recent theoretical predictions, strain-stiffening modeled via the Gent constitutive relation [Jin and Suo, JMPS, 2015, 74, 68-79] is found to govern both crease onset and crease density. Specifically, crease onset matches prediction using only experimentally-measured parameters. Neo-Hookean solids are found to prefer initiating creasing with many short creases that join to form a collapsed state with only a few creases, whereas creasing in Gent solids initiates with a few creases that propagate across the cavity surface. These experimental observations are explained by energy minimization using finite element simulation of a cylindrical crease geometry.


Compartmented neuron cultures for directional infection by alpha herpesviruses.
Compartmented neuronal cultures allow experimenters to establish separate fluid environments for neuronal axons and the soma from which they emanate. Physical isolation of cell bodies and axons is achieved by culturing neurons in tri-chambered Teflon rings. Dissociated ganglia are plated in one end compartment of the trichamber, and axonal growth is guided underneath watertight silicone grease barriers into a separate compartment. Since the axons and cell bodies are located in different compartments, they can be infected and assayed separately. We describe the assembly and use of compartmented neuronal cultures for in vitro study of directional infection of neurons by alpha herpesviruses. Selective application of viral inoculum to only one compartment ensures that the remainder of the neuron is not contaminated by input inoculum. This allows for quantification of viral spread, and unambiguous interpretation of immunofluorescence and electron microscopy images.


Cloning and sequencing of a 1.3 KB variant of human thyrotropin receptor mRNA lacking the transmembrane domain.
We amplified human thyroidal cDNA using oligonucleotide primers designed to reveal putative human thyrotropin receptor (hTSHR) mRNA variants encoding the extracellular, ligand-binding domain but lacking the transmembrane domain. Whereas the major 4.3 kb hTSHR mRNA species was not amplified to detectable levels, several shorter products were detected. A strongly amplified 1 kb product was cloned and sequenced. It contained coding sequences at the 5' end which were colinear with exons 1-8 of the hTSHR gene, encoding most of the extracellular domain. This was followed at the 3' end by additional coding and noncoding information not present in the 4.3 kb transcript. A probe specific for the 5' end recognized polyadenylated thyroidal transcripts of 4.3, 1.7, and 1.3 kb, indicating the presence of several hTSHR mRNA variants. A probe specific for the 3' end recognized only the 1.3 kb transcript. The level of the 1.3 kb variant (hTSHR-v 1.3 mRNA) was about half that of the 4.3 kb hTSHR mRNA and twice that of the 1.7 kb variant. The presence of a thyroidal mRNA encoding both the signal peptide and ligand-binding region of the hTSHR, but not the seven transmembrane helices, provides the potential to produce soluble receptors which could play important roles in thyroid physiology and/or autoimmune thyroid disease.


Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression.
Animal models of psychiatric disorders are usually discussed with regard to three criteria first elaborated by Willner; face, predictive and construct validity. Here, we draw the history of these concepts and then try to redraw and refine these criteria, using the framework of the diathesis model of depression that has been proposed by several authors. We thus propose a set of five major criteria (with sub-categories for some of them); homological validity (including species validity and strain validity), pathogenic validity (including ontopathogenic validity and triggering validity), mechanistic validity, face validity (including ethological and biomarker validity) and predictive validity (including induction and remission validity). Homological validity requires that an adequate species and strain be chosen: considering species validity, primates will be considered to have a higher score than drosophila, and considering strains, a high stress reactivity in a strain scores higher than a low stress reactivity in another strain. Pathological validity corresponds to the fact that, in order to shape pathological characteristics, the organism has been manipulated both during the developmental period (for example, maternal separation: ontopathogenic validity) and during adulthood (for example, stress: triggering validity). Mechanistic validity corresponds to the fact that the cognitive (for example, cognitive bias) or biological mechanisms (such as dysfunction of the hormonal stress axis regulation) underlying the disorder are identical in both humans and animals. Face validity corresponds to the observable behavioral (ethological validity) or biological (biomarker validity) outcomes: for example anhedonic behavior (ethological validity) or elevated corticosterone (biomarker validity). Finally, predictive validity corresponds to the identity of the relationship between the triggering factor and the outcome (induction validity) and between the effects of the treatments on the two organisms (remission validity). The relevance of this framework is then discussed regarding various animal models of depression.


The transmission dynamics of the human immunodeficiency virus type 1 in the male homosexual community in the United Kingdom: the influence of changes in sexual behaviour.
This paper examines the transmission dynamics of human immune deficiency virus type 1 (HIV-1) in the male homosexual population in the U.K. via numerical studies employing a mathematical model representing the principal epidemiological process. The model is based on an assumption of proportionate mixing between different sexual-activity classes (defined by the rate of sexual partner change per unit of time) and incorporates heterogeneity in sexual activity, distributed infection and incubation periods and the recruitment of susceptibles to the sexually active population. The sensitivity of model predictions to various assumptions and parameter assignments is examined. Numerical studies of model behaviour focus on the influence of changes in the magnitudes of the transmission parameters, associated with three periods of infectiousness during the incubation period of acquired immune deficiency syndrome (AIDS), on the magnitude and duration of the epidemic and on the level of the endemic equilibrium state. Predicted temporal trends in the incidence of AIDS are shown to be particularly sensitive to changes in the intensities and durations of the stages of infectiousness. Most of the paper addresses the influence of changes in sexual behaviour on the magnitude and duration of the epidemic. Numerical simulations show that the manner in which behavioural changes occur and who is influenced by such changes (i.e. infecteds or susceptibles, the sexually active population or new recruits to this population) have a major impact on the future timecourse of the epidemic. The greatest reduction in the incidence of AIDS over the coming decades is induced by changes in the rate of sexual-partner change among the sexually active population, particularly those currently infected. The time periods at which changes in behaviour occur, in relation to the starting point of the epidemic (assumed to be 1979), are also of particular significance to the future pattern of the incidence of disease and infection. Changes in behaviour early on in the timecourse of the epidemic have a much greater impact than equivalent changes at latter time points. On the basis of limited data on the pattern of change in sexual behaviour among the male homosexual community in the U.K., numerical studies of model behaviour tentatively suggest that the epidemic is at, or near to, a period of peak incidence of the disease AIDS. Analyses suggest that, following the peak in incidence, there will be a period of slow decline over many decades provided recent changes in behaviour are maintained in the coming years.(ABSTRACT TRUNCATED AT 400 WORDS)


Vascular muscarinic receptors: pharmacological characterization in the bovine coronary artery.
The goal of this study was to make functional comparisons between muscarinic receptors mediating endothelial-dependent relaxation responses in the rabbit ear artery and receptors mediating endothelial-independent contractile responses. Ring segments of the bovine coronary artery with the endothelium removed proved to be an excellent model for studying the properties of muscarinic receptors mediating vascular smooth muscle contraction. Although endothelial-dependent relaxation responses could be seen with the calcium ionophore A-23187, no relaxation responses to cholinergic agonists were seen in the bovine coronary artery, whether or not the endothelium was present or in the presence or absence of smooth muscle tone. In ring segments of the bovine coronary artery or the rabbit ear artery, the cholinergic agonists, acetylcholine, methacholine and carbachol, proved to be approximately equipotent in evoking contraction or relaxation, respectively. In contrast, the putative M1 selective agonist McN-A-343 did not produce any effect in either tissue; nor did McN-A-343 have any effect on a perfused rabbit ear artery segment. Measurement of antagonist affinities indicated that the bovine coronary artery muscarinic receptors show low affinity for both pirenzepine (pKB = 6.9) and AF-DX 116 (11-2-[[2-[diethylaminomethyl]-1-piperidinyl]acetyl]-5,11- dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one) (pKB = 6.3). Pirenzepine affinity was also low in the perfused rabbit ear artery preparation.(ABSTRACT TRUNCATED AT 250 WORDS)


Sick leave and disability pension in inflammatory bowel disease: a systematic review.
Inflammatory bowel disease has considerable effects on work-related outcomes and leads to high societal costs due to sick leave and disability pension. The aims of this study were to systematically review evidence on work-related outcomes that are relevant to productivity losses and to evaluate whether medical or surgical interventions have a positive impact on patients' work ability. A systematic literature search in PubMed was conducted in June 2013. Abstracts were screened by two independent reviewers, and full-text articles describing the frequency of work-related outcomes were retrieved. Two independent reviewers extracted data according to the PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses. Findings were organized by study design (non-interventional/interventional). Non-interventional studies were structured according to whether they presented data in comparison to control groups or not and interventional studies were summarized according to type of intervention. This review included 30 non-interventional (15 with comparison groups and 15 without comparison group) and 17 interventional studies (9 surgical and 8 medical). The majority of the studies reported a high burden of work-related outcomes among inflammatory bowel disease patients regardless of the methodology used. While biologic agents showed positive effect on work absenteeism and presenteeism in randomized clinical trials, the impact of surgical interventions needs further evaluation. Inflammatory bowel disease patients experience a high burden in work-related outcomes. Additional data on productivity losses and the long-term impact of interventions is needed to help inform decision-makers about treatment options and their benefits in reducing productivity losses in inflammatory bowel disease patients.


FastMMD: Ensemble of Circular Discrepancy for Efficient Two-Sample Test.
The maximum mean discrepancy (MMD) is a recently proposed test statistic for the two-sample test. Its quadratic time complexity, however, greatly hampers its availability to large-scale applications. To accelerate the MMD calculation, in this study we propose an efficient method called FastMMD. The core idea of FastMMD is to equivalently transform the MMD with shift-invariant kernels into the amplitude expectation of a linear combination of sinusoid components based on Bochner's theorem and Fourier transform (Rahimi & Recht, 2007). Taking advantage of sampling the Fourier transform, FastMMD decreases the time complexity for MMD calculation from O(N(2)d) to O(LN d), where N and d are the size and dimension of the sample set, respectively. Here, L is the number of basis functions for approximating kernels that determines the approximation accuracy. For kernels that are spherically invariant, the computation can be further accelerated to O(LN log d) by using the Fastfood technique (Le, Sarlós, & Smola, 2013). The uniform convergence of our method has also been theoretically proved in both unbiased and biased estimates. We also provide a geometric explanation for our method, ensemble of circular discrepancy, which helps us understand the insight of MMD and we hope will lead to more extensive metrics for assessing the two-sample test task. Experimental results substantiate that the accuracy of FastMMD is similar to that of MMD and with faster computation and lower variance than existing MMD approximation methods.