Study on public perceptions and protective behaviors regarding Lyme disease among the general public in the Netherlands: implications for prevention programs.
Lyme disease (LD) is the most common tick-borne disease in the United States and in Europe. The aim of this study was to examine knowledge, perceived risk, feelings of anxiety, and behavioral responses of the general public in relation to tick bites and LD in the Netherlands. From a representative Internet panel a random sample was drawn of 550 panel members aged 18 years and older (8-15 November 2010) who were invited to complete an online questionnaire. Response rate (362/550, 66%). This study demonstrates that knowledge, level of concern, and perceived efficacy are the main determinants of preventive behavior. 35% (n = 125/362) of the respondents reported a good general knowledge of LD. While 95% (n = 344/362) perceived LD as severe or very severe, the minority (n = 130/362, 36%) perceived their risk of LD to be low. Respondents were more likely to check their skin after being outdoors and remove ticks if necessary, than to wear protective clothing and/or use insect repellent skin products. The percentage of respondents taking preventive measures ranged from 6% for using insect repellent skin products, to 37% for wearing protective clothing. History of tick bites, higher levels of knowledge and moderate/high levels of worry were significant predictors of checking the skin. Significant predictors of wearing protective clothing were being unemployed/retired, higher knowledge levels, higher levels of worry about LD and higher levels of perceived efficacy of wearing protective clothing. Prevention programs targeting tick bites and LD should aim at influencing people's perceptions and increasing their knowledge and perceived efficacy of protective behavior. This can be done by strengthening motivators (e.g. knowledge, concern about LD, perceived efficacy of wearing protective clothing) and removing barriers (e.g. low perceived personal risk, not knowing how to recognize a tick). The challenge is to take our study findings and translate them into appropriate prevention strategies.


Molecular analysis of the replication region of the pCIZ2 plasmid from the multiple bacteriocin producer strain Enterococcus faecium L50.
The sequence analysis of the 7383 bp plasmid pCIZ2 from Enterococcus faecium L50 enabled the identification of a DNA region involved in its replication. The structural organization of the pCIZ2 replication region is highly similar to those of well-known theta-replicating plasmids. It contains an untranslated region, the putative replication origin (ori), constituted by two sets of direct repeats of 12 and 22 bp (iterons), and followed by three open-reading frames (orf8 to orf10). orf8 encodes the replication initiation protein (RepE). The transcriptional start site of the replication locus was identified 13 nucleotides upstream of the repE start codon. A two-dimensional agarose gel electrophoresis analysis revealed pCIZ2 intermediates profile typical of the theta-type replication mechanism. Subcloning of different DNA fragments of the pCIZ2 replication region in Escherichia coli and, subsequently, in the plasmidless E. faecium L50/14-2 allowed the determination of the minimal replicon on a 1.2kb DNA fragment containing only the overall ori and repE which also act in trans. The involvement of orf9 in the plasmid copy number and in the plasmid stability was investigated. The pCIZ2 recombinant plasmids constitute narrow-host range shuttle cloning vectors (E. coli-E. faecium) that could be very useful for enterococcal genes studies, allowing an easy identification due to their histochemical recognition.


Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies.
Pancreatic cancer has few early symptoms, is usually diagnosed at late stages, and has a high case-fatality rate. Identifying modifiable risk factors is crucial to reducing pancreatic cancer morbidity and mortality. Prior studies have suggested that specific foods and nutrients, such as dairy products and constituents, may play a role in pancreatic carcinogenesis. In this pooled analysis of the primary data from 14 prospective cohort studies, 2212 incident pancreatic cancer cases were identified during follow-up among 862 680 individuals. Adjusting for smoking habits, personal history of diabetes, alcohol intake, body mass index (BMI), and energy intake, multivariable study-specific hazard ratios (MVHR) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards models and then pooled using a random effects model. There was no association between total milk intake and pancreatic cancer risk (MVHR = 0.98, 95% CI = 0.82-1.18 comparing ≥500 with 1-69.9 g/day). Similarly, intakes of low-fat milk, whole milk, cheese, cottage cheese, yogurt, and ice-cream were not associated with pancreatic cancer risk. No statistically significant association was observed between dietary (MVHR = 0.96, 95% CI = 0.77-1.19) and total calcium (MVHR = 0.89, 95% CI = 0.71-1.12) intake and pancreatic cancer risk overall when comparing intakes ≥1300 with <500 mg/day. In addition, null associations were observed for dietary and total vitamin D intake and pancreatic cancer risk. Findings were consistent within sex, smoking status, and BMI strata or when the case definition was limited to pancreatic adenocarcinoma. Overall, these findings do not support the hypothesis that consumption of dairy foods, calcium, or vitamin D during adulthood is associated with pancreatic cancer risk.


The selective localization of murine pleuropneumonia-like organisms in the female genital tract on intraperitoneal injection in mice.
Acute oophoritis and salpingitis were commonly observed in weanling mice injected intraperitoneally with murine pleuropneumonia-like organisms of the catarrhal type (4 strains). Organisms of the injected strain were regularly recovered in cultures from the ovary or uterus during the 3rd to the 5th week but not after the 12th week. They were also obtained from the vagina through the 5th week and with varying results, depending on the strain, from the heart's blood through the 1st week. PPLO injected into the vagina survived for some weeks but did not migrate inwardly nor were they transmitted outwardly to exposed mice. In male mice peritoneal abscesses were sometimes present but the genital organs were normal and free from PPLO. Otitis media, with positive exudate cultures, occurred more often in females and varied in rate with the strain of PPLO. PPLO of the conjunctival type failed to survive in the abdominal cavity of mice and produced no reaction in either the genital or the respiratory tract.


Oxygen consumption in aortic tissue from rabbits with diet-induced atherosclerosis.
The inner parts of the arterial wall depend upon diffusion for nutrition and oxygenation. During the atherosclerotic process, increased intimal thickness leads to impaired diffusion, and at the same time the oxygen requirements increase. On this basis it has been suggested that the balance between the supply and demand of oxygen in the arterial wall may be important for the fate of the initiated lesion. In the first part of the present study, the oxygen consumption was measured during perfusion in aortic intima-media segments from cholesterol-fed rabbits. The results indicated that the oxygen consumption per DNA increased with increasing degree of atherosclerotic involvement up to a certain level. For more diseased aortas, however, the oxygen consumption decreased again. In the second part of the study, the oxygen consumption was measured in foam cell and smooth muscle cell fractions isolated from rabbit aortic intima-media. These measurements indicated that the oxygen consumption of isolated foam cells was three times higher than that of isolated smooth muscle cells. It is proposed in the study that the increased oxygen consumption of the less diseased aortas reflected an increased proportion of foam cells in the arterial wall. As the lesions grow and the number of foam cells in the intima increases, the available diffusion capacity for oxygen and nutrients to deeper parts of the lesion may become insufficient, leading to the observed decrease in cellular oxygen consumption of the more diseased samples. Hypoxic cell damage and further tissue reactions may occur and the healing of the initiated lesion may be endangered.


Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD.
Growing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum of neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, which encodes the autophagy receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects in disease-associated variants have not been described. A key protein-protein interaction in autophagy is the recognition of a lipid-anchored form of LC3 (LC3-II) within the phagophore membrane by SQSTM1, mediated through its LC3-interacting region (LIR), and notably some ALS-FTLD mutations map to this region. Here we show that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B. We place our observations on a firm quantitative footing by showing the L341V-mutant LIR is associated with a ∼3-fold reduction in LC3B binding affinity and using protein NMR we rationalize the structural basis for the effect. This functional deficit is realized in motor neuron-like cells, with the L341V mutant EGFP-mCherry-SQSTM1 less readily incorporated into acidic autophagic vesicles than the wild type. Our data supports a model in which the L341V mutation limits the critical step of SQSTM1 recruitment to the phagophore. The oligomeric nature of SQSTM1, which presents multiple LIRs to template growth of the phagophore, potentially gives rise to avidity effects which amplify the relatively modest impact of any single mutation on LC3B binding. Over the lifetime of a neuron, impaired autophagy could expose a vulnerability, which ultimately tips the balance from cell survival toward cell death.


Lattice dynamics of the tin sulphides SnS2, SnS and Sn2S3: vibrational spectra and thermal transport.
We present an in-depth first-principles study of the lattice dynamics of the tin sulphides SnS2, Pnma and π-cubic SnS and Sn2S3. An analysis of the harmonic phonon dispersion and vibrational density of states reveals phonon bandgaps between low- and high-frequency modes consisting of Sn and S motion, respectively, and evidences a bond-strength hierarchy in the low-dimensional SnS2, Pnma SnS and Sn2S3 crystals. We model and perform a complete characterisation of the infrared and Raman spectra, including temperature-dependent anharmonic linewidths calculated using many-body perturbation theory. We illustrate how vibrational spectroscopy could be used to identify and characterise phase impurities in tin sulphide samples. The spectral linewidths are used to model the thermal transport, and the calculations indicate that the low-dimensional Sn2S3 has a very low lattice thermal conductivity, potentially giving it superior performance to SnS as a candidate thermoelectric material.


Ligand-induced assembly and activation of the gamma interferon receptor in intact cells.
Functionally active gamma interferon (IFN-gamma) receptors consist of an alpha subunit required for ligand binding and signal transduction and a beta subunit required primarily for signaling. Although the receptor alpha chain has been well characterized, little is known about the specific role of the receptor beta chain in IFN-gamma signaling. Expression of the wild-type human IFN-gamma receptor beta chain in murine L cells that stably express the human IFN-gamma receptor alpha chain (L.hgR) produced a murine cell line (L.hgR.myc beta) that responded to human IFN-gamma. Mutagenesis of the receptor beta-chain intracellular domain revealed that only two closely spaced, membrane-proximal sequences (P263PSIP267 and I270EEYL274) are required for function. Coprecipitation studies showed that these sequences are necessary for the specific and constitutive association of the receptor beta chain with the JAK-2 tyrosine kinase. These experiments also revealed that the IFN-gamma receptor alpha and beta chains are not preassociated on the surface of unstimulated cells but rather are induced to associate in an IFN-gamma-dependent fashion. A chimeric protein in which the intracellular domain of the beta chain was replaced by JAK-2 complemented human IFN-gamma signaling and biologic responsiveness in L.hgR. In contrast, a c-src-containing beta-chain chimera did not. These results indicate that the sole obligate role of the IFN-gamma receptor beta chain in signaling is to recruit JAK-2 into the ligand-assembled receptor complex.


Immunohistochemistry detected and localized cannabinoid receptor type 2 in bovine fetal pancreas at late gestation.
At present, data on the endocannabinoid system expression and distribution in the pancreatic gland appear scarce and controversial as descriptions are limited to humans and laboratory animals. Since the bovine pancreas is very similar to the human in endocrine portion development and control, studies on the fetal gland could prove to be very interesting, as an abnormal maternal condition during late pregnancy may be a predisposing trigger for adult metabolic disorders. The present investigation studied cannabinoid receptor type 2 presence and distribution in the bovine fetal pancreas towards the end of gestation. Histological analyses revealed numerous endocrinal cell clusters or islets which were distributed among exocrine adenomeri in connectival tissue. Immunohistochemistry showed that endocrine-islets contained some CB2-positive cells with a very peculiar localization that is a few primarily localized at the edges of islets and some of them also scattered in the center of the cluster. Characteristically, also the epithelium of the excretory ducts and the smooth muscle layers of the smaller arteries, in the interlobular glandular septa, tested positive for the CB2 endocannabinoid receptor. Conse - quently, the endocannabinoid system, via the cannabinoid receptor type 2, was hypothesized to play a major role in controlling pancreas function from normal fetal development to correct metabolic functioning in adulthood.


Review of heart-lung transplantation at Stanford.
Long-term survival after heart-lung transplantation was first achieved in 1981 at Stanford and a total of 217 heart-lung transplantations had been performed by June 2008. This review summarizes Stanford's cumulative experience with heart-lung transplantation, demonstrates the progress that has been made, and discusses past and persistent problems. Diagnostic tools and treatment options for infectious diseases and rejection have changed and patient survival markedly improved over the almost three decades. Eight patients lived longer than 20 years. Further options to treat infections and strategies to control bronchiolitis obliterans syndrome, the main causes of early and long-term mortality, respectively, are required to achieve routine long-term survival.


Fission yeast Msp1 is a mitochondrial dynamin-related protein.
We recently identified Msp1p, a fission yeast Schizosaccharomyces pombe dynamin-related protein, which is essential for the maintenance of mitochondrial DNA. The Msp1p sequence displays typical features of a mitochondrial protein. Here we report in vitro and in vivo data that validate that prediction. We demonstrate that the targeting sequence of Msp1p is processed by recombinant mitochondrial processing peptidase and that Msp1p is imported into S. pombe mitochondria in vitro in the presence of cellular extracts. We show that the first 109 residues of Msp1p encompass a functional peptide signal that is sufficient to direct chimera to mitochondria. Immunofluorescence studies indicate that Msp1p staining colocalises with a mitochondrial marker and electron microscopy shows that the protein is located inside the mitochondria. Mitochondrial enrichment and fractionation further confirm that localisation and show that Msp1p is anchored to the matrix side of the mitochondrial inner membrane. Finally, we report that overexpression of the Msp1 protein results in gross alteration of the mitochondrial structure and function. All together our results suggest that Msp1p is an essential component for mitochondrial maintenance.


Antibodies to the desmoglein 1 precursor proprotein but not to the mature cell surface protein cloned from individuals without pemphigus.
In pemphigus foliaceus (PF), autoantibodies against desmoglein 1 (Dsg1) cause blisters. Using Ab phage display, we have cloned mAbs from a PF patient. These mAbs, like those from a previous patient, were directed against mature Dsg1 (matDsg1) on the cell surface of keratinocytes and precursor Dsg1 (preDsg1) in the cytoplasm. To determine whether individuals without pemphigus have B cell tolerance to Dsg1, we cloned mAbs from two patients with thrombotic thrombocytopenic purpura and a healthy person. We found mAbs against preDsg1, but not matDsg1. All but 1 of the 23 anti-preDsg1 mAbs from PF patients and those without PF used the VH3-09 (or closely related VH3-20) H chain gene, whereas no PF anti-matDsg1 used these genes. V(H) cDNA encoding anti-preDsg1 had significantly fewer somatic mutations than did anti-matDsg1 cDNA, consistent with chronic Ag-driven hypermutation of the latter compared with the former. These data indicate that individuals without PF do not have B cell tolerance to preDsg1 and that loss of tolerance to matDsg1 is not due to epitope shifting of anti-preDsg1 B cells (because of different V(H) gene usage). However, presentation of peptides from Dsg1 by preDsg1-specific B cells may be one step in developing autoimmunity in PF.


Nanoparticle separation based on size-dependent aggregation of nanoparticles due to the critical Casimir effect.
Nanoparticles typically have an inherent wide size distribution that may affect the performance and reliability of many nanomaterials. Because the synthesis and purification of nanoparticles with desirable sizes are crucial to the applications of nanoparticles in various fields including medicine, biology, health care, and energy, there is a great need to search for more efficient and generic methods for size-selective nanoparticle purification/separation. Here we propose and conclusively demonstrate the effectiveness of a size-selective particle purification/separation method based on the critical Casimir force. The critical Casimir force is a generic interaction between colloidal particles near the solvent critical point and has been extensively studied in the past several decades due to its importance in reversibly controlling the aggregation and stability of colloidal particles. Combining multiple experimental techniques, we found that the critical Casimir force-induced aggregation depends on relative particle sizes in a system with larger ones aggregating first and the smaller ones remaining in solution. Based on this observation, a new size-dependent nanoparticle purification/separation method is proposed and demonstrated to be very efficient in purifying commercial silica nanoparticles in the lutidine/water binary solvent. Due to the ubiquity of the critical Casimir force for many colloidal particles in binary solvents, this method might be applicable to many types of colloidal particles.


Communicative effectiveness of pantomime gesture in people with aphasia.
Human communication occurs through both verbal and visual/motoric modalities. Simultaneous conversational speech and gesture occurs across all cultures and age groups. When verbal communication is compromised, more of the communicative load can be transferred to the gesture modality. Although people with aphasia produce meaning-laden gestures, the communicative value of these has not been adequately investigated. To investigate the communicative effectiveness of pantomime gesture produced spontaneously by individuals with aphasia during conversational discourse. Sixty-seven undergraduate students wrote down the messages conveyed by 11 people with aphasia that produced pantomime while engaged in conversational discourse. Students were presented with a speech-only, a gesture-only and a combined speech and gesture condition and guessed messages in both a free description and a multiple-choice task. As hypothesized, listener comprehension was more accurate in the combined pantomime gesture and speech condition as compared with the gesture- or speech-only conditions. Participants achieved greater accuracy in the multiple-choice task as compared with the free-description task, but only in the gesture-only condition. The communicative effectiveness of the pantomime gestures increased as the fluency of the participants with aphasia decreased. These results indicate that when pantomime gesture was presented with aphasic speech, the combination had strong communicative effectiveness. Future studies could investigate how pantomimes can be integrated into interventions for people with aphasia, particularly emphasizing elicitation of pantomimes in as natural a context as possible and highlighting the opportunity for efficient message repair.


Apurinic/apyrimidinic endonuclease/redox effector factor-1(APE/Ref-1): a unique target for the prevention and treatment of human melanoma.
Management of melanoma is a growing and challenging public health issue requiring novel and multidisciplinary approaches to achieve more efficient prevention and therapeutic benefits. The aim of this article is to show the critical role of APE/Ref-1 on melanomagenesis and progression. APE/Ref-1 serves as a redox-sensitive node of convergence of various signals as well as a DNA-repair enzyme, and its activation protects melanocytes and melanoma cells from chronic oxidative stress and promotes cell survival via mediation of downstream pathways. APE/Ref-1 is a strong candidate as a potential drug-treatable target for the prevention and treatment of human melanoma. Lead compounds exhibiting inhibitory effects on APE/Ref-1 are also reviewed. We anticipate potential clinical benefit in the future through inhibition of APE/Ref-1 and/or Ref-1-mediated signaling.


Olfactory attractants and parity affect prenatal androgens and territoriality of coyote breeding pairs.
Hormones are fundamental mediators of personality traits intimately linked with reproductive success. Hence, alterations to endocrine factors may dramatically affect individual behavior that has subsequent fitness consequences. Yet it is unclear how hormonal or behavioral traits change with environmental stressors or over multiple reproductive opportunities, particularly for biparental fauna. To simulate an environmental stressor, we exposed captive coyote (Canis latrans) pairs to novel coyote odor attractants (i.e. commercial scent lures) mid-gestation to influence territorial behaviors, fecal glucocorticoid (FGMs) and fecal androgen metabolites (FAMs). In addition, we observed coyote pairs as first-time and experienced breeders to assess the influence of parity on our measures. Treatment pairs received the odors four times over a 20-day period, while control pairs received water. Odor-treated pairs scent-marked (e.g. urinated, ground scratched) and investigated odors more frequently than control pairs, and had higher FAMs when odors were provided. Pairs had higher FAMs as first-time versus experienced breeders, indicating that parity also affected androgen production during gestation. Moreover, repeatability in scent-marking behaviors corresponded with FGMs and FAMs, implying that coyote territoriality during gestation is underpinned by individually-specific hormone profiles. Our results suggest coyote androgens during gestation are sensitive to conspecific olfactory stimuli and prior breeding experience. Consequently, fluctuations in social or other environmental stimuli as well as increasing parity may acutely affect coyote traits essential to reproductive success.


Comparison of the prognostic value of genomic grade index, Ki67 expression and mitotic activity index in early node-positive breast cancer patients.
Background The genomic grade index (GGI) completes the prognostic value of histological grade (HG). Other proliferation markers include the mitotic activity index (MAI) and the Ki67 immunohistochemistry (IHC) status. We compared the prognostic value of GGI, HG, MAI, Ki67 IHC and messenger RNA (mRNA) status in node-positive breast cancer (BC) patients treated with adjuvant anthracycline-based chemotherapy in the prospective PACS01 trial. Patients and methods The five proliferation-related parameters (GGI, Ki67 mRNA expression and centrally determined HG, MAI, and Ki67 IHC status) of tumours were available for 204 cases and analysed as continuous values. We compared the correlations of each one with the other proliferation-related parameters and with histoclinical variables including the disease-free survival (DFS). Results Expected correlations were observed between the five parameters and for each parameter with biological features (hormone-receptor and HER2 status, molecular subtypes), but the GGI displayed the strongest correlations. The GGI outperformed the prognostic performance of the four other proliferation-related parameters for the DFS in all 204 patients and in the 95 HG2 patients. In multivariate analysis including the classical prognostic factors, only GGI remained significant. Finally, the GGI outperformed the prognostic performance of MKI67 mRNA expression in a series of 1599 samples and 656 HG2 cases. Conclusions In this small pilot biomarker study ancillary to the PACS01 trial, the GGI outperforms the prognostic performance of centrally determined HG, MAI, Ki67 IHC status and mRNA expression. Further validation is warranted in larger series.


Vein of Galen Malformations: The Texas Children's Hospital Experience in the Modern Endovascular Era.
Vein of Galen malformations (VOGM) comprise nearly a third of pediatric cerebrovascular anomalies, with potentially devastating neurological and systemic complications. Advances in endovascular therapies have dramatically improved outcomes compared to historical surgical treatments, and neurosurgeons are an essential component of the multidisciplinary critical care team. To retrospectively review pediatric patients with VOGM treated at Texas Children's Hospital (TCH), a quaternary referral center, over 15 yr, and present lessons learned in treating children with modern endovascular techniques. Charts from TCH were retrospectively reviewed for the past 15 yr. Patients with diagnosis including "Vein of Galen," "Vein of Galen malformation," "Vein of Galen aneurysmal malformation," or any abbreviations (ie, VOG, VOGM, VOGAM) were reviewed. Presentation, imaging, treatment specifics, and clinical outcomes were reported. There were 18 patients with VOGM managed at TCH from 2002 to 2018 with a total of 29 embolizations. Seventeen were performed with a single embolisate (NBCA or Onyx), and 12 with a combination. A dual lumen balloon catheter was used as an adjunct in 3 embolizations. Complications occurred in 5 embolizations (24%), including hemorrhage, embolisate migration, and femoral vessel occlusion. Surviving patients were followed for a mean of 38 mo, with 12 having normal or near-normal neurological development. VOGM can present with a myriad of neurological and systemic symptoms, potentially in extremis. Neurosurgical involvement in these cases is critical, as urgent treatment can be lifesaving. Patients may require multiple treatment sessions using a variety of endovascular tools and techniques.


Diffractively coupled Fabry-Perot resonator with power-recycling.
We demonstrate the optical coupling of two cavities without light transmission through a substrate. As the all-reflective coupling component, we use a dielectric low-efficiency 3-port diffraction grating. In contrast to a conventional transmissive coupling component, such an all-reflective coupler avoids all thermal effects that are associated with light absorption in the substrate. An all-reflective scheme for cavity coupling is of interest in the field of gravitational wave detection. In such detectors light that is resonantly enhanced inside the so-called power-recycling cavity is coupled to (kilometre-scale) Fabry-Perot resonators representing the arms of a Michelson interferometer. We realized such an all-reflective coupling in a table-top experiment. Our findings are in qualitative agreement with the theoretical model incorporating the characteristics of the 3-port grating used, and therefore encourage the application of all-reflective cavity couplers in future gravitational wave detectors.


Joint modeling of longitudinal and competing-risk data using cumulative incidence functions for the failure submodels accounting for potential failure cause misclassification through double sampling.
Most of the literature on joint modeling of longitudinal and competing-risk data is based on cause-specific hazards, although modeling of the cumulative incidence function (CIF) is an easier and more direct approach to evaluate the prognosis of an event. We propose a flexible class of shared parameter models to jointly model a normally distributed marker over time and multiple causes of failure using CIFs for the survival submodels, with CIFs depending on the "true" marker value over time (i.e., removing the measurement error). The generalized odds rate transformation is applied, thus a proportional subdistribution hazards model is a special case. The requirement that the all-cause CIF should be bounded by 1 is formally considered. The proposed models are extended to account for potential failure cause misclassification, where the true failure causes are available in a small random sample of individuals. We also provide a multistate representation of the whole population by defining mutually exclusive states based on the marker values and the competing risks. Based solely on the assumed joint model, we derive fully Bayesian posterior samples for state occupation and transition probabilities. The proposed approach is evaluated in a simulation study and, as an illustration, it is fitted to real data from people with HIV.


Post-translational insertion of boron in proteins to probe and modulate function.
Boron is absent in proteins, yet is a micronutrient. It possesses unique bonding that could expand biological function including modes of Lewis acidity not available to typical elements of life. Here we show that post-translational Cβ-Bγ bond formation provides mild, direct, site-selective access to the minimally sized residue boronoalanine (Bal) in proteins. Precise anchoring of boron within complex biomolecular systems allows dative bond-mediated, site-dependent protein Lewis acid-base-pairing (LABP) by Bal. Dynamic protein-LABP creates tunable inter- and intramolecular ligand-host interactions, while reactive protein-LABP reveals reactively accessible sites through migratory boron-to-oxygen Cβ-Oγ covalent bond formation. These modes of dative bonding can also generate de novo function, such as control of thermo- and proteolytic stability in a target protein, or observation of transient structural features via chemical exchange. These results indicate that controlled insertion of boron facilitates stability modulation, structure determination, de novo binding activities and redox-responsive 'mutation'.


Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity.
To save energy, the European directives from the Eco-design of Energy Using Products (2005/32/CE) have recommended the replacement of incandescent lamps by more economic devices such as Light Emitting Diodes (LEDs). However, the emission spectrum of these devices is enriched in blue radiations, known to be potentially dangerous to the retina. Recent studies showed that light exposure contributes to the onset of early stages of age-related macular degeneration (AMD). Here, we investigate, in albinos and pigmented rats, the effects of different exposure protocols. Twenty-four hours exposure at high luminance was compared to a cyclic (dark/light) exposure at domestic levels for 1week and 1month, using different LEDs (Cold-white, blue and green), as well as fluorocompact bulbs and fluorescent tubes. The data suggest that the blue component of the white-LED may cause retinal toxicity at occupational domestic illuminance and not only in extreme experimental conditions, as previously reported. It is important to note that the current regulations and standards have been established on the basis of acute light exposure and do not take into account the effects of repeated exposure.


Male reproductive toxicity of lead in animals and humans. ASCLEPIOS Study Group.
To critically review the literature on male reproductive toxicity of lead in animals and humans. A systematic literature search identified a total of 32 experimental studies in animals and 22 epidemiological studies, one case report on humans and five review articles or documents. The studies were evaluated by paying attention mainly to sample size, study design, exposure, and dose characterisation, analytical method standardisation, and quality assurance. Several studies on rats and other rodents indicated that blood lead concentrations > 30-40 micrograms/dl were associated with impairment of spermatogenesis and reduced concentrations of androgens. However, other animal studies, mainly about histopathological, spermatozoal, and hormonal end points, indicated that certain species and strains were quite resistant to the reproductive toxicity of lead and that different testicular lead concentrations could account for these differences. The human studies focused mainly on semen quality, endocrine function, and birth rates in occupationally exposed subjects, and showed that exposure to concentrations of inorganic lead > 40 micrograms/dl in blood impaired male reproductive function by reducing sperm count, volume, and density, or changing sperm motility and morphology. No relevant effects were detected on endocrine profile. Several factors make it difficult to extrapolate the animal data to the human situation. The difficulties are mainly due to differences between species in reproductive end points and to the level of exposure. Concentrations of blood lead > 40 micrograms/dl seemed to be associated with a decrease in sperm count, volume, motility, and morphological alterations and a possible modest effect on endocrine profile. Dose-response relation, in particular at a threshold level, is poorly understood, and site, mode, or mechanism of action are unknown. Also, the effects were not always the same or associated in the same on sperm count and concentration. Some methodological issues and indications for future studies are discussed.


Teaching evidence-based practice at the University of Texas Health Science Center at San Antonio dental school.
The overarching goal of the Evidence-Based Practice Program at San Antonio is to provide our graduates with life-long learning skills that will enable them to keep up-to-date and equip them with the best possible patient care skills during their 30-40 years of practice. Students are taught to (1) ask focused clinical questions, (2) search the biomedical research literature (PubMed) for the most recent and highest level of evidence, (3) critically evaluate the evidence, and (4) make clinical judgments about the applicability of the evidence for their patients. Students must demonstrate competency with these "just-in-time" learning skills through writing concise one-page Critically Appraised Topics (CATs) on focused clinical questions. The school has established an online searchable library of these Critically Appraised Topics. This library provides students and faculty with rapid, up-to-date evidence-based answers to clinical questions. The long-range plan is to make this online library available to practitioners and the public.


Modeling single-neuron dynamics and computations: a balance of detail and abstraction.
The fundamental building block of every nervous system is the single neuron. Understanding how these exquisitely structured elements operate is an integral part of the quest to solve the mysteries of the brain. Quantitative mathematical models have proved to be an indispensable tool in pursuing this goal. We review recent advances and examine how single-cell models on five levels of complexity, from black-box approaches to detailed compartmental simulations, address key questions about neural dynamics and signal processing.


Anti-tumor necrosis factor drug survival in axial spondyloarthritis is independent of the classification criteria.
To compare the impact of meeting specific classification criteria [modified New York (mNY), European Spondyloarthropathy Study Group (ESSG), and Assessment of SpondyloArthritis international Society (ASAS) criteria] on anti-tumor necrosis factor (anti-TNF) drug retention, and to determine predictive factors of better drug survival. All patients fulfilling the ESSG criteria for axial spondyloarthritis (SpA) with available data on the axial ASAS and mNY criteria, and who had received at least one anti-TNF treatment were retrospectively retrieved in a single academic institution in Switzerland. Drug retention was computed using survival analysis (Kaplan-Meier), adjusted for potential confounders. Of the 137 patients classified as having axial SpA using the ESSG criteria, 112 also met the ASAS axial SpA criteria, and 77 fulfilled the mNY criteria. Drug retention rates at 12 and 24 months for the first biologic therapy were not significantly different between the diagnostic groups. Only the small ASAS non-classified axial SpA group (25 patients) showed a nonsignificant trend toward shorter drug survival. Elevated CRP level, but not the presence of bone marrow edema on magnetic resonance imaging (MRI) scans, was associated with significantly better drug retention (OR 7.9, ICR 4-14). In this cohort, anti-TNF drug survival was independent of the classification criteria. Elevated CRP level, but not positive MRI, was associated with better drug retention.


The self-systems of aggressive children: a cluster-analytic investigation.
The purpose of the present study was to identify clinically relevant subtypes of aggressive children based on measures of children's self-systems and significant others' perceptions of relationship quality. In a sample of aggressive second- and third-graders, a cluster analysis of these children's perceptions of support and significant others' (mother, teacher, and peers) perceptions of relationship quality revealed one subgroup in which self- and other-ratings were both below the group mean (concordant-negative), one in which both were above the sample mean (concordant-positive), and one in which they were discrepant (high child-report and low other-report). All three clusters were rated as more aggressive than controls. However, children in the discrepant group were rated as considerably more aggressive and delinquent than those in the two concordant clusters, who did not differ from each other on measures of internalizing and externalizing behaviors. Results are discussed from an attachment perspective and in terms of the clinical significance of this self-other discrepancy.


In-vitro efficacy of synergistic antibiotic combinations in multidrug resistant Pseudomonas aeruginosa strains.
Combination antibiotic treatment is preferred in nosocomial infections caused by Pseudomonas aeruginosa (P. aeruginosa). In vitro synergism tests were used to choose the combinations which might be used in clinic. The aim of this study was to investigate the synergistic efficacy of synergistic antibiotic combinations in multidrug resistant P. aeruginosa strains. Synergistic efficacies of ceftazidime-tobramycin, piperacillin/tazobactam-tobramycin, imipenem-tobramycin, imipenem-isepamycin, imipenem-ciprofloxacin and ciprofloxacin-tobramycin combinations were investigated by checkerboard technique in 12 multiple-resistant and 13 susceptible P. aeruginosa strains. The ratios of synergy were observed in ceftazidime-tobramycin and piperacillin/tazobactam-tobramycin combinations as 67%, and 50%, respectively, in resistant strains, whereas synergy was not detected in other combinations. The ratios of synergy were observed in ceftazidime-tobramycin, piperacillin/tazobactam-tobramycin, imipenem-tobramycin, imipenem-ciprofloxacin and imipenem-isepamycin combinations as 31%, 46%, 15%, 8%, 8%, and respectively, in susceptible strains, whereas synergy was not detected in ciprofloxacin-tobramycin combination. Antagonism was not observed in any of the combinations. Although the synergistic ratios were high in combinations with ceftazidime or piperacillin/tazobactam and tobramycin, the concentrations in these combinations could not usually reach clinically available levels. Thus, the solution of the problems caused by multiple resistant P. aeruginosa should be based on the prevention of the development of resistance and spread of the causative agent between patients.


Heat wave intensity and daily mortality in four of the largest cities of Spain.
In the current context of climate change, heat waves have become a significant problem for human health. This study assesses the effects of heat wave intensity on mortality (natural, respiratory and cardiovascular causes) in four of the largest cities of Spain (Barcelona, Bilbao, Madrid and Seville) during the period between 1990 and 2014. To model the heat wave severity the Excess Heat Factor (EHF) was used. The EHF is a two-component index. The first is the comparison of the three-day average daily mean temperature with the 95th percentile. The second component is a measure of the temperatures reached during the three-day period compared with the recent past (the previous 30 days). The city-specific exposure-response curves showed a non-linear J-shaped relationship between mortality and the EHF. Overall city-specific mortality risk estimates in natural causes for 1st vs. 99th percentile increases range from the highest mortality risk with 2.73 (95% CI: 2.34-3.18) in Seville to a risk of 1.78 (95% CI: 1.62-1.97) and 1.78 (95% CI: 1.45-2.19) in Barcelona and Bilbao, respectively. When we compare our results with risk estimates for the analyzed Spanish cities in other studies, the heat wave related mortality risks seem to be clearly higher. Furthermore, it has been demonstrated that different heat wave days of the same event do not present the same degree of severity/intensity. Thus, the intensity of a heat wave is an important mortality risk indicator during heat wave days. Due to the low number of studies on the EHF as a heat wave intensity indicator and heat-related mortality and morbidity, further research is required to validate its application in other geographic areas and focus populations.


Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides.
Alternative splicing of the pyruvate kinase M gene involves a choice between mutually exclusive exons 9 and 10. Use of exon 10 to generate the M2 isoform is crucial for aerobic glycolysis (the Warburg effect) and tumour growth. We previously demonstrated that splicing enhancer elements that activate exon 10 are mainly found in exon 10 itself, and deleting or mutating these elements increases the inclusion of exon 9 in cancer cells. To systematically search for new enhancer elements in exon 10 and develop an effective pharmacological method to force a switch from PK-M2 to PK-M1, we carried out an antisense oligonucleotide (ASO) screen. We found potent ASOs that target a novel enhancer in exon 10 and strongly switch the splicing of endogenous PK-M transcripts to include exon 9. We further show that the ASO-mediated switch in alternative splicing leads to apoptosis in glioblastoma cell lines, and this is caused by the downregulation of PK-M2, and not by the upregulation of PK-M1. These data highlight the potential of ASO-mediated inhibition of PK-M2 splicing as therapy for cancer.


The effect of the MC4R gene on boar taint compounds, sexual maturity and behaviour in growing-finishing boars and gilts.
Societal pressure to ban surgical castration of male piglets is rising due to animal welfare concerns, thus other methods to prevent boar taint need to be explored. Genetic selection against boar taint appears to be a long-term sustainable alternative. However, as boar taint is linked to reproductive hormones, it is important to consider possible negative side effects such as delayed sexual maturity or changes in behaviour. We reported earlier that the melanocortin-4 receptor (MC4R) marker can be used to reduce boar taint levels in fat of boars. The objective of this study was to evaluate whether MC4R marker-assisted selection for lower boar taint prevalence affects plasma levels of boar taint compounds and testosterone; sexual maturity; behaviour; skin lesions; and lameness in boars and gilts. Using an intervention study with a 2×2 design, 264 boars and gilts differing on position 893 of the MC4R gene (AA v. GG) were compared. The MC4R polymorphism did not affect the plasma concentration of either androstenone or testosterone at different time points, whereas the concentration of skatole was significantly lower (P=0.003) and the concentration of indole tended to be lower (P=0.074) in GG compared with AA boars. A higher percentage of gilts of the GG genotype were in puberty at slaughter age compared with AA gilts (P<0.001). The age of the boars at sexual maturity (as indicated by the first positive preputial smear test) did not differ between AA and GG boars. In contrast, weight of GG boars at sexual maturity tended to be lower (P=0.065). During the period from 6 weeks of age to slaughter, boars and gilts of the GG genotype showed more playing behaviour (P=0.015) and less passive and feeding behaviour (P=0.003). They showed more skin lesions on their back and caudal area (P=0.022), and tended to show more skin lesions on their head and anterior area (P=0.093) compared with AA animals. In conclusion, the polymorphism in the MC4R gene can be used as a marker without negative effects on reproduction characteristics in boars and gilts. Genetic selection towards a lower prevalence of boar taint will lead to more active pigs with more skin lesions. Management strategies may therefore be necessary to reduce skin lesions in the selected animals.


Sustained oscillations in extended genetic oscillatory systems.
Various dynamic cellular behaviors have been successfully modeled in terms of elementary circuitries showing particular characteristics such as negative feedback loops for sustained oscillations. Given, however, the increasing evidences indicating that cellular components do not function in isolation but form a complex interwoven network, it is still unclear to what extent the conclusions drawn from the elementary circuit analogy hold for systems that are highly interacting with surrounding environments. In this article, we consider a specific example of genetic oscillator systems, the so-called repressilator, as a starting point toward a systematic investigation into the dynamic consequences of the extension through interlocking of elementary biological circuits. From in silico analyses with both continuous and Boolean dynamics approaches to the four-node extension of the repressilator, we found that 1), the capability of sustained oscillation depends on the topology of extended systems; and 2), the stability of oscillation under the extension also depends on the coupling topology. We then deduce two empirical rules favoring the sustained oscillations, termed the coherent coupling and the homogeneous regulation. These simple rules will help us prioritize candidate patterns of network wiring, guiding both the experimental investigations for further physiological verification and the synthetic designs for bioengineering.


Managing diabetes: what to do about cardiovascular disease.
Type 2 diabetes increases the risk of coronary heart disease (CHD) 2-4-fold, making CHD the predominant cause of death in patients with diabetes. Currently identified risk factors include, among others, hyperglycaemia, hypertension and dyslipidaemia. Since studies show that intensive glycaemic control alone will not overcome the excess CHD risk, reducing blood pressure by any means and lipid levels by using statins and fibrates is effective in reducing CHD and associated mortality in patients with type 2 diabetes. Other interventions include aspirin therapy and the use of angiotensin-converting enzyme (ACE) inhibitors.


Stereolithographic printing of ionically-crosslinked alginate hydrogels for degradable biomaterials and microfluidics.
3D printed biomaterials with spatial and temporal functionality could enable interfacial manipulation of fluid flows and motile cells. However, such dynamic biomaterials are challenging to implement since they must be responsive to multiple, biocompatible stimuli. Here, we show stereolithographic printing of hydrogels using noncovalent (ionic) crosslinking, which enables reversible patterning with controlled degradation. We demonstrate this approach using sodium alginate, photoacid generators and various combinations of divalent cation salts, which can be used to tune the hydrogel degradation kinetics, pattern fidelity, and mechanical properties. This approach is first utilized to template perfusable microfluidic channels within a second encapsulating hydrogel for T-junction and gradient devices. The presence and degradation of printed alginate microstructures were further verified to have minimal toxicity on epithelial cells. Degradable alginate barriers were used to direct collective cell migration from different initial geometries, revealing differences in front speed and leader cell formation. Overall, this demonstration of light-based 3D printing using non-covalent crosslinking may enable adaptive and stimuli-responsive biomaterials, which could be utilized for bio-inspired sensing, actuation, drug delivery, and tissue engineering.


Kr/Kc but not dN/dS correlates positively with body mass in birds, raising implications for inferring lineage-specific selection.
The ratio of the rates of non-synonymous and synonymous substitution (dN/dS) is commonly used to estimate selection in coding sequences. It is often suggested that, all else being equal, dN/dS should be lower in populations with large effective size (Ne) due to increased efficacy of purifying selection. As Ne is difficult to measure directly, life history traits such as body mass, which is typically negatively associated with population size, have commonly been used as proxies in empirical tests of this hypothesis. However, evidence of whether the expected positive correlation between body mass and dN/dS is consistently observed is conflicting. Employing whole genome sequence data from 48 avian species, we assess the relationship between rates of molecular evolution and life history in birds. We find a negative correlation between dN/dS and body mass, contrary to nearly neutral expectation. This raises the question whether the correlation might be a method artefact. We therefore in turn consider non-stationary base composition, divergence time and saturation as possible explanations, but find no clear patterns. However, in striking contrast to dN/dS, the ratio of radical to conservative amino acid substitutions (Kr/Kc) correlates positively with body mass. Our results in principle accord with the notion that non-synonymous substitutions causing radical amino acid changes are more efficiently removed by selection in large populations, consistent with nearly neutral theory. These findings have implications for the use of dN/dS and suggest that caution is warranted when drawing conclusions about lineage-specific modes of protein evolution using this metric.


Anabolic Steroids Reduce Muscle Degeneration Associated With Rotator Cuff Tendon Release in Sheep.
Chronic rotator cuff tendon tearing is associated with irreversible atrophy, fatty infiltration, and interstitial fibrosis of the corresponding muscle. Anabolic steroids can prevent musculotendinous degeneration during retraction and/or can reverse these changes after operative repair of the retracted musculotendinous unit in sheep. Controlled laboratory study. The infraspinatus tendon was released in 18 alpine sheep. All sheep underwent repair of the retracted musculotendinous unit after 16 weeks and were sacrificed after 22 weeks; 6 sheep served as controls, 6 sheep were treated with weekly intramuscular injection of 150 mg of nandrolone decanoate after infraspinatus (ISP) repair (group N6W), and 6 sheep were treated with 150 mg of nandrolone decanoate immediately after tendon release (group N22W). Muscle biopsy specimens were taken before tendon release and after 16 and 22 weeks. Muscle volume and fatty infiltration (on MRI), myotendinous retraction, and muscle density (on computed tomography) were measured immediately after ISP release, after 6 weeks, and before ISP repair and sacrifice. Muscle volume on MRI decreased to a mean (±SD) of 80% ± 8% of the original volume after 6 weeks, remained stable at 78% ± 11% after 16 weeks, and decreased further to 69% ± 9% after 22 weeks in the control group. These findings were no different from those in group N22W (72% ± 9% at 6 weeks, 73% ± 6% at 16 weeks, and 67% ± 5% at 22 weeks). Conversely, the N6W group did not show a decrease in ISP volume after repair; this finding differed significantly from the response in the control and N22W groups. Fatty infiltration (on MRI) continuously increased in the control group (12% ± 4% at tendon release, 17% ± 4% after 6 weeks, 50% ± 9% after 16 weeks, and 60% ± 8% after 22 weeks) and the N6W group. However, application of anabolic steroids at the time of tendon release (N22W group) significantly reduced fatty infiltration after 16 (16% ± 5%; P < .001) and 22 weeks (22% ± 7%; P < .001). In a sheep model of rotator cuff tendon tear, further muscle atrophy can be prevented with the application of anabolic steroids starting immediately after tendon repair. In addition, fatty muscle infiltration can largely be prevented if the steroids are applied immediately after tendon release. Study findings may lead to the development of treatment strategies to prevent or reduce muscle degeneration caused by rotator cuff tendon tearing.


The Middle Miocene ape Pierolapithecus catalaunicus exhibits extant great ape-like morphometric affinities on its patella: inferences on knee function and evolution.
The mosaic nature of the Miocene ape postcranium hinders the reconstruction of the positional behavior and locomotion of these taxa based on isolated elements only. The fossil great ape Pierolapithecus catalaunicus (IPS 21350 skeleton; 11.9 Ma) exhibits a relatively wide and shallow thorax with moderate hand length and phalangeal curvature, dorsally-oriented metacarpophalangeal joints, and loss of ulnocarpal articulation. This evidence reveals enhanced orthograde postures without modern ape-like below-branch suspensory adaptations. Therefore, it has been proposed that natural selection enhanced vertical climbing (and not suspension per se) in Pierolapithecus catalaunicus. Although limb long bones are not available for this species, its patella (IPS 21350.37) can potentially provide insights into its knee function and thus on the complexity of its total morphological pattern. Here we provide a detailed description and morphometric analyses of IPS 21350.37, which are based on four external dimensions intended to capture the overall patellar shape. Our results reveal that the patella of Pierolapithecus is similar to that of extant great apes: proximodistally short, mediolaterally broad and anteroposteriorly thin. Previous biomechanical studies of the anthropoid knee based on the same measurements proposed that the modern great ape patella reflects a mobile knee joint while the long, narrow and thick patella of platyrrhine and especially cercopithecoid monkeys would increase the quadriceps moment arm in knee extension during walking, galloping, climbing and leaping. The patella of Pierolapithecus differs not only from that of monkeys and hylobatids, but also from that of basal hominoids (e.g., Proconsul and Nacholapithecus), which display slightly thinner patellae than extant great apes (the previously-inferred plesiomorphic hominoid condition). If patellar shape in Pierolapithecus is related to modern great ape-like knee function, our results suggest that increased knee mobility might have originally evolved in relation to enhanced climbing capabilities in great apes (such as specialized vertical climbing).


Degree of musical expertise modulates higher order brain functioning.
Using functional magnetic resonance imaging, we show for the first time that levels of musical expertise stepwise modulate higher order brain functioning. This suggests that degree of training intensity drives such cerebral plasticity. Participants (non-musicians, amateurs, and expert musicians) listened to a comprehensive set of specifically composed string quartets with hierarchically manipulated endings. In particular, we implemented 2 irregularities at musical closure that differed in salience but were both within the tonality of the piece (in-key). Behavioral sensitivity scores (d') of both transgressions perfectly separated participants according to their level of musical expertise. By contrasting brain responses to harmonic transgressions against regular endings, functional brain imaging data showed compelling evidence for stepwise modulation of brain responses by both violation strength and expertise level in a fronto-temporal network hosting universal functions of working memory and attention. Additional independent testing evidenced an advantage in visual working memory for the professionals, which could be predicted by musical training intensity. The here introduced findings of brain plasticity demonstrate the progressive impact of musical training on cognitive brain functions that may manifest well beyond the field of music processing.


The effectiveness of an integrated BIM/UAV model in managing safety on construction sites.
Introduction. A variety of approaches exist to achieve better construction safety performance, but only a few consider a combination of building information modeling (BIM) and unmanned aerial vehicles (UAVs). Method. This article presents a four-dimensional (4D) BIM/UAV-enabled safety management model based on IDEF0 language. In the first step, potential hazards are identified with the help of safety specialists' experiences and BIM software used in the design of the structure. Then, a UAV monitors the location of the potential hazards. The third step involves the integration of the 4D BIM-based model and the information obtained from the UAV. Finally, the combined data are analyzed and interpreted, and site safety staff are notified about measures to be put in place to prevent accidents. Results. This model shows a strong relationship between the design and construction phases by using BIM in the design phase and UAVs in the construction phase. The proposed safety model was evaluated by construction safety specialists in a two-pronged approach. Conclusion. The number of fatal, non-fatal and property damage-causing accidents may be significantly lower when the proposed system was used. Practical application. This model allows safety specialists to identify hazards and develop suitable mitigation strategies.


Two-photon lensless endoscope.
We report a first demonstration of two-photon endoscopic imaging with a lensless endoscope. The endoscope probe is a double-clad bundle of single-mode fibers; point excitation and scanning is achieved by coherent combining of femtosecond light pulses propagating in the single-mode fibers; and back-scattered two-photon signal is collected through the multi-mode inner cladding. We demonstrate the two-photon endoscope on a test sample of rhodamine 6G crystals.


Multicenter experience in translumbar type II endoleak treatment in the hybrid room with needle trajectory planning and fusion guidance.
The objective of this study was to evaluate the efficacy of treating type II endoleaks (T2Ls) after aortic endovascular repair with image guidance translumbar puncture using intraoperative cone beam computed tomography with preprocedure computed tomography angiography fusion in hybrid operating rooms. Twenty-six consecutive T2L patients in three different institutions were treated between March 2015 and September 2017 by direct translumbar puncture of the abdominal aortic aneurysm (AAA) sac after previous endovascular aortic repair. All patients were treated at a single setting in a cardiovascular hybrid operating room with a workstation featuring needle trajectory planning and guidance software. Aneurysm sac size change from the index treatment, freedom from recurrent endoleak after treatment, demographics, risk factors, and procedure factors were analyzed with univariate analysis. All patients (N = 26; 19 male, 7 female; age range, 59-95 years; mean body mass index, 27.44 ± 3.06 kg/m2) underwent treatment for AAA sac expansion or symptoms. Four patients had failed to respond to previous catheter-directed T2L treatment. The most common risk factors included hypertension, hypercholesterolemia, coronary artery disease, tobacco use, and diabetes. Time to initial endoleak diagnosis ranged from 2 to 1914 days (average, 404 days). Aneurysm size after initial repair was 60.3 ± 7.5 mm; sac size had increased 10.1 ± 6.5 mm at the time of treatment. Onyx (Medtronic, Irvine, Calif) or glue (n-butyl cyanoacrylate) and coil embolization was used in 20 cases, and 6 patients were treated with coiling alone. There was no difference between the patients treated with coils alone and those treated with coils or glue (P > .05) in terms of freedom from failure. Total procedure time was 75.9 ± 40.7 minutes; contrast material volume, 19.9 ± 29 mL; fluoroscopy time, 13.74 ± 12.2 minutes; and radiation dose, 121.16 ± 167.7 mGy. After embolization, the mean sac diameter decreased by 2.2 mm to 67.5 ± 9.8 mm. Average follow-up period was 214 days. In 19 patients, the sac reduced in size between 0.2 and 19.1 mm per 100 days; in 2 patients, there was continued AAA expansion (3.4-4.3 mm per 100 days); there was no change in the sac size in 5 patients after the procedure. There were no AAA ruptures during the study period. Once T2L was treated, the recurrence rate was low at 11.5%. This initial multicenter evaluation of the effectiveness of fusion image-guided translumbar obliteration of T2L demonstrated that the technique was effective at all three study centers and showed excellent efficacy to reduce AAA sac size. This may become a more effective and efficient method of treating T2L compared with transarterial or transcaval embolization because of its high success rate and technical ease.


Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer.
This randomized, prospective, placebo-controlled clinical trial compares the influence on nutritional status and survival of hydrazine sulfate with placebo addition to cisplatin-containing combination chemotherapy in patients with unresectable non-small-cell lung cancer (NSCLC). The trial consisted of 65 patients with advanced, unresectable NSCLC who had had no prior chemotherapy, were at least partially ambulatory (Eastern Cooperative Oncology Group [ECOG] performance status [PS] level 0-2), and who had adequate hematologic, renal, and hepatic function. All patients received the same defined combination chemotherapy (cisplatin, vinblastine, and bleomycin) and the same defined dietary counseling with the addition of either three times daily oral hydrazine sulfate (60 mg) or placebo capsules. Hydrazine sulfate compared with placebo addition to chemotherapy resulted in significantly greater caloric intake and albumin maintenance (P less than .05). Considering all patients, survival was greater for the hydrazine sulfate compared with placebo group (median survival, 292 v 187 days), but the difference did not achieve statistical significance. In favorable PS patients (PS 0-1), survival was significantly prolonged (median survival, 328 days v 209 days; P less than .05) for hydrazine sulfate compared with placebo addition. In a multifactor analysis, PS, weight loss, and liver involvement were the final variables. Objective response frequency and toxicity were comparable on both arms. Hydrazine sulfate may favorably influence nutritional status and clinical outcome of patients with NSCLC. Further definitive studies of hydrazine sulfate addition to therapeutic regimens in NSCLC are warranted.


Pleiotropic effects of glitazones: a double edge sword?
Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor γ (PPARγ) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARγ-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARγ-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.


Regulation of FoxP3 regulatory T cells and Th17 cells by retinoids.
Vitamin A has both positive and negative regulatory functions in the immune system. While vitamin A is required for normal formation of immune cells and epithelial cell barriers, vitamin A deficiency can lead to increased inflammatory responses and tissue damage. The mechanism with which vitamin A and its metabolites such as retinoids negatively regulate inflammatory responses has not been clearly defined. Recently, it has been established that retinoids promote the generation of immune-suppressive FoxP3+ regulatory T cells while they suppress the T cell differentiation into inflammatory Th17 cells in the periphery such as intestine. These novel functions of retinoids provide a potentially important immune regulatory mechanism. In this review, we discuss the functions of retinoids in the development of the FoxP3+ cells and Th17 cells, the phenotype and functions of retinoid-induced FoxP3+ T cells, and the impact of retinoid-induced FoxP3+ T cells on the immune tolerance.


Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells.
Over the past two decades there have been significant advances in our understanding of both the anatomy and function of the melanopsin system. It has become clear that rather than acting as a simple irradiance detector the melanopsin system is in fact far more complicated. The range of behavioural systems known to be influenced by melanopsin activity is increasing with time, and it is now clear that melanopsin contributes not only to multiple non-image forming systems but also has a role in visual pathways. How melanopsin is capable of driving so many different behaviours is unclear, but recent evidence suggests that the answer may lie in the diversity of melanopsin light responses and the functional specialisation of photosensitive retinal ganglion cell (pRGC) subtypes. In this review, we shall overview the current understanding of the melanopsin system, and evaluate the evidence for the hypothesis that individual pRGC subtypes not only perform specific roles, but are functionally specialised to do so. We conclude that while, currently, the available data somewhat support this hypothesis, we currently lack the necessary detail to fully understand how the functional diversity of pRGC subtypes correlates with different behavioural responses, and ultimately why such complexity is required within the melanopsin system. What we are lacking is a cohesive understanding of how light responses differ between the pRGC subtypes (based not only on anatomical classification but also based on their site of innervation); how these diverse light responses are generated, and most importantly how these responses relate to the physiological functions they underpin.


Gastrointestinal Absorption and Renal Excretion of Fluoride After Ingestion of a High-Fluoride Dentifrice.
This study aimed to evaluate the gastrointestinal absorption and renal excretion of fluoride after the ingestion of high-fluoride dentifrice. Twelve volunteers participated in this in vivo, crossover, and blinded study. In three experimental phases, the volunteers were randomly assigned to one of three treatment groups, who ingested either the following: distilled and deionized water (control), conventional dentifrice (1100 μg/g), or high-fluoride dentifrice (5000 μg/g). Both dentifrices contained fluoride in the form of NaF/SiO2. To determine the rate of fluoride absorption, non-stimulated saliva was collected for up to 120 min after ingestion and the area under the curve of the salivary fluoride concentration was plotted as a function of time and the maximum concentration determined. All urine produced during the 24 h before and after ingestion was collected, and urinary excretion was calculated from the difference between the urinary fluoride concentrations in the two periods. A specific ion electrode coupled to an ion analyzer was used to measure fluoride concentrations. Statistical analysis was performed by ANOVA followed by Tukey's test with p set at 5%. All measured parameters were highest after the ingestion of the dentifrice with 5000 μg/g (p < 0.001), confirming that this has an increased level of bioavailable fluoride compared with the conventional dentifrice. The high-fluoride dentifrice increases the concentration of salivary fluoride, which may explain its greater anticaries effect. However, it poses a potential risk of causing dental fluorosis and so should not be used by children.


Integration of heterogeneous expression data sets extends the role of the retinol pathway in diabetes and insulin resistance.
Type 2 diabetes is a chronic metabolic disease that involves both environmental and genetic factors. To understand the genetics of type 2 diabetes and insulin resistance, the DIabetes Genome Anatomy Project (DGAP) was launched to profile gene expression in a variety of related animal models and human subjects. We asked whether these heterogeneous models can be integrated to provide consistent and robust biological insights into the biology of insulin resistance. We perform integrative analysis of the 16 DGAP data sets that span multiple tissues, conditions, array types, laboratories, species, genetic backgrounds and study designs. For each data set, we identify differentially expressed genes compared with control. Then, for the combined data, we rank genes according to the frequency with which they were found to be statistically significant across data sets. This analysis reveals RetSat as a widely shared component of mechanisms involved in insulin resistance and sensitivity and adds to the growing importance of the retinol pathway in diabetes, adipogenesis and insulin resistance. Top candidates obtained from our analysis have been confirmed in recent laboratory studies.


The most recent advances in pathophysiology and management of tumour necrosis factor receptor-associated periodic syndrome (TRAPS): personal experience and literature review.
Tumour necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterised by recurrent episodes of long-lasting fever and inflammation in different regions of the body, as musculo-skeletal system, skin, gastrointestinal tube, serosal membranes and eye. Inflammatory attacks usually start in the pediatric age with initial corticosteroid-responsiveness. Most reported cases of TRAPS involve patients of European ancestry and diagnosis can be formulated by the combination of genetic analysis and a compatible phenotype. Its prognosis is strictly dependent on the appearance of amyloidosis, secondary to uncontrolled relapsing inflammation. Thanks to a better understanding of its pathogenesis, the disease is now managed with anti-interleukin (IL)-1 antagonists, rather than corticosteroids or tumour necrosis factor (TNF) inhibitors. The aim of this review is to describe the current understanding and advances of TRAPS genetic basis, pathogenesis and management options by integrating the most recent data in the medical literature.


Evolution and Global Transmission of a Multidrug-Resistant, Community-Associated Methicillin-Resistant Staphylococcus aureus Lineage from the Indian Subcontinent.
The evolution and global transmission of antimicrobial resistance have been well documented for Gram-negative bacteria and health care-associated epidemic pathogens, often emerging from regions with heavy antimicrobial use. However, the degree to which similar processes occur with Gram-positive bacteria in the community setting is less well understood. In this study, we traced the recent origins and global spread of a multidrug-resistant, community-associated Staphylococcus aureus lineage from the Indian subcontinent, the Bengal Bay clone (ST772). We generated whole-genome sequence data of 340 isolates from 14 countries, including the first isolates from Bangladesh and India, to reconstruct the evolutionary history and genomic epidemiology of the lineage. Our data show that the clone emerged on the Indian subcontinent in the early 1960s and disseminated rapidly in the 1990s. Short-term outbreaks in community and health care settings occurred following intercontinental transmission, typically associated with travel and family contacts on the subcontinent, but ongoing endemic transmission was uncommon. Acquisition of a multidrug resistance integrated plasmid was instrumental in the emergence of a single dominant and globally disseminated clade in the early 1990s. Phenotypic data on biofilm, growth, and toxicity point to antimicrobial resistance as the driving force in the evolution of ST772. The Bengal Bay clone therefore combines the multidrug resistance of traditional health care-associated clones with the epidemiological transmission of community-associated methicillin-resistant S. aureus (MRSA). Our study demonstrates the importance of whole-genome sequencing for tracking the evolution of emerging and resistant pathogens. It provides a critical framework for ongoing surveillance of the clone on the Indian subcontinent and elsewhere.IMPORTANCE The Bengal Bay clone (ST772) is a community-associated and multidrug-resistant Staphylococcus aureus lineage first isolated from Bangladesh and India in 2004. In this study, we showed that the Bengal Bay clone emerged from a virulent progenitor circulating on the Indian subcontinent. Its subsequent global transmission was associated with travel or family contact in the region. ST772 progressively acquired specific resistance elements at limited cost to its fitness and continues to be exported globally, resulting in small-scale community and health care outbreaks. The Bengal Bay clone therefore combines the virulence potential and epidemiology of community-associated clones with the multidrug resistance of health care-associated S. aureus lineages. This study demonstrates the importance of whole-genome sequencing for the surveillance of highly antibiotic-resistant pathogens, which may emerge in the community setting of regions with poor antibiotic stewardship and rapidly spread into hospitals and communities across the world.


Endothelin B receptors contribute to retinal ganglion cell loss in a rat model of glaucoma.
Glaucoma is an optic neuropathy, commonly associated with elevated intraocular pressure (IOP) characterized by optic nerve degeneration, cupping of the optic disc, and loss of retinal ganglion cells which could lead to loss of vision. Endothelin-1 (ET-1) is a 21-amino acid vasoactive peptide that plays a key role in the pathogenesis of glaucoma; however, the receptors mediating these effects have not been defined. In the current study, endothelin B (ET(B)) receptor expression was assessed in vivo, in the Morrison's ocular hypertension model of glaucoma in rats. Elevation of IOP in Brown Norway rats produced increased expression of ET(B) receptors in the retina, mainly in retinal ganglion cells (RGCs), nerve fiber layer (NFL), and also in the inner plexiform layer (IPL) and inner nuclear layer (INL). To determine the role of ET(B) receptors in neurodegeneration, Wistar-Kyoto wild type (WT) and ET(B) receptor-deficient (KO) rats were subjected to retrograde labeling with Fluoro-Gold (FG), following which IOP was elevated in one eye while the contralateral eye served as control. IOP elevation for 4 weeks in WT rats caused an appreciable loss of RGCs, which was significantly attenuated in KO rats. In addition, degenerative changes in the optic nerve were greatly reduced in KO rats compared to those in WT rats. Taken together, elevated intraocular pressure mediated increase in ET(B) receptor expression and its activation may contribute to a decrease in RGC survival as seen in glaucoma. These findings raise the possibility of using endothelin receptor antagonists as neuroprotective agents for the treatment of glaucoma.


Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous motor neuron disease for which no effective treatment is available, despite decades of research into SOD1-mutant familial ALS (FALS). The majority of ALS patients have no familial history, making the modeling of sporadic ALS (SALS) essential to the development of ALS therapeutics. However, as mutations underlying ALS pathogenesis have not yet been identified, it remains difficult to establish useful models of SALS. Using induced pluripotent stem cell (iPSC) technology to generate stem and differentiated cells retaining the patients' full genetic information, we have established a large number of in vitro cellular models of SALS. These models showed phenotypic differences in their pattern of neuronal degeneration, types of abnormal protein aggregates, cell death mechanisms, and onset and progression of these phenotypes in vitro among cases. We therefore developed a system for case clustering capable of subdividing these heterogeneous SALS models by their in vitro characteristics. We further evaluated multiple-phenotype rescue of these subclassified SALS models using agents selected from non-SOD1 FALS models, and identified ropinirole as a potential therapeutic candidate. Integration of the datasets acquired in this study permitted the visualization of molecular pathologies shared across a wide range of SALS models.


PGC-1α mediates differentiation of mesenchymal stem cells to brown adipose cells.
Mesenchymal stem cells (MSCs) are a multipotent cell type that can differentiate into non-hematopoietic cells, such as adipocytes. Adipocyte tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals. White adipose tissue is the primary site for triglyceride storage, while brown adipose tissue is specialized in energy expenditure. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) controls several aspects of mitochondrial biogenesis. In this study, we hypothesized that PGC-1α plays a role in brown fat differentiation of MSCs. Immortalized human MSCs were infected with adenovirus carrying PGC-1α cDNA to create PGC-1α-expressing MSCs. The genetic profiling of PGC-1α-expressing MSCs shows the significant increase of genes related to mitochondrial functions and lipid metabolism compared to that of MSCs. When expressed in MSCs, PGC-1α activates robust mitochondrial biogenesis and respiration. The increase of oxygen consumption and reactive oxygen species represents a cellular readout of increased activity of the respiratory chain. The expression of thermogenic markers, such as cytochrome C and complex II, was significantly increased in MSCs with treatment of adenovirus expressing PGC-1α. Moreover, PGC-1α markedly inhibited the osteogenesis of MSCs under osteogenic induction. During adipogenesis, PGC-1α-expressing MSCs showed a significant increase in brown fat markers and a decrease in white fat markers. Notably, PGC-1α knockdown inhibited adipocyte differentiation of MSCs. In summary, our data reveal an important role of PGC-1α in promoting brown fat differentiation of MSCs, and provide a new therapeutic approach for the treatment of obesity.


Can magnetic resonance imaging of the hand and wrist differentiate between rheumatoid arthritis and psoriatic arthritis in the early stages of the disease?
To investigate whether rheumatoid arthritis (RA) and psoriatic arthritis (PsA) can be differentiated in the early stages of the disease (duration of symptoms ≤1 year) on the basis of magnetic resonance imaging (MRI) features of the hand and wrist. Twenty early RA and 17 early PsA patients with symptomatic involvement of the wrist and hand joints and inconclusive radiographic studies were examined prospectively with contrast-enhanced MRI. Images were evaluated in accordance with the Outcome Measures in Rheumatology Clinical Trials recommendations. Certain MRI features, such as the presence of enthesitis or extensive diaphyseal bone marrow edema, were observed exclusively in PsA (P = 0.0001). These distinctive findings were present in nearly 71% (12/17) of PsA patients. Diffuse and, in some cases, pronounced soft-tissue edema spreading to the subcutis was also seen more frequently in patients with PsA (P = 0.002). There were no significant differences in the frequency of synovitis, bone erosions, subchondral bone edema, or tenosynovitis between the 2 groups. However, in RA extensor tendons were involved more often than the flexor tendons, whereas in PsA the opposite was observed (P = 0.014). With respect to the discriminatory power of the different MRI findings examined, only the presence of enthesitis or diaphyseal bone edema and, to a lesser extent, the pattern of hand tendon involvement and the presence of soft-tissue edema accurately differentiated PsA from RA (all these features achieved accuracies greater than 0.70). We observed significant differences in the MRI findings of the hand and wrist that can help to distinguish between RA and PsA in the early stages of disease. This imaging method could help to assist in the differential diagnostic process in selected patients in whom diagnosis cannot be unequivocally established after conventional clinical, biochemical, and radiographic examinations.


Anterior segment optical coherence tomography parameters in phacomorphic angle closure and mature cataracts.
To describe anterior segment optical coherence tomography (AS-OCT) parameters in phacomorphic angle closure eyes, mature cataract eyes, and their fellow eyes, and identify those parameters that could be used to differentiate phacomorphic angle closure eyes from those with mature cataract and no phacomorphic angle closure. In this cross-sectional study, a total of 33 phacomorphic angle closure subjects and 34 control patients with unilateral mature cataracts were enrolled. All patients underwent AS-OCT imaging and A-scan biometry of both eyes. Anterior chamber depth (ACD), anterior chamber area (ACA), iris thickness, iris curvature, lens vault (LV), and angle parameters, including angle opening distance (AOD750) and trabecular-iris space area (TISA750), were measured in qualified images using customized software and compared among eyes with phacomorphic angle closure, mature cataract eyes, and their fellow eyes. There was no significant difference in axial length among the four groups. Phacomorphic angle closure had the smallest angle (AOD750, TISA750) and anterior chamber parameters (ACD, ACA, anterior chamber width) and the greatest LV among the groups. This pattern was similar when comparing fellow eyes of mature cataract patients and fellow eyes of phacomorphic angle closure. Anterior chamber area less than 18.62 mm(2), ACD less than 2.60 mm, LV greater than 532.0 μm, and AOD750 less than 0.218 mm had the highest odds ratios (ORs) for distinguishing fellow eyes of phacomorphic angle closure versus fellow eyes of mature cataracts, with OR values of 9.90, 8.31, 7.91, and 7.91, respectively. Logistic regression showed that ACA less than 18.62 was the major parameter associated with fellow eyes of phacomorphic angle closure (OR = 10.96, P < 0.001). Anterior chamber depth, ACA, AOD750, and LV are powerful indicators in differentiating phacomorphic angle closure eyes from those with mature cataract and their fellow eyes.


Stabilization of the sacroiliac joint.
Lower back pain and pain involving the area of the posterior iliac spine are extremely common. Degeneration of the sacroiliac joint (SIJ) is one potential cause for lower back pain and pain radiating into the groin or buttocks. Degenerative changes to the lumbar spine and sacroiliac joints are common. A recent study evaluating SIJ abnormalities in a primary low back pain population demonstrated 31.7% of patients demonstrated SI joint abnormalities. (4) As is the case for the evaluation and management of isolated lower back pain, the evaluation, management, and role for surgical intervention in SIJ pain is very controversial. Many patients have degenerative changes of the disc, facet joints, and SIJs. A recent systematic review performed to determine the diagnostic accuracy of tests available to clinicians to identify the disc, facet joint, or SIJ as the source of low back pain concluded that tests do exist that change the probability of the disc or SIJ (but not the facet joint) as the source of low back pain. (3) It was also concluded that the usefulness of these tests in clinical practice, particularly for guiding treatment selection, remains unclear. (3) Although there is general agreement that SIJ pathological changes are a potential cause of pain, there is far less agreement about the optimal management of these conditions. A variety of conditions can cause SIJ dysfunction including degenerative and inflammatory arthritis, trauma, prior lumbosacral fusion, hip arthritis, limb length inequality, infections, and neoplasia. (8) There is increasing evidence that image intensifier-guided single periarticular injection can correctly localize pain to the SIJ but the optimal management strategy remains controversial. Recent publications have compared surgical versus injection treatments and fusion versus denervation procedures. (1 , 8) A systematic review found improvement regardless of the treatment, with most studies reporting over 40% improvement in pain as measured by VAS or NRS scores. (8) It cautioned that one of the studies reported 17.6% of patients experiencing mild/no pain compared with 82.4% experiencing marked/severe pain at 39 months after SIJ fusion procedures. (6 , 8) This systematic review also noted that despite improvements in reported pain, less than half of patients who had work status reported as returning to work. (8) Because of the functional and socioeconomic consequences of chronic lower back pain, numerous surgical treatments to improve this condition have been attempted by spinal surgeons through the years. Arthrodesis of the SIJ is a surgical procedure with a long history dating to the beginnings of spinal surgery. (7) Poor results, high complication rates and the need for additional surgical procedures have generally diminished the enthusiasm for this procedure until recently. (6) A variety of "minimally invasive" procedures have been recently introduced that have rekindled enthusiasm for the surgical management of SIJ pathology. The technique demonstrated in the "Stabilization of the SIJ with SI-Bone" is one of these new techniques. There has been a recent publication detailing the very short term clinical outcomes with this technique that reported encouraging results. (5) In this series of 50 patients, quality of life questionnaires were available for 49 patients preoperatively, 41 patients at 3 months, 40 at 6 months and only 27 at 12 months, complicating the ability to accurately assess true outcomes. Although the focus of this video by Geisler is on the surgical technique, there should have been more information provided on the expected surgical outcomes and potential complications of SIJ fusion. (2) The video only gives minimal information on how to appropriately select patients with potential SIJ pathology for surgical intervention. There are insufficient recommendations on the clinical and radiographic follow-up needed for this procedure. A concern with this implant is whether the porous plasma spray coating on the implant actually results in bone growth across the SIJ or only serves as a stabilizer. If true fusion does not result, deterioration in the clinical result could occur over time. This video nicely demonstrates the surgical technique of stabilization of the SIJ with SI-Bone product. There are numerous unanswered questions regarding patient selection for SIJ fusion or stabilization. There are an increasing number of surgical techniques for treating SIJ pathology and it is not clear which method may provide the best outcomes. Without prospective trials with nonconflicted surgeons and standardized selection criteria, the true role for SIJ fusion procedures in the management of chronic lower back pain will remain murky. The consequences of the unsupported enthusiasm for the surgical management of discogenic back pain still negatively impacts the public perception of spinal surgeons. Much more high quality information is needed regarding the surgical management of SIJ pathology before widespread use of this technique should be adopted.


Ethanol Impairs NRF2/Antioxidant and Growth Signaling in the Intact Placenta In Vivo and in Human Trophoblasts.
NRF2 is a redox-sensitive transcription factor that depending on the duration or magnitude of the stress, either translocates to the nucleus (beneficial) or is degraded in the cytosol (harmful). However, the role of NRF2-based mechanism(s) under ethanol (E)-induced developmental toxicity in the placental context remains unknown. Here, we used a rat prenatal model of maternal alcohol stress consisting of intermittent ethanol vapor (IEV) daily from GD11 to GD20 with a 6 h ON/18 h OFF in a vapor chamber and in vitro placental model consisting of HTR-8 trophoblasts exposed to 86 mM of E for either 24 h or 48 h. The role of NRF2 was evaluated through the NRF2-transactivation reporter assay, qRT-PCR, and Western blotting for NRF2 and cell growth-promoting protein, and cell proliferation assay. In utero and in vitro E decreased the nuclear NRF2 content and diminished its transactivation ability along with dysregulation of the proliferation indices, PCNA, CYCLIN-D1, and p21. This was associated with a ~50% reduction in cell proliferation in vitro in trophoblasts. Interestingly, this was found to be partially rescued by ectopic Nrf2 overexpression. These results indicate that ethanol-induced dysregulation of NRF2 coordinately regulates PCNA/CYCLIN-D1/p21 involving growth network, at least partially to set a stage for placental perturbations.


Approach to the new oral anticoagulants in family practice: part 1: comparing the options.
To compare key features of the new oral anticoagulants (NOACs)-dabigatran, rivaroxaban, and apixaban-and to address questions that arise when comparing the NOACs. PubMed was searched for recent (January 2008 to week 32 of 2013) clinical studies relating to NOAC use for stroke prevention in atrial fibrillation (AF) and for the treatment of acute venous thromboembolism (VTE). All NOACs are at least as effective as warfarin for stroke prevention in patients with nonvalvular AF, and are at least as safe in terms of bleeding risk according to 3 large trials. Meta-analyses of these trials have shown that, compared with warfarin therapy, NOACs reduced total mortality, cardiovascular mortality, and intracranial bleeding, and there was a trend toward less overall bleeding. Practical advantages of NOACs over warfarin include fixed once- or twice-daily oral dosing without the need for coagulation monitoring, and few known or defined drug or food interactions. Potential drawbacks of NOACs include a risk of bleeding that might be increased in patients older than 75 years, increased major gastrointestinal bleeding with high-dose dabigatran, increased dyspepsia with dabigatran, the lack of a routine laboratory test to reliably measure anticoagulant effect, and the lack of an antidote for reversal. No direct comparisons of NOACs have been made in randomized controlled trials, and the choice of NOAC is influenced by individual patient characteristics, including risk of stroke or VTE, risk of bleeding, and comorbidity (eg, renal dysfunction). The NOACs represent important alternatives in the management of patients with AF and VTE, especially for patients who have difficulty accessing regular coagulation monitoring. The companion to this article addresses common "what if" questions that arise in the long-term clinical follow-up and management of patients receiving NOACs.


Effects of ACE I/D polymorphism on prostate cancer risk, tumor grade and metastatis.
The aim was to substantiate the putative significance of angiotensin-converting enzyme (ACE) (insertion/deletion) I/D polymorphism on prostate cancer risk, BTPSA-A TPSA (before treatment-after treatment prostate-specific antigen) levels and tumor development. 48 prostate cancer patients and 51 healthy volunteers were included. The ACE I/D genotypes were determined by PCR (polymerase chain reaction) and RFLP (restriction fragment length polymorphism) techniques. The DD genotype may have detrimental and the II genotype may have protective effect on prostate cancer (p = 0.03). The highest before treatment PSA (BTPSA) values were found in the patient group having the DD genotype (p = 0.017). PSA-AT levels were higher in homozygous mutant DD than homozygous II and the decrease in PSA-AT level was found to be statistically significant in each genotype (p = 0.000). Patients with the D allele showed a higher prevalence of late stage prostate carcinoma when compared to the patients with II genotype (p = 0.022) and the detrimental effects of the D allele, both in lymph node metastases and distant metastasis were observed. The risk of prostate cancer development, the PSA level and tumor metastasis may be associated with genetic variation in the ACE I/D genotypes which may be used as an important biomarker for further studies.


Normobaric and hyperbaric oxygen therapy for migraine and cluster headache.
Migraine and cluster headaches are severe and disabling. Migraine affects up to 18% of women, while cluster headaches are much less common (0.2% of the population). A number of acute and prophylactic therapies are available. Hyperbaric oxygen therapy (HBOT) is the therapeutic administration of 100% oxygen at environmental pressures greater than one atmosphere, while normobaric oxygen therapy (NBOT) is oxygen administered at one atmosphere. To assess the safety and effectiveness of HBOT and NBOT for treating and preventing migraine and cluster headaches. We searched the following in May 2008: CENTRAL, MEDLINE, EMBASE, CINAHL, DORCTIHM and reference lists from relevant articles. Relevant journals were hand searched and researchers contacted. Randomised trials comparing HBOT or NBOT with one another, other active therapies, placebo (sham) interventions or no treatment in patients with migraine or cluster headache. Three reviewers independently evaluated study quality and extracted data. Nine small trials involving 201 participants were included. Five trials compared HBOT versus sham therapy for acute migraine, two compared HBOT to sham therapy for cluster headache and two evaluated NBOT for cluster headache. Pooling of data from three trials suggested that HBOT was effective in relieving migraine headaches compared to sham therapy (relative risk (RR) 5.97, 95% confidence interval (CI) 1.46 to 24.38, P = 0.01). There was no evidence that HBOT could prevent migraine episodes, reduce the incidence of nausea and vomiting or reduce the requirement for rescue medication. There was a trend to better outcome in a single trial evaluating HBOT for the termination of cluster headache (RR 11.38, 95% CI 0.77 to 167.85, P = 0.08), but this trial had low power.NBOT was effective in terminating cluster headache compared to sham in a single small study (RR 7.88, 95% CI 1.13 to 54.66, P = 0.04), but not superior to ergotamine administration in another small trial (RR 1.17, 95% CI 0.94 to 1.46, P = 0.16). Seventy-six per cent of patients responded to NBOT in these two trials. No serious adverse effects of HBOT or NBOT were reported. There was some evidence that HBOT was effective for the termination of acute migraine in an unselected population, and weak evidence that NBOT was similarly effective in cluster headache. Given the cost and poor availability of HBOT, more research should be done on patients unresponsive to standard therapy. NBOT is cheap, safe and easy to apply, so will probably continue to be used despite the limited evidence in this review.