[Various aspects of improving the results of the treatment of intestinal fistulas].
An observation of 184 patients treated for different intestinal fistulas allowed to conclude that the developed and introduced into clinic methods of hermetization of incomplete fistulas with the help of a porolon sponge and treatment of complete fistulas by special devices of original construction facilitates valuable preparation of patients to surgery and improves results of the surgical treatment of the disease.


Human gamete fusion can bypass beta1 integrin requirement.
Since alpha6beta1 integrin has been shown to function as a sperm adhesion receptor in the mouse, we investigated the potential role of beta1 integrin in the gamete fusion process in humans. The expression of beta1 integrin was morphologically analysed by indirect immunofluorescence and confocal microscopy. A homogeneous and intense staining was detected at the plasma membrane, and in some subcortical vesicles of germinal vesicle stage oocytes (GV). Beta1 almost disappeared from oolemma and cytoplasm of metaphase I (MI) oocytes, but was re-expressed as asymmetrical patches at the plasma membrane of metaphase II stage oocytes (MII). A functional fusion assay based on Hoechst or calcein-AM dye transfer from one gamete to the other showed that maturing oocytes were able to fuse with an increasing number of spermatozoa (11-22 from GV to MII respectively), and that fused spermatozoa co-localized with beta1 integrin patches. Human gamete fusion was only partially inhibited either by RGD-containing peptide (GRGDTP), or by blocking anti-human beta1 integrin monoclonal antibody (DE9), with a maximum of 50% inhibition. Despite the combined addition of GRGDTP and blocking mouse anti-human beta1 integrin DE9 in the assay, a complete inhibition of fusion could not be achieved. A mouse polyclonal antibody raised against human oocyte membranes was more potent in inhibiting the fusion. Since beta1 integrin expression at the plasma membrane was not correlated to oocyte fusibility, and since it was only partially inhibited by DE9 and/or RGD peptide, we suggest that human gamete fusion can bypass the beta1 requirement. Beta1 integrin certainly participates in human gamete fusion by acting in co-operation with multiple integrin/disintegrin couples or another cofactor, not yet identified.


Autonomic influence on pregnancy outcome in IDDM.
We evaluated the autonomic influence on pregnancy outcome with prospective study of 100 consecutive pregnancies in women with insulin-dependent diabetes mellitus (IDDM). Tests of cardiovascular autonomic nervous function were performed at the beginning of each pregnancy, and two groups were formed. Group 1 was comprised of 23 pregnancies with autonomic dysfunction, and group 2 was comprised of 77 pregnancies with no abnormalities in cardiovascular tests. Elective abortion was later induced for medical reasons in two cases in group 1, and these women were excluded from the study. The groups were comparable with respect to age, duration of diabetes, and presence of nephropathy. Both groups also achieved comparable glycemic control during pregnancy. There were no significant differences between groups 1 and 2 in any specific pregnancy complication (spontaneous abortions, 5 vs. 3%; perinatal mortality, 10 vs. 1%; congenital malformations, 10 vs. 4%; respiratory distress syndrome, 5 vs. 8%; preeclampsia, 20 vs. 10%; maternal ketoacidosis, 4 vs. 0%; and maternal hypoglycemic accidents, 10 vs. 4%, respectively), but the frequency of pregnancies with at least one of the above complications was greater in group 1 (52 vs. 23%, P = 0.01). Stepwise logistic regression analysis showed the association between autonomic dysfunction and pregnancy outcome to be independent of high initial glycosylated hemoglobin levels, long duration of diabetes, and nephropathy. Maternal autonomic dysfunction seems to be associated with an increased frequency of overall pregnancy complications but does not significantly interfere with the achievement of tight metabolic control during pregnancy.


[Recurrent bronchopneumonia and Morgagni hernia].
The Morgagni hernia occurs behind the sternum and is a rare diaphragmatic defect although the late diagnosis may result in important clinic symptoms and poor prognosis. The authors present a case report of a child with 11 months and respiratory symptoms with chronic pulmonary infections and several hospitalizations without etiologic diagnosis. The conclusion was for the early Morgagni hernia diagnosis and the prevention of chronic complications.


[Fertility preservation in adolescent cancer patients].
Recent advances in cancer therapy have improved the survival rate of infant and adolescent facing cancers. The objective of treatment is not only to cure cancer but also to limit its secondary consequences. Impaired fertility is an important sequel of numerous treatments against cancer. Therefore, efforts to maintain fertility must be a major consideration in the treatment plan. This review focuses on various options for preserving fertility in adolescents. In female patients, ovarian transposition out of the radiation field may considerably reduce the radiation received by the ovaries. The benefits of GnRH analogue are not yet clear and apoptosis inhibiting agents are unavailable. Embryo freezing is the most reliable method to preserve fertility. This method is time-intensive, requires a partner, and ovarian stimulation may not always be compatible with the need of starting treatment against cancer immediately. Oocyte cryopreservation is an experimental technique that can be used in post-pubertal patients irrespective of their marital status. The cryopreservation of mature oocytes has similar constrains as embryo freezing ; in addition the technique is not as well-established and the pregnancy rates obtained are much lower than those achieved with embryos. Freezing of immature oocytes followed by in vitro maturation in spite of its theoretical advantages is inefficient in current practice. Ovarian tissue cryopreservation offers great hope because it has the potential to preserve a large number of primordial follicles without any ovarian stimulation and preliminary trials have shown some success. For male adolescents cancer patients semen cryopreservation is a successful alternative that should be offered systematically when cancer therapies that may impair gonadal function are indicated. For prepubertal males there is presently no standardized technique for preserving fertility ; however, the development of testicular germ-cell harvest needs to be considered.


Population-averaged atlas of the macroscale human structural connectome and its network topology.
A comprehensive map of the structural connectome in the human brain has been a coveted resource for understanding macroscopic brain networks. Here we report an expert-vetted, population-averaged atlas of the structural connectome derived from diffusion MRI data (N = 842). This was achieved by creating a high-resolution template of diffusion patterns averaged across individual subjects and using tractography to generate 550,000 trajectories of representative white matter fascicles annotated by 80 anatomical labels. The trajectories were subsequently clustered and labeled by a team of experienced neuroanatomists in order to conform to prior neuroanatomical knowledge. A multi-level network topology was then described using whole-brain connectograms, with subdivisions of the association pathways showing small-worldness in intra-hemisphere connections, projection pathways showing hub structures at thalamus, putamen, and brainstem, and commissural pathways showing bridges connecting cerebral hemispheres to provide global efficiency. This atlas of the structural connectome provides representative organization of human brain white matter, complementary to traditional histologically-derived and voxel-based white matter atlases, allowing for better modeling and simulation of brain connectivity for future connectome studies.


Claudin-4 Expression is Associated With Survival in Ovarian Cancer But Not With Chemotherapy Response.
The tight junction protein claudin-4 has been reported to be overexpressed in advanced ovarian cancer. We investigated the prognostic significance of claudin-4 overexpression and whether claudin-4 expression could predict platinum response in primary ovarian carcinoma (OC). Claudin-4 expression was evaluated by immunohistochemistry in a tissue microarray of 140 OCs. Multivariable Cox-regression models were used to assess the effect of claudin-4 overexpression on progression-free survival and overall survival (OS). Kaplan-Meier survival analyses and the logrank test were performed comparing claudin-4 high and low groups. The association between claudin-4 expression and platinum resistance was assessed using risk ratios and the Pearson χ test. A dataset of >1500 epithelial ovarian cancers was used to study the association between CLDN4 mRNA and survival. Of 140 evaluable cases, 71 (51%) displayed high claudin-4 expression. Claudin-4 overexpression predicted shorter 5-yr progression-free survival and OS in univariable analyses [hazard ratio (HR)=1.6 (1.1-2.5), P=0.020 and HR=1.6 (1.0-2.4), P=0.041, respectively]. Hazard of relapse was similar [HR=1.5 (1.0-2.4)] after adjustment for age, stage, type, and BRCA1/2 status in a multivariable analysis, but the evidence was slightly weaker (P=0.076). Validation in an external cohort confirmed the association between high expression of CLDN4 and poor 10-yr OS [HR=1.3 (1.1-1.5), P<0.001]. However, no confident association between claudin-4 and platinum sensitivity was found in our cohort [risk ratio=1.2 (0.7-2.0), P=0.3]. These findings suggest that high expression of claudin-4 may have a prognostic value in OC. The role of claudin-4 in the development of platinum resistance remains unclear.


Graph convolutional networks for epigenetic state prediction using both sequence and 3D genome data.
Predictive models of DNA chromatin profile (i.e. epigenetic state), such as transcription factor binding, are essential for understanding regulatory processes and developing gene therapies. It is known that the 3D genome, or spatial structure of DNA, is highly influential in the chromatin profile. Deep neural networks have achieved state of the art performance on chromatin profile prediction by using short windows of DNA sequences independently. These methods, however, ignore the long-range dependencies when predicting the chromatin profiles because modeling the 3D genome is challenging. In this work, we introduce ChromeGCN, a graph convolutional network for chromatin profile prediction by fusing both local sequence and long-range 3D genome information. By incorporating the 3D genome, we relax the independent and identically distributed assumption of local windows for a better representation of DNA. ChromeGCN explicitly incorporates known long-range interactions into the modeling, allowing us to identify and interpret those important long-range dependencies in influencing chromatin profiles. We show experimentally that by fusing sequential and 3D genome data using ChromeGCN, we get a significant improvement over the state-of-the-art deep learning methods as indicated by three metrics. Importantly, we show that ChromeGCN is particularly useful for identifying epigenetic effects in those DNA windows that have a high degree of interactions with other DNA windows. https://github.com/QData/ChromeGCN. Supplementary data are available at Bioinformatics online.


Impact of hydroxyurea on clinical events in the BABY HUG trial.
The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov).


Antibody capture from corn endosperm extracts by packed bed and expanded bed adsorption.
Topical treatments of chronic infections with monoclonal antibodies will require large quantities of antibodies. Because plants have been proven capable of producing multisubunit antibodies and provide for large-scale production, they are likely hosts to enable such applications. Recovery costs must also be low because of the relatively high dosages required. Hence, we have examined the purification of a human secretory antibody from corn endosperm extracts by processing alternatives of packed bed and expanded bed adsorption (EBA). Because of the limited availability of the transgenic corn host, the system was modeled by adding the antibody to extracts of nontransgenic corn endosperm. Complete clarification of a crude extract followed by packed bed adsorption provided antibody product in 75% yield with 2.3-fold purification (with antibody accounting for 24% of total protein). The small size of the packed bed, cation-exchange resin SP-Sepharose FF and the absence of a dense core (present in EBA resins) allowed for more favorable breakthrough performance compared to EBA resins evaluated. Four adsorbents specifically designed for EBA operation, with different physical properties (size and density), chemical properties (ligand), and base matrices were tested: SP-steel core resin (UpFront Chromatography), Streamline SP and Streamline DEAE (Amersham Biosciences), and CM Hyper-Z (BioSepra/Ciphergen Biosystems). Of these, the small hyperdiffuse-style resin from BioSepra had the most favorable adsorption characteristics. However, it could not be utilized with crude feeds due to severe interactions with corn endosperm solids that led to bed collapse. UpFront SP-steel core resin, because of its relatively smaller size and hence lower internal mass transfer resistance, was superior to the Streamline resins and operated successfully with application of a crude corn extract filtered to remove all solids of >44 microm. However, the EBA performance with this adsorbent provided a yield of only 61% and purification factor of 2.1 (with antibody being 22% of total protein). Process simulation showed that capital costs were roughly equal between packed and expanded bed processes, but the EBA design required four times greater operating expenditures. The use of corn endosperm as the starting tissue proved advantageous as the amount of contaminating protein was reduced approximately 80 times compared to corn germ and approximately 600 times compared to canola. Finally, three different inlet designs (mesh, glass beads, and mechanical mixing) were evaluated on the basis of their ability to produce efficient flow distribution as measured by residence time distribution analysis. All three provided adequate distribution (axial mixing was not as limiting as mass transfer to the adsorption process), while resins with different physical properties did not influence flow distribution efficiency values (i.e., Peclet number and HETP) when operated with the same inlet design.


A New Kinetic, Automated Assay to Determine the Ferroxidase Activity of Ceruloplasmin.
A new kinetic and automated assay was developed to determine ceruloplasmin ferroxidase activity. Ferrous ions are turned into ferric ions via catalytic activity of the ferroxidase enzyme. Acetohydroxamic acid, a chromogen, forms a colored complex with ferric ions. This reaction was measured kinetically. Significant and strong correlations were obtained between the new acetohydroxamic method and the p-phenylenediamine oxidase (r = 0.988, p <0.001), o-dianisidine oxidase (r = 0.981, p <0.001), norfloxacine oxidase (r = 0.989, p <0.001) and nephelometric methods (r = 0.861, p <0.001). This reliable, applicable, user-friendly, and low-priced method can be performed fully automatically or with manual spectrophotometry, and can be used to measure the ferroxidase activity of ceruloplasmin.


[Correction of early cognitive disorders in school-age children operated under total intravenous anaesthesia].
The aim of the study was to assess the possibility and effectiveness of hopaten acid use for early postoperative cognitive dysfunction correction in children of school age. In compliance with inclusion and exclusion criteria, totally 40 children of school age (7-16 years old, ASA status I-II) with surgical pathology: (varicocele, cryptorchidism, inguinal hernia) were included A comperative assessment of neuropsychic status during pre - and postoperative are period in children, operated under propofol-fentanyl total intravenous anesthesia (TIVA) was conducted All patients were randomized to the control (without cepebroprotection 1st group, 20 children) and experimental (using cepebroprotection with hopaten acid within 1 month after the operation, 2nd group, 20 children) groups. Dimension of the study: Harvard standard monitoring, respiratory gas composition, neuropsychic tests (Bourdon test, "10 words test", etc.). For full compatibility groups (age, ASA status and anthropometric data, equal operation duration and the equipotential drug dosage adjustment is revealed, that in group of propofol-fentanyl TIVA in the early postoperative period in school age children postoperative cognitive dysfunction (POCD) is developing, which in case of absence of the corresponding correction is maintained after 1 month after operation (at least) in 80% of cases. In the application of hopaten acid cerebroprotection (40 mg/kg per day) severity of POCD reliably is reduced or compensated by the time of discharge from the hospital (3-7-th day when non-traumatic interventions), and 1 month after the operation in 30% of patients experienced improvement of cognitive functions, which proves the effectiveness of hopaten acid for POCD treatment. In case of propofol-fentanyl TIVA anesthesia in children of school age is indicated preventive prescription of multimodal cerebroprotectors without age limitations (for example hopaten acid (40 mg/kg per day) for POCD treatment.


Symbiont modifies host life-history traits that affect gene flow.
The evolution of herbivore-host plant specialization requires low levels of gene flow between populations on alternate plant species. Accordingly, selection for host plant specialization is most effective when genotypes have minimal exposure to, and few mating opportunities with individuals from, alternate habitats. Maternally transmitted bacterial symbionts are common in insect herbivores and can influence host fecundity under a variety of conditions. Symbiont-mediated effects on host life-history strategies, however, are largely unknown. Here, we show that the facultative bacterial symbiont Candidatus Regiella insecticola strikingly alters both dispersal and mating in the pea aphid, Acyrthosiphon pisum. Pea aphids containing Regiella produced only half the number of winged offspring in response to crowding and, for two out of three aphid lineages, altered the timing of sexual reproduction in response to conditions mimicking seasonal changes, than did aphids lacking Regiella. These symbiont-associated changes in dispersal and mating are likely to have played a key role in the initiation of genetic differentiation and in the evolution of pea aphid-host plant specialization. As symbionts are widespread in insects, symbiont-induced life history changes may have promoted specialization, and potentially speciation, in many organisms.


Association of T-Cell Receptor Repertoire Use With Response to Combined Trastuzumab-Lapatinib Treatment of HER2-Positive Breast Cancer: Secondary Analysis of the NeoALTTO Randomized Clinical Trial.
Dual anti-HER2 blockade increased the rate of pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) trial, and high immune gene expression was associated with pCR in all treatment arms. So far, no marker has been identified that is specifically associated with the benefit from dual HER2 blockade. To examine if use of the T-cell β chain variable genes adds to the potential association of immune gene signatures with response to dual HER2 blockade. In the NeoALTTO trial, HER2-positive patients recruited between January 5, 2008, and May 27, 2010, were treated with paclitaxel plus either lapatinib or trastuzumab or both as neoadjuvant therapy. In this study, RNA sequencing data from baseline tumor specimens of 245 patients in the NeoALTTO trial were analyzed and reads were aligned to TRBV gene reference sequences using a previously published Basic Local Alignment Search Tool T-cell receptor mapping pipeline. Total TRBV gene use, Shannon entropy, and gene richness were calculated for each tumor, and nonnegative matrix factorization was used to define TRBV co-use metagenes (TMGs). The association between TRBV metrics, tumor genomic metrics, and response was assessed with multivariable logistic regression. Statistical analysis was performed from January 23 to December 2, 2017. The association between TRBV use metrics and pCR. Among the 245 women with available data (mean [SD] age, 49 [11] years), total TRBV use correlated positively with a gene expression signature for immune activity (Spearman ρ = 0.93; P < .001). High use of TRBV11-3 and TMG2, characterized by high use of TRBV4.3, TRBV6.3, and TRBV7.2, was associated with a higher rate of pCR to dual HER2-targeted therapy (TRBV11-3 interaction: odds ratio, 2.63 [95% CI, 1.22-6.47]; P = .02; TMG2 interaction: odds ratio, 3.39 [95% CI, 1.57-8.27]; P = .004). Immune-rich cancers with high TMG2 levels (n = 92) had significantly better response to dual HER2-targeted treatment compared with the single therapy arms (rate of pCR, 68% [95% CI, 52%-83%] vs 21% [95% CI, 10%-31%]; P < .001), whereas those with low TMG2 levels did not benefit from dual therapy. High TMG2 levels were also associated with a higher rate of pCR to the combined therapy in immune-poor tumors (n = 30; pCR, 50% [95% CI, 22%-78%] vs 6% [95% CI, 0%-16%]; P = .009). Use patterns of TRBV genes potentially provide information about the association with response to dual HER2 blockade beyond immune gene signatures. High use of TRBV11.3 or TRBV4.3, TRBV6.3, and TRBV7.2 identifies patients who have a better response to dual HER2 targeted therapy. ClinicalTrials.gov Identifier: NCT00553358.


Developing Clinical Risk Prediction Models for Worsening Heart Failure Events and Death by Left Ventricular Ejection Fraction.
Background There is a need to develop electronic health record-based predictive models for worsening heart failure (WHF) events across clinical settings and across the spectrum of left ventricular ejection fraction (LVEF). Methods and Results We studied adults with heart failure (HF) from 2011 to 2019 within an integrated health care delivery system. WHF encounters were ascertained using natural language processing and structured data. We conducted boosted decision tree ensemble models to predict 1-year hospitalizations, emergency department visits/observation stays, and outpatient encounters for WHF and all-cause death within each LVEF category: HF with reduced ejection fraction (EF) (LVEF <40%), HF with mildly reduced EF (LVEF 40%-49%), and HF with preserved EF (LVEF ≥50%). Model discrimination was evaluated using area under the curve and calibration using mean squared error. We identified 338 426 adults with HF: 61 045 (18.0%) had HF with reduced EF, 49 618 (14.7%) had HF with mildly reduced EF, and 227 763 (67.3%) had HF with preserved EF. The 1-year risks of any WHF event and death were, respectively, 22.3% and 13.0% for HF with reduced EF, 17.0% and 10.1% for HF with mildly reduced EF, and 16.3% and 10.3% for HF with preserved EF. The WHF model displayed an area under the curve of 0.76 and mean squared error of 0.13, whereas the model for death displayed an area under the curve of 0.83 and mean squared error of 0.076. Performance and predictors were similar across WHF encounter types and LVEF categories. Conclusions We developed risk prediction models for 1-year WHF events and death across the LVEF spectrum using structured and unstructured electronic health record data and observed no substantial differences in model performance or predictors except for death, despite differences in underlying HF cause.


Chromosomal aberrations and aneuploidy in oral potentially malignant lesions: distinctive features for tongue.
The mucosae of the oral cavity are different at the histological level but appear all equally exposed to common genotoxic agents. As a result of this exposure, changes in the mucosal epithelia may develop giving rise to Oral Potentially Malignant Lesions (OPMLs), which with time may in turn progress to Oral Squamous Cell Carcinomas (OSCCs). Therefore, much effort should be devoted to identify features able to predict the likeliness of progression associated with an OPML. Such features may be helpful in assisting the clinician to establish both appropriate therapies and follow-up schedules. Here, we report a pilot study that compared the occurrence of DNA aneuploidy and chromosomal copy number aberrations (CNAs) in the OPMLs from different oral anatomical subsites. Samples from histologically diagnosed OPMLs were processed for high resolution DNA flow cytometry (hr DNA-FCM) in order to determine the relative DNA content expressed by the DNA index (DI). Additionally, array-Comparative Genomic Hybridization (a-CGH) analysis was performed on DNA obtained from diploid nuclei suspensions directly. When aneuploid nuclei were detected, these were physically separated from diploid nuclei on the base of their DI values by means of a DNA-FCM-Sorter in order to improve the a-CGH analysis. Tongue OPMLs were more frequently associated with DNA aneuploidy and CNAs than OPMLs arising from all the other mucosal subsites. We suggest that the follow-up and the management of the patients with tongue OPMLs should receive a distinctive special attention. Clearly, this hypothesis should be validated in a prospective clinical study.


An association study of the signal transducer and activator of transcription 6 gene with periodic psychosis.
Recent molecular and genetic investigations have suggested that the current nosology for major psychiatric disorders, based on the "two-entities-principal" is not accurate with respect to clinical observations; patient groups that do not fit to the current operative diagnostic boundaries are readily identified. We aimed to perform an investigation of the signal transducer and activator of transcription 6 (STAT6) gene (located on 12q13), which has an important role in the apoptotic cascade, with patients suffering from periodic psychosis. Genetic association study has been employed for the current work. Investigated six tag-SNPs were chosen from Hapmap database. Among six tag-SNPs, one marker (rs10783813), located in the STAT6 gene, showed modest association (p<0.05), although no marker or haplotype block showed association after Bonferroni's correction. Future studies will reveal the etiological role of STAT6, and of other genes of the apoptotic cascade, in major psychiatric disorders.


The effect of smoking on obesity: Evidence from a randomized trial.
This paper aims to identify the causal effect of smoking on body mass index (BMI) using data from the Lung Health Study, a randomized trial of smoking cessation treatments. Since nicotine is a metabolic stimulant and appetite suppressant, quitting or reducing smoking could lead to weight gain. Using randomized treatment assignment to instrument for smoking, we estimate that quitting smoking leads to an average long-run weight gain of 1.8-1.9 BMI units, or 11-12 pounds at the average height. Semi-parametric models provide evidence of a diminishing marginal effect of smoking on BMI, while subsample regressions show that the impact is largest for younger individuals, those with no college degree, and those in the lowest quartile of baseline BMI.


Sub-Foveal Choroidal Thickness In Healthy Nepalese Population.
This study was conducted primarily to measure sub-foveal choroidal thickness (SFCT) in healthy Nepalese population. Also, the correlation of SFCT with age, inter-eye difference of SFCT, inter-gender variation and inter-ethnic variation of SFCT was observed. A cross-sectional, hospital based study in 162 participants (324 eyes) of six ethnic groups (Brahmin, Chhetri, Newar, Tamang, Muslim, and Gurung) was conducted. The mean age of participants was 37.37 ± 15.02 years. All the participants underwent SFCT measurement using Spectral Domain Optical Coherence Tomography (Spectralis HRA+OCT, Heidelberg Engineering, Germany) with the help of in-built caliber. Age, inter-gender, inter-eye and inter-ethnic differences in SFCT were recorded and analyzed. The average SFCT of right eye (RE) and left eye (LE) was 307.98 ± 74.64 µm and 312.63 ± 76.90 µm respectively, with average SFCT of 310.31 ± 75.70 µm for both eyes. SFCT of only the RE was selected for further calculation due to insignificant inter-eye difference of SFCT (p = 0.128). There was a significant negative correlation of SFCT with age (r = -0.705, p = 0.01). A regression analysis showed thinning of SFCT by 3.50 ± 0.278 µm per year. In another context, SFCT of male and female was 305.49 ± 79.72 µm and 313.55 ± 70.76 µm respectively. However, there was no significant inter-gender difference (p = 0.51). Similarly, inter-ethnic variations of SFCT was also statistically non -significant (p = 0.74). SFCT was negatively correlated with the age of participants, implying a decrease in choroidal thickness (CT) with an increase in age. Age can be considered as an important factor in the measurement of SFCT. Gender and ethnic groups did not have a significant role in the measurement and comparison of SFCT.


Postpartum depression and infant feeding practices in a low income urban settlement in Nairobi-Kenya.
Postpartum depression can compromise caregiving activities, including infant feeding practices, resulting in child malnutrition. The purpose of this study was to examine the effects of postpartum depression on infant feeding practices and malnutrition among women in an urban low income settlement in Nairobi-Kenya. We conducted a cross-sectional study based in Kariobangi North Health Centre in Nairobi County. The study sample included 200 mother-infant pairs visiting the Maternal and Child Health clinics for infant immunization at 6-14 weeks postpartum. We assessed postpartum depression using the Edinburgh Postpartum Depression Scale. Infant feeding practices were assessed based on World Health Organization infant and young child feeding guidelines. Nutritional status (weight for age) was ascertained using infants' growth monitoring card (percentiles and z-score). We conducted logistic regression analyses to determine the relative odds of non-exclusive breast feeding and infant underweight among mothers with postpartum depression. The prevalence of PPD was 13.0% (95% CI 8.3-17.7%). Taking into account differences in socioeconomic status of depressed and non-depressed mothers, non-depressed mothers had a 6.14 (95% CI 2.45-13.36) times higher odds of practicing exclusive breastfeeding than mothers who were depressed. Mothers with PPD had a 4.40 (95% CI 1.91-11.93) time higher odds of having an underweight infant than mothers without depression. This study contributes towards filling the knowledge gap regarding the adverse effects of postpartum depression on infant health in sub-Saharan Africa. We recommend more research on PPD using longitudinal designs to establish temporal ordering of these important public health problems and development of community-based interventions to address post-partum depression.


Full-dimensional analytical potential energy surface describing the gas-phase Cl + C2H6 reaction and kinetics study of rate constants and kinetic isotope effects.
Within the Born-Oppenheimer approximation a full-dimensional analytical potential energy surface, PES-2017, was developed for the gas-phase hydrogen abstraction reaction between the chlorine atom and ethane, which is a nine body system. This surface presents a valence-bond/molecular mechanics functional form dependent on 60 parameters and is fitted to high-level ab initio calculations. This reaction presents little exothermicity, -2.30 kcal mol-1, with a low height barrier, 2.44 kcal mol-1, and intermediate complexes in the entrance and exit channels. We found that the energetic description was strongly dependent on the ab initio level used and it presented a very flat topology in the entrance channel, which represents a theoretical challenge in the fitting process. In general, PES-2017 reproduces the ab initio information used as input, which is merely a test of self-consistency. As a first test of the quality of the PES-2017, a theoretical kinetics study was performed in the temperature range 200-1400 K using two approaches, i.e. the variational transition-state theory and quasi-classical trajectory calculations, with spin-orbit effects. The rate constants show reasonable agreement with experiments in the whole temperature range, with the largest differences at the lowest temperatures, and this behaviour agrees with previous theoretical studies, thus indicating the inherent difficulties in the theoretical simulation of the kinetics of the title reaction. Different sources of error were analysed, such as the limitations of the PES and theoretical methods, recrossing effects, and the tunnelling effect, which is negligible in this reaction, and the manner in which the spin-orbit effects were included in this non-relativistic study. We found that the variation of spin-orbit coupling along the reaction path, and the influence of the reactivity of the excited Cl(2P1/2) state, have relative importance, but do not explain the whole discrepancy. Finally, the activation energy and the kinetics isotope effects reproduce the experimental information.


[Clinical analysis of 182 cases with facial nerve injury].
To investigate the recovery patterns and the influencing factors of facial nerve injury in maxillofacial surgery by retrospective analysis of a serial clinical data. A total of 182 patients with facial nerve injury were reviewed. The cause of injury, the initial facial nerve function after trauma, the treatment, the initial recovery time of facial nerve function and the total recovery time were recorded. The factors that influenced the outcome of facial nerve function were analyzed. The facial nerve branch injury was common in maxillofacial injury. The injury pattern, location, age and reconstruction time all had effects on the function recovery of the facial nerve. Within 6 months, 45 of 49 (92%) anatomic injured patients completely recovered in 6 months; 53 of 59 patients (90%) began to recover when nerve had been ruptured. In 12 months, 33 of 35 patients (94%) after nerve anastomosed and 5 of 8 patients (62%) with nerve transplantation got complete recovery. Preserving the facial nerve during surgery is very important. If the facial nerve is injured, reconstructive surgery should be applied as soon as possible.


Prehospital opioid dose and myocardial injury in patients with ST elevation myocardial infarction.
To characterise the relationship between opioid dose and myocardial infarct size in patients with ST elevation myocardial infarction (STEMI). Patients given opioid treatment by emergency medical services with confirmed STEMI were included in this secondary, retrospective cohort analysis of the Air versus Oxygen in Myocardial Infarction (AVOID) study. Patients with cardiogenic shock were excluded. The primary endpoint was comparison of cardiac biomarkers as a measure of infarct size based on opioid dose (low ≤8.75 mg, intermediate 8.76-15 mg and high >15 mg of intravenous morphine equivalent dose). 422 patients were included in the analysis. There was a significantly higher proportion of patients with Thrombolysis in Myocardial Infarction (TIMI) 0 or 1 flow pre-percutaneous coronary intervention (PCI) (94% vs 81%, p=0.005) and greater use of thrombus aspiration catheters (59% vs 30%, p<0.001) in the high compared with low-dose opioid group. After adjustment for potential confounders, every 1 mg of intravenous morphine equivalent dose was associated with a 1.4% (95% CI 0.2%, 2.7%, p=0.028) increase in peak creatine kinase; however, this was no longer significant after adjustment for TIMI flow pre-PCI. Our study suggests no benefit of higher opioid dose and a dose-dependent signal between opioid dose and increased myocardial infarct size. Prospective randomised controlled trials are required to establish causality given that this may also be explained by patients with a greater ischaemic burden requiring higher opioid doses due to more severe pain. Future research also needs to focus on strategies to mitigate the opioid-P2Y12 inhibitor interaction and non-opioid analgesia to treat ischaemic chest pain.


Visible red and infrared light alters gene expression in human marrow stromal fibroblast cells.
This study tested whether or not gene expression in human marrow stromal fibroblast (MSF) cells depends on light wavelength and energy density. Primary cultures of isolated human bone marrow stem cells (hBMSC) were exposed to visible red (VR, 633 nm) and infrared (IR, 830 nm) radiation wavelengths from a light emitting diode (LED) over a range of energy densities (0.5, 1.0, 1.5, and 2.0 Joules/cm2) Cultured cells were assayed for cell proliferation, osteogenic potential, adipogenesis, mRNA and protein content. mRNA was analyzed by microarray and compared among different wavelengths and energy densities. Mesenchymal and epithelial cell responses were compared to determine whether responses were cell type specific. Protein array analysis was used to further analyze key pathways identified by microarrays. Different wavelengths and energy densities produced unique sets of genes identified by microarray analysis. Pathway analysis pointed to TGF-beta 1 in the visible red and Akt 1 in the infrared wavelengths as key pathways to study. TGF-beta protein arrays suggested switching from canonical to non-canonical TGF-beta pathways with increases to longer IR wavelengths. Microarrays suggest RANKL and MMP 10 followed IR energy density dose-response curves. Epithelial and mesenchymal cells respond differently to stimulation by light suggesting cell type-specific response is possible. These studies demonstrate differential gene expression with different wavelengths, energy densities and cell types. These differences in gene expression have the potential to be exploited for therapeutic purposes and can help explain contradictory results in the literature when wavelengths, energy densities and cell types differ.


Higher-Order Conditioning With Simultaneous and Backward Conditioned Stimulus: Implications for Models of Pavlovian Conditioning.
In a new environment, humans and animals can detect and learn that cues predict meaningful outcomes, and use this information to adapt their responses. This process is termed Pavlovian conditioning. Pavlovian conditioning is also observed for stimuli that predict outcome-associated cues; a second type of conditioning is termed higher-order Pavlovian conditioning. In this review, we will focus on higher-order conditioning studies with simultaneous and backward conditioned stimuli. We will examine how the results from these experiments pose a challenge to models of Pavlovian conditioning like the Temporal Difference (TD) models, in which learning is mainly driven by reward prediction errors. Contrasting with this view, the results suggest that humans and animals can form complex representations of the (temporal) structure of the task, and use this information to guide behavior, which seems consistent with model-based reinforcement learning. Future investigations involving these procedures could result in important new insights on the mechanisms that underlie Pavlovian conditioning.


Aging reduces liver resiliency by dysregulating Hedgehog signaling.
Older age is a major risk factor for damage to many tissues, including liver. Aging undermines resiliency and impairs liver regeneration. The mechanisms whereby aging reduces resiliency are poorly understood. Hedgehog is a signaling pathway with critical mitogenic and morphogenic functions during development. Recent studies indicate that Hedgehog regulates metabolic homeostasis in adult liver. The present study evaluates the hypothesis that Hedgehog signaling becomes dysregulated in hepatocytes during aging, resulting in decreased resiliency and therefore, impaired regeneration and enhanced vulnerability to damage. Partial hepatectomy (PH) was performed on young and old wild-type mice and Smoothened (Smo)-floxed mice treated with viral vectors to conditionally delete Smo and disrupt Hedgehog signaling specifically in hepatocytes. Changes in signaling were correlated with changes in regenerative responses and compared among groups. Old livers had fewer hepatocytes proliferating after PH. RNA sequencing identified Hedgehog as a top downregulated pathway in old hepatocytes before and after the regenerative challenge. Deleting Smo in young hepatocytes before PH prevented Hedgehog pathway activation after PH and inhibited regeneration. Gene Ontogeny analysis demonstrated that both old and Smo-deleted young hepatocytes had activation of pathways involved in innate immune responses and suppression of several signaling pathways that control liver growth and metabolism. Hedgehog inhibition promoted telomere shortening and mitochondrial dysfunction in hepatocytes, consequences of aging that promote inflammation and impair tissue growth and metabolic homeostasis. Hedgehog signaling is dysregulated in old hepatocytes. This accelerates aging, resulting in decreased resiliency and therefore, impaired liver regeneration and enhanced vulnerability to damage.


Perivascular Cuffing as the Sole Imaging Finding of Pancreatic Cancer.
Perivascular cuffing as the sole imaging manifestation of pancreatic ductal adenocarcinoma (PDAC) is an under-recognized entity. To present this rare finding and differentiate it from retroperitoneal fibrosis and vasculitis. Patients with abdominal vasculature cuffing were retrospectively collected (January 2011 to September 2017). We evaluated vessels involved, wall thickness, length of involvement and extra-vascular manifestations. Fourteen patients with perivascular cuffing were retrieved: three with celiac and superior mesenteric artery (SMA) perivascular cuffing as the only manifestation of surgically proven PDAC, seven with abdominal vasculitis, and four with retroperitoneal fibrosis. PDAC patients exhibited perivascular cuffing of either or both celiac and SMA (3/3). Vasculitis patients showed aortitis with or without iliac or SMA cuffing (3/7) or cuffing of either or both celiac and SMA (4/7). Retroperitoneal fibrosis involved the aorta (4/4), common iliac (4/4), and renal arteries (2/4). Hydronephrosis was present in 3/4 of retroperitoneal fibrosis patients. PDAC and vasculitis demonstrated reduced wall thickness in comparison to retroperitoneal fibrosis (PDAC: 1.0 ± 0.2 cm, vasculitis: 1.2 ± 0.5 cm, retroperitoneal fibrosis: 2.4 ± 0.4 cm; P = 0.002). There was no significant difference in length of vascular involvement (PDAC: 6.3 ± 2.1 cm, vasculitis: 7.1 ± 2.6 cm, retroperitoneal fibrosis: 8.7 ± 0.5 cm). Celiac and SMA perivascular cuffing can be the sole finding in PDAC and may be indistinguishable from vasculitis. This entity may differ from retroperitoneal fibrosis as it spares the aorta, iliac, and renal arteries and demonstrates thinner walls and no hydronephrosis.


Examining the interrelatedness of patient and spousal stress in heart failure: conceptual model and pilot data.
Recent research has highlighted the positive influence that spouses can have on patient outcomes. It is not clear whether patients and spouses influence each other's well-being reciprocally or whether spousal well-being affects the success of patients' disease management. Our goals were 2-fold: (a) to propose a conceptual framework to examine the reciprocity between patient and spouses' well-being, especially as it relates to disease management, and (b) to begin to assess the validity of this model using pilot data. Twenty-three veterans with heart failure (HF) and their spouses were recruited into a pilot cross-sectional observational study. Participants completed psychosocial surveys to assess depressive symptoms, caregiver burden, relationship satisfaction, and disease management. Descriptive analyses and bivariate correlations between these measures were calculated. Using standard cutoffs, analyses suggested clinically significant depressive symptoms in patients (Center for Epidemiological Studies-Depression score >16; mean, 21.8 [SD, 13]) and a high level of caregiver burden among spouses (Zarit Burden Interview score >15; mean, 22.4 [SD, 15.4]). Both patients and spouses reported high relationship satisfaction levels (Dyadic Adjustment Scale score >100; mean, 112.6 [SD, 26.5] and 115.9 [SD, 14.4], respectively). On average, patients reported poor disease management (Self-care of Heart Failure Index subscale <70 across all subscales: confidence = 53.3 [SD, 28.2]; maintenance = 59.7 [SD, 17.3]; management = 54.0 [SD, 19.4]). Patient depressive symptoms were positively correlated with spouse depressive symptoms (r = 0.53) and caregiver burden (r = 0.64; all P's < .05). Spouses' depressive symptoms were additionally correlated with lower levels of perceived social support among patients (r = -0.47), poor patient relationship satisfaction (r = -0.51), and worse patient confidence in HF management (r = -0.48). Greater caregiver burden was associated with more patient disease complaints (r = 0.49), poorer patients' relationship satisfaction (r = -0.72), and poorer patients' perceived social support (r = -0.73). These results provide preliminary support to the proposed conceptual model. Further research is necessary to determine which spousal factors appear to be most relevant to disease management. Disease management interventions may benefit from engaging spouses in a way that enhances their role without adding to their burden.


[Role of methods of cellular and molecular biology in pathology].
If the 1980s can be called "era of immunohistochemistry", the 1990s are passing under the sign of active introduction into pathology of molecular and cellular biology methods. Particularly widespread is the technology of obtaining transgenic mice with hyperexpression or knocking out of certain genes, polymerase chain reaction and in situ hybridization. The latter two methods are actively used both in experimental and clinical pathology. All the above methods not only provide additional information in parallel with routine morphological methods but not infrequently are of crucial importance in the diagnosis and prognosis.


A systematic review of the effect of nocturnal hemodialysis on blood pressure, left ventricular hypertrophy, anemia, mineral metabolism, and health-related quality of life.
Nocturnal hemodialysis is a novel form of dialysis where patients perform dialysis 6 nights per week while they sleep. Multiple publications report significant improvements in selected clinical outcomes, although the strength of these results is limited by shortcomings in study design. A systematic review of the current available literature was undertaken to examine the effect of nocturnal hemodialysis on key health outcomes. An inclusive search of medical databases was undertaken to identify all nocturnal hemodialysis studies. These results were manually reviewed for relevance to nocturnal hemodialysis and its impact on the following predefined health outcomes: blood pressure control, left ventricular hypertrophy, anemia, mineral metabolism, and health related quality of life. Case reports, short-term studies (<4 weeks), studies without comparator groups, and studies not reporting data in a quantitative fashion were excluded. The results of the remaining studies were reported in tabular format. Of the initial 270 studies identified, only 14 met inclusion/exclusion criteria. No studies examining the impact of nocturnal hemodialysis on mortality were identified. All studies reported improved blood pressure control after conversion to nocturnal hemodialysis. Data regarding the other health outcomes of interest revealed mixed results. Nocturnal hemodialysis is a potential alternative to conventional intermittent hemodialysis. Before significant resources are invested in initiating nocturnal hemodialysis programs, further data on mortality and cardiovascular morbidity, preferably from randomized clinical trials, are required.


Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study.
To determine whether the use of angiotensin converting enzyme inhibitors (ACEIs), compared with use of angiotensin receptor blockers, is associated with an increased risk of lung cancer. Population based cohort study. United Kingdom Clinical Practice Research Datalink. A cohort of 992 061 patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2015 was identified and followed until 31 December 2016. Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident lung cancer associated with the time varying use of ACEIs, compared with use of angiotensin receptor blockers, overall, by cumulative duration of use, and by time since initiation. The cohort was followed for a mean of 6.4 (SD 4.7) years, generating 7952 incident lung cancer events (crude incidence 1.3 (95% confidence interval 1.2 to 1.3) per 1000 person years). Overall, use of ACEIs was associated with an increased risk of lung cancer (incidence rate 1.6 v 1.2 per 1000 person years; hazard ratio 1.14, 95% confidence interval 1.01 to 1.29), compared with use of angiotensin receptor blockers. Hazard ratios gradually increased with longer durations of use, with an association evident after five years of use (hazard ratio 1.22, 1.06 to 1.40) and peaking after more than 10 years of use (1.31, 1.08 to 1.59). Similar findings were observed with time since initiation. In this population based cohort study, the use of ACEIs was associated with an increased risk of lung cancer. The association was particularly elevated among people using ACEIs for more than five years. Additional studies, with long term follow-up, are needed to investigate the effects of these drugs on incidence of lung cancer.


Nutritional proteins in milk and the protein requirement of normal infants.
All whey proteins in human milk are not absorbed and thus not nutritionally available. There is evidence that secretory immunoglobulin A (SIgA), lactoferrin, and lysozyme are resistant to proteolytic action, and the major part of these protective proteins is excreted in the infant's stool. An exclusively breast-fed infant would thus have a mean intake of 1.3 g of protein per kilogram of body weight per day during the first month and about 0.9 g/kg/d during the third month. Term infants fed with formulas containing 1.5 g of protein per deciliter show metabolic changes that indicate that the infants receive more protein than they require for growth; these changes are not seen in breast-fed infants or in infants receiving a whey-predominant formula containing only 1.1 g/dL of protein. A reevaluation of protein requirement and intake during infancy is suggested.


Cyst fluid from a murine model of polycystic kidney disease stimulates fluid secretion, cyclic adenosine monophosphate accumulation, and cell proliferation by Madin-Darby canine kidney cells in vitro.
Cyst fluids from subjects with autosomal dominant polycystic kidney disease (ADPKD) cause polarized monolayers of MDCK cells to secrete fluid toward the apical compartment in vitro. To determine the extent to which secretagogue accumulation may be a general feature of polycystic diseases, cyst fluid from mice with a slowly progressive form of hereditary PKD (DBA/2FG-pcy/pcy) was added to polarized MDCK monolayers. Basolateral application of cyst fluids (diluted with culture medium to 15% final concentration) from 13 different animals 16 to 35 weeks old increased the fluid secretion rate from a baseline of 0.023 +/- 0.003 to 0.111 +/- 0.017 microL/cm2/h (P < 0.005). There was a direct relation between the concentration of cyst fluid and the rate of net fluid secretion. The secretory activity of cyst fluid was not altered by pronase treatment or boiling. Cyst fluid (10%) added to the basolateral surfaces of polarized MDCK monolayers for 24 hours increased cell cyclic adenosine monophosphate (AMP) levels from a baseline of 6.3 +/- 0.2 to 17.3 +/- 0.3 pmoles/monolayer (n = 3, P < 0.05). The capacity of cyst fluid to increase cyclic AMP levels was not changed by pronase treatment or boiling. There was a direct relation between the level of cellular cyclic AMP and the rate of transepithelial fluid secretion caused by cyst fluid. Cyst fluid increased thymidine incorporation by Madin-Darby canine kidney (MDCK) cells to an extent equal to that caused by epidermal growth factor and caused MDCK cells to form cysts in collagen matricies.(ABSTRACT TRUNCATED AT 250 WORDS)


[Natural hybridization between two subspecies of the house mouse, Mus musculus domesticus and Mus musculus castaneus, near Lake Casitas, California].
The house mouse Mus musculus is a polytypic species, distributed worldwide, with three main subspecies: M. m. musculus in the North-East of Eurasia, M. m. castaneus in South-East Asia, and M. m. domesticus in Europe, the Near-East, and Africa. This last subspecies may also be found in Australia and the Americas, where it was brought by European colonization. Previous studies, however, have shown the presence of specific antiviral determinants of Asian origin in a mouse population at Lake Casitas, California. In this study, an analysis of the variability at 35 enzyme loci demonstrates the hybrid nature of this Californian population intermediate between M. m. castaneus and M. m. musculus. Restriction fragment length polymorphisms of two fragments of the mitochondrial DNA also confirm unambiguously the presence of two types of matrilines in comparable frequencies in our sample. Nevertheless, the study of a subspecies-specific Y chromosome microdeletion in the Zfy2 gene reveals only the M. m. domesticus haplotype at Lake Casitas, a phenomenon comparable with the one observed in other hybrid zones of the M. musculus complex. These findings testify once more that genetic exchanges between subspecies inside the broader M. musculus gene pool are still possible.


Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein.
Human interleukin-18 (hIL-18) is a cytokine that plays an important role in inflammation and host defense against microbes. Its activity is regulated in vivo by a naturally occurring antagonist, the human IL-18-binding protein (IL-18BP). Functional homologs of human IL-18BP are encoded by all orthopoxviruses, including variola virus, the causative agent of smallpox. They contribute to virulence by suppressing IL-18-mediated immune responses. Here, we describe the 2.0-A resolution crystal structure of an orthopoxvirus IL-18BP, ectromelia virus IL-18BP (ectvIL-18BP), in complex with hIL-18. The hIL-18 structure in the complex shows significant conformational change at the binding interface compared with the structure of ligand-free hIL-18, indicating that the binding is mediated by an induced-fit mechanism. EctvIL-18BP adopts a canonical Ig fold and interacts via one edge of its beta-sandwich with 3 cavities on the hIL-18 surface through extensive hydrophobic and hydrogen bonding interactions. Most of the ectvIL-18BP residues that participate in these interactions are conserved in both human and viral homologs, explaining their functional equivalence despite limited sequence homology. EctvIL-18BP blocks a putative receptor-binding site on IL-18, thus preventing IL-18 from engaging its receptor. Our structure provides insights into how IL-18BPs modulate hIL-18 activity. The revealed binding interface provides the basis for rational design of inhibitors against orthopoxvirus IL-18BP (for treating orthopoxvirus infection) or hIL-18 (for treating certain inflammatory and autoimmune diseases).


Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes.
Spatial and temporal resolution of intracellular signaling can be achieved by compartmentalizing transduction units. Myopodin is a dual-compartment, actin-bundling protein that shuttles between the nucleus and the Z-disc of myocytes in a differentiation- and stress-dependent fashion. Importin alpha binding and nuclear import of myopodin are regulated by serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. Here we show that in the heart myopodin forms a Z-disc signaling complex with alpha-actinin, calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), muscle-specific A-kinase anchoring protein, and myomegalin. Phosphorylation of myopodin by protein kinase A (PKA) or CaMKII mediates 14-3-3 binding and nuclear import in myoblasts. Dephosphorylation of myopodin by calcineurin abrogates 14-3-3beta binding. Activation of PKA or inhibition of calcineurin in adult cardiac myocytes releases myopodin from the Z-disc and induces its nuclear import. The identification of myopodin as a direct target of PKA, CaMKII, and calcineurin defines a novel intracellular signaling pathway whereby changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart.


[Activation of immune cells in sarcoidosis: immunopathogenic and clinical implications].
Sarcoidosis is a frequent, systemic, granulomatous disorder with predominant involvement of the hilar lymph nodes and the pulmonary parenchyma. By bronchoalveolar lavage an activation of alveolar immune cells has been observed yielding a detailed concept of the immunopathogenesis of the disease from which new, clinically applicable staging parameters are delineated.


Mechanisms of protein degradation in mantle muscle and proposed gill remodeling in starved Sepia officinalis.
Cephalopods have relatively high rates of protein synthesis compared to rates of protein degradation, along with minimal carbohydrate and lipid reserves. During food deprivation on board protein is catabolized as a metabolic fuel. The aim of the current study was to assess whether biochemical indices of protein synthesis and proteolytic mechanisms were altered in cuttlefish, Sepia officinalis, starved for 7 days. In mantle muscle, food deprivation is associated with a decrease in protein synthesis, as indicated by a decrease in the total RNA level and dephosphorylation of key signaling molecules, such as the eukaryote binding protein, 4E-BP1 (regulator of translation) and Akt. The ubiquitination-proteasome system (UPS) is activated as shown by an increase in the levels of proteasome β-subunit mRNA, polyubiquitinated protein, and polyubiquitin mRNA. As well, cathepsin activity levels are increased, suggesting increased proteolysis through the lysosomal pathway. Together, these mechanisms could supply amino acids as metabolic fuels. In gill, the situation is quite different. It appears that during the first stages of starvation, both protein synthesis and protein degradation are enhanced in gill. This is based upon increased phosphorylation of 4E-BP1 and enhanced levels of UPS indicators, especially 20S proteasome activity and polyubiquitin mRNA. It is proposed that an increased protein turnover is related to gill remodeling perhaps to retain essential hemolymph-borne compounds.


Multimodality imaging in Europe: a survey by the European Society of Radiology (ESR) and the European Association of Nuclear Medicine (EANM).
PURPOSE: Multimodality imaging represents an area of rapid growth with important professional implications for both radiologists and nuclear medicine physicians throughout Europe. As a preliminary step for future action aimed at improving the quality and accessibility of PET-SPECT/CT multimodality imaging practice in Europe, the European Society of Radiology (ESR) and the European Association of Nuclear Medicine (EANM) performed a survey among the individual memberships of both societies to obtain information on the status of multimodality imaging in their facilities and their future visions on training for combined modalities. METHODS: A questionnaire was forwarded to all individual members of ESR and EANM. The main subject matter of the questionnaire related to: (1) study performance, current procedures and current equipment, including its supervisory personnel at respondents' individual facilities, and (2) vision of future practice, performance and the potential for combined interdisciplinary viewing and training for future professionals. RESULTS: The reporting and the billing procedures of multimodality imaging studies are very heterogeneous in European countries. The majority of the members of both societies believe that the proportion of PET/CT conducted as a full diagnostic CT with contrast enhancement will increase over time. As expected, 18F-FDG is the most used PET tracer for clinical applications. The large majority of respondents were in favour of an interdisciplinary training programme, being developed on a European level together by ESR and EANM and the respective sections of the European Union of Medical Specialists. CONCLUSION: The results of this survey show that there is wide heterogeneity in the current practice of multimodality imaging in Europe. This situation may limit the full potential and integration of multimodality imaging within the clinical arena. There is a strong desire within both specialties for the development of interdisciplinary training to address some of these issues.


Long bone osteomyelitis. An overview.
Osteomyelitis has always been a difficult disease to classify, diagnose, and treat. Its etiology and course are not fully understood. A review of the traditional aspects of osteomyelitis is presented along with the discussion of a more recent classification system.


In vitro and in vivo effects of clove on pro-inflammatory cytokines production by macrophages.
Biological properties of clove have been reported, but little is known about its effect on the immune system. This work was aimed to investigate the effect in vivo of a water-soluble part of hydroalcoholic extract of clove on pro-inflammatory cytokines (IL-1beta and IL-6) production by macrophages of BALB/c mice. The action of the essential oil of clove on the production of these cytokines macrophages was also investigated in vitro. The chemical compositions of the extract and of the oil were also investigated. Treatment of mice with water extract of clove was found to inhibit macrophages to produce both IL-1beta and IL-6. The essential oil of clove also inhibited the production of these cytokines in vitro. Eugenol was found to be the major component of the clove extract and essential oil, and probably is the causative agent of cytokine inhibition. Taken together, these data suggest an anti-inflammatory action of this spice.


CD90/Thy-1, a Cancer-Associated Cell Surface Signaling Molecule.
CD90 is a membrane GPI-anchored protein with one Ig V-type superfamily domain that was initially described in mouse T cells. Besides the specific expression pattern and functions of CD90 that were described in normal tissues, i.e., neurons, fibroblasts and T cells, increasing evidences are currently highlighting the possible involvement of CD90 in cancer. This review first provides a brief overview on CD90 gene, mRNA and protein features and then describes the established links between CD90 and cancer. Finally, we report newly uncovered functional connections between CD90 and endoplasmic reticulum (ER) stress signaling and discuss their potential impact on cancer development.


Anti-smoking campaign in Multan, Pakistan.
Smoking is a serious public health concern, particularly among young people. This communication describes an anti-smoking campaign targeted at the students of Nishtar Medical College and Bahauddin Zakariya University in Multan. The aim was to promote sports and discourage smoking though community participation and mobilization. A mixed media strategy was adopted and information and education materials were developed. A seminar was held giving information on smoking, its hazards, quitting strategies and experiences. This was followed by a cricket match played between the students at which further brochures were distributed and slogans displayed. The activity was very successful and succeeded in mobilizing the community and putting over the anti-smoking message. Such events could be used to promote other issues related to lifestyle.


Hepatitis C virus infection in 'primary' Sjögren's syndrome: prevalence and clinical significance in a series of 90 patients.
To determine the prevalence and clinical significance of hepatitis C virus (HCV) infection in a large cohort of patients with "primary' Sjögren's syndrome (SS). 90 consecutive patients (83 female and seven male) were included, with a mean age of 62 years (range 31-80) who prospectively visited our unit. All patients fulfilled the European Community criteria for SS and underwent a complete history, physical examination, as well as biochemical and immunological evaluation for liver disease. Serum from all patients was tested for antibodies to HCV by third generation enzyme linked immunoassay and positivity was confirmed by polymerase chain reaction. Antibodies to HCV were present in 13 (14%) patients with 'primary' SS. When compared with patients without HCV infection, patients with HCV infection presented a higher prevalence of hepatic involvement, (100% v 8%, p < 0.05). Transcutaneous liver biopsy was performed in five patients with HCV infection, and specimens obtained showed in all cases a chronic active hepatitis with varying degrees of portal inflammation. HCV infection is frequent in patients with "primary' SS and liver involvement is presented in all these patients. The possible pathogenic role of HCV infection in these patients is still unclear.


Involvement of cell cycle and mitogen-activated pathways in induction of parathyroid hormone-related protein gene expression in rat aortic smooth muscle cells.
PTH-related protein (PTHrP) is induced in aortic vascular smooth muscle cells (VSMC) in association with mitogen-stimulated proliferation. In this study we examined the role of the cell cycle in the control of PTHrP gene expression. In asynchronously cycling cells grown in serum-containing medium, PTHrP-immunoreactive cells were enriched in G2+M, as revealed by fluorescence-activated cell sorting using a specific monoclonal antibody. PTHrP messenger RNA (mRNA) increased transiently in cells after release from chemically induced cell cycle blockade; levels increased by 10-fold at 2 h, coincident with expression of histone-4 mRNA and enrichment of VSMC in the early S phase. However, PTHrP mRNA levels then declined abruptly while the proportion of cells in the S phase and histone-4 mRNA levels remained constant for 8 h. When cell cycle-arrested cells were exposed to fresh serum-containing medium, angiotensin-II, or phorbol ester without removing the cell cycle blocking agents, PTHrP mRNA levels were induced over a time course identical to that observed in cells released from the blockade. This suggests that progression through the cycle per se is not necessary for mitogen-induced PTHrP mRNA expression, and that conventional chemical synchronization is not adequate to examine the cell cycle dependency of PTHrP mRNA abundance in VSMC. By contrast, in two different PTHrP-producing carcinoma cell lines, PTHrP and its mRNA were not altered as a function of cell cycle, demonstrating that different mechanisms control PTHrP expression in these cancer cells. In conclusion, constitutive immunoreactive levels of PTHrP are low in normally cycling VSMC (but not cancer cells) and accumulate during the latter stages of the cell cycle, suggesting a role for this protein in the process of smooth muscle cell division. However, separate mechanisms, which are independent of cell cycle, operate through a protein kinase-C-dependent pathway(s) to mediate the stimulation of PTHrP gene expression by vasoconstrictors such as angiotensin-II.


The Poly(ADP-ribose) Polymerase Enzyme Tankyrase Antagonizes Activity of the β-Catenin Destruction Complex through ADP-ribosylation of Axin and APC2.
Most colon cancer cases are initiated by truncating mutations in the tumor suppressor, adenomatous polyposis coli (APC). APC is a critical negative regulator of the Wnt signaling pathway that participates in a multi-protein "destruction complex" to target the key effector protein β-catenin for ubiquitin-mediated proteolysis. Prior work has established that the poly(ADP-ribose) polymerase (PARP) enzyme Tankyrase (TNKS) antagonizes destruction complex activity by promoting degradation of the scaffold protein Axin, and recent work suggests that TNKS inhibition is a promising cancer therapy. We performed a yeast two-hybrid (Y2H) screen and uncovered TNKS as a putative binding partner of Drosophila APC2, suggesting that TNKS may play multiple roles in destruction complex regulation. We find that TNKS binds a C-terminal RPQPSG motif in Drosophila APC2, and that this motif is conserved in human APC2, but not human APC1. In addition, we find that APC2 can recruit TNKS into the β-catenin destruction complex, placing the APC2/TNKS interaction at the correct intracellular location to regulate β-catenin proteolysis. We further show that TNKS directly PARylates both Drosophila Axin and APC2, but that PARylation does not globally regulate APC2 protein levels as it does for Axin. Moreover, TNKS inhibition in colon cancer cells decreases β-catenin signaling, which we find cannot be explained solely through Axin stabilization. Instead, our findings suggest that TNKS regulates destruction complex activity at the level of both Axin and APC2, providing further mechanistic insight into TNKS inhibition as a potential Wnt pathway cancer therapy.


Hepatoprotective Effects of Silymarin on Liver Injury via Irisin Upregulation and Oxidative Stress Reduction in Rats with Type 2 Diabetes.
Diabetes is one of the most prevalent metabolic diseases. Irisin (FNDC5 protein) is involved in the new strategy of combating type 2 diabetes. In the liver, the antidiabetic mechanism of silymarin at the molecular level is unknown. This study investigated the effects of silymarin on irisin and the related gene expression and oxidative stress status in the liver of type 2 diabetic rats. Thirty-six rats were divided into 6 groups (n=6 each) by simple randomization: control, control+silymarin (60 mg/kg daily in normal saline orally for 60 days), control+silymarin (120 mg/kg daily in normal saline orally for 60 days), diabetic, diabetic+silymarin (60 mg/kg daily for 60 days), and diabetic+silymarin (120 mg/kg daily for 60 days). Biochemical parameters were measured by spectrophotometric and immunoassay methods, and quantitative polymerase chain reaction was used to evaluate gene expression. The data were analyzed by one-way ANOVA, followed by the Tukey test, using SPSS software, version 16.0. The results were considered statistically significant at a P value less than 0.05. In the diabetic rats treated with silymarin (60 and 120 mg/kg), by comparison with the diabetic group, body weight (P=0.04 and P=0.02), insulin (P<0.001), expression of PGC-1α (P=0.04 and P=0.02), expression of FNDC5 (P=0.03 and P=0.01), and concentration of irisin in the liver (P=0.02 and P=0.01) and serum (P<0.001) were significantly increased, whereas the levels of glucose (P<0.001), HOMA-IR (P=0.03 and P=0.01), and liver injury markers (P<0.001) were significantly reduced. Oxidative stress status and histopathological changes were improved in the treated groups. These results suggest that silymarin because of its ability to upregulate irisin and antioxidant effects can be considered an antidiabetic agent.


S100P is a novel interaction partner and regulator of IQGAP1.
Ca(2+)-binding proteins of the S100 family participate in intracellular Ca(2+) signaling by binding to and regulating specific cellular targets in their Ca(2+)-loaded conformation. Because the information on specific cellular targets of different S100 proteins is still limited, we developed an affinity approach that selects for protein targets only binding to the physiologically active dimer of an S100 protein. Using this approach, we here identify IQGAP1 as a novel and dimer-specific target of S100P, a member of the S100 family enriched in the cortical cytoskeleton. The interaction between S100P and IQGAP1 is strictly Ca(2+)-dependent and characterized by a dissociation constant of 0.2 μM. Binding occurs primarily through the IQ domain of IQGAP1 and the first EF hand loop of S100P, thus representing a novel structural principle of S100-target protein interactions. Upon cell stimulation, S100P and IQGAP1 co-localize at or in close proximity to the plasma membrane, and complex formation can be linked to altered signal transduction properties of IQGAP1. Specifically, the EGF-induced tyrosine phosphorylation of IQGAP1 that is thought to function in assembling signaling intermediates at IQGAP1 scaffolds in the subplasmalemmal region is markedly reduced in cells overexpressing S100P but not in cells expressing an S100P mutant deficient in IQGAP1 binding. Furthermore, B-Raf binding to IQGAP1 and MEK1/2 activation occurring downstream of IQGAP1 in EGF-triggered signaling cascades are compromised at elevated S100P levels. Thus, S100P is a novel Ca(2+)-dependent regulator of IQGAP1 that can down-regulate the function of IQGAP1 as a signaling intermediate by direct interaction.


Effect of motor vehicle emissions on respiratory health in an urban area.
Motor vehicles emit particulate matter < 2.5 microm in diameter (PM(2.5)), and as a result, PM(2.5) concentrations tend to be elevated near busy streets. Studies of the relationship between motor vehicle emissions and respiratory health are generally limited by difficulties in exposure assessment. We developed a refined exposure model and implemented it using a geographic information system to estimate the average daily census enumeration area (EA) exposure to PM(2.5). Southeast Toronto, the study area, includes 334 EAs and covers 16 km(2) of urban area. We used hospital admission diagnostic codes from 1990 to 1992 to measure respiratory and genitourinary conditions. We assessed the effect of EA exposure on hospital admissions using a Poisson mixed-effects model and examined the spatial distributions of variables. Exposure to PM(2.5) has a significant effect on admission rates for a subset of respiratory diagnoses (asthma, bronchitis, chronic obstructive pulmonary disease, pneumonia, upper respiratory tract infection), with a relative risk of 1.24 (95% confidence interval, 1.05-1.45) for a log(10) increase in exposure. We noted a weaker effect of exposure on hospitalization for all respiratory conditions, and no effect on hospitalization for nonrespiratory conditions.


Efficient RNA virus control in Drosophila requires the RNA methyltransferase Dnmt2.
Drosophila use small-interfering RNA mechanisms to limit the amplification of viral genomes. However, it is unclear how small RNA interference components recognize and separate viral from cellular RNA. Dnmt2 enzymes are highly conserved RNA methyltransferases with substrate specificity towards cellular tRNAs. We report here that Dnmt2 is required for efficient innate immune responses in Drosophila. Dnmt2 mutant flies accumulate increasing levels of Drosophila C virus and show activated innate immune responses. Binding of Dnmt2 to DCV RNA suggests that Dnmt2 contributes to virus control directly, possibly by RNA methylation. These observations demonstrate a role for Dnmt2 in antiviral defence.


[Iron and nonheme iron protein metabolism in ejaculates with varying degrees of fertility].
Spermoplasm of 21 fertile and 96 subfertile males was examined for Fe, transferrin and scaferrin the concentrations of which were compared to 14 morphofunctional and physicochemical parameters of ejaculate fertility. Fe and non-hemic spermoplasm ferroproteins are involved in male reproduction: participate in ejaculate thinning, in formation of viscosity and sperm pH, are important for normal spermatogenesis and intercellular interactions. The findings can be applied in diagnosis of male subfertility and control of ongoing treatment, hold promise for improvement of fertilizing ability of the sperm used for artificial insemination and extracorporeal fertilization.


Spontaneous left anterior descending coronary artery dissection in a patient with neurofibromatosis.
Neurofibromatosis (NF) is a genetic disorder inherited in an autosomal dominant pattern. Subtypes I and II are the most well recognized, and among these, Type I has associated vasculopathy. Less than 3% of patients have vascular involvement, with the renal artery as the most commonly involved vessel. Dissection and rupture of aneurysms in larger arteries such as the subclavian and the aorta have been previously reported. This is the first reported case of a spontaneous coronary artery dissection in a patient with NF-I. Imperative in the percutaneous treatment of coronary artery dissections is early recognition and proactive decision making. Recognition of a possible association between NF and coronary dissections will further facilitate successful and prompt management of this otherwise rare entity.


Perceptions of patient-provider communication and receipt of mental health treatment among older adults with depressive symptoms.
This study aimed to: (1) determine if and how perceptions towards healthcare providers differ between older adults with and without clinically signifcant depressive symptoms (CSDS), and (2) assess whether perceptions towards providers are associated with receipt of mental health treatment among older adults with CSDS. Data from the 2013 and 2014 Medical Expenditure Panel Survey were used to examine CSDS prevalence, receipt of mental health treatment, and perceptions of provider communication among community-dwelling adults ≥ age 65 (N = 6,936) using four of the 'How Well Doctors Communicate' composite items from the Consumer Assessment of Healthcare Providers and Systems(CAHPS). Multivariate logistic regression was used. CSDS are associated with greater odds of having 'poor' perceptions of provider communication on all four CAHPS communication measures. Perceptions of provider communication are similar among older adults with CSDS who received and did not receive mental health treatment, except on an item measuring a provider's ability to explain information in ways patients understand. Older adults with CSDS have more negative perceptions of the quality of their communication with healthcare providers than their peers. Healthcare systems should consider how to accommodate these patients' unique needs and communication preferences to ensure receipt of quality care.


Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias.
Inappropriate activation of the renin-angiotensin system may play a part in the development of preeclampsia. An insertion/deletion polymorphism within the angiotensin-I converting enzyme gene (ACE-I/D) has shown to be reliably associated with differences in angiotensin-converting enzyme (ACE) activity. However, previous studies of the ACE-I/D variant and preeclampsia have been individually underpowered to detect plausible genotypic risks. A prospective case-control study was conducted in 1,711 unrelated young pregnant women (665 preeclamptic and 1,046 healthy pregnant controls) recruited from five Colombian cities. Maternal blood was obtained to genotype for the ACE-I/D polymorphism. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) using logistic regression models were obtained to evaluate the strength of the association between ACE-I/D variant and preeclampsia risk. A meta-analysis was then undertaken of all published studies to February 2006 evaluating the ACE-I/D variant in preeclampsia. An additive model (per-D-allele) revealed a null association between the ACE-I/D variant and preeclampsia risk (crude OR = 0.95 [95% CI, 0.81-1.10]) in the new case-control study. Similar results were obtained after adjusting for confounders (adjusted per-allele OR = 0.90 [95% CI, 0.77-1.06]) and using other genetic models of inheritance. A meta-analysis (2,596 cases and 3,828 controls from 22 studies) showed a per-allele OR of 1.26 (95% CI, 1.07-1.49). An analysis stratified by study size showed an attenuated OR toward the null as study size increased. It is highly likely that the observed small nominal increase in risk of preeclampsia associated with the ACE D-allele is due to small-study bias, similar to that observed in cardiovascular disease. Reliable assessment of the origins of preeclampsia using a genetic approach may require the establishment of a collaborating consortium to generate a dataset of adequate size.


Effects of Turmeric (Curcuma longa) Extract in streptozocin-induced diabetic model.
Herbal remedies have been used for centuries to ameliorate complications of diabetes mellitus (DM). The aim of this study is to compare the effects of the oral curcumin supplement versus parenteral administration of turmeric extract on diabetic complications in a streptozocin (STZ) diabetic model. STZ DM rats received low and high doses turmeric extract intraperitoneally as well as oral curcumin. Curcumin and turmeric extracts significantly reduced blood glucose and creatinine levels, but not urea, and caused an increase in uric acid. Low dose improved liver enzymes, while higher dose and oral administration caused an increase in the ALT and AST. All groups showed an improvement in the serum cholesterol, while the triglycerides were not improved in the high and oral treatment. Histological evaluation showed islet cell protection. High-dose injection showed almost intact renal corpuscles as well as tubular structures with minimal degeneration. Treatment showed limited protection of Liver tissue. PRACTICAL APPLICATION: Curcumin has been heavily marketed as a protective agent. The current study shows some potential risk of curcumin use. Oral and injectable curcumin should be used with caution. Turmeric extract and oral curcumin supplement showed protective effects on pancreatic, and renal structure and function. Although both did show some improvement in liver function, higher doses caused disturbance in liver enzymes and did not show histological evidence of liver tissue protection.


Evidence for crossed Andreev reflection in superconductor-ferromagnet hybrid structures.
We have measured the nonlocal resistance of aluminum-iron spin-valve structures fabricated by e-beam lithography and shadow evaporation. The sample geometry consists of an aluminum bar with two or more ferromagnetic wires forming point contacts to the aluminum at varying distances from each other. In the normal state of aluminum, we observe a spin-valve signal which allows us to control the relative orientation of the magnetizations of the ferromagnetic contacts. In the superconducting state, at low temperatures and excitation voltages well below the gap, we observe a spin-dependent nonlocal resistance which decays on a smaller length scale than the normal-state spin-valve signal. The sign, magnitude, and decay length of this signal are consistent with predictions made for crossed Andreev reflection.


Comparison of three Listeria monocytogenes strains in a guinea-pig model simulating food-borne exposure.
Three different Listeria monocytogenes strains, LO28 (a laboratory strain with truncated InlA), 4446 (a clinical isolate) and 7291 (a food isolate), were compared in a guinea-pig model designed to mimic food-borne exposure. The objectives were (1) to verify the applicability of the animal model for distinguishing between Listeria with different virulence properties and (2) to explore whether it was possible to reduce the required number of animals by dosing with mixed cultures instead of monocultures. Consistent with in vitro observations of infectivity in Caco-2 cells, faecal densities and presence in selected organs were considerably lower for LO28 than for the other two strains. Additionally, the animal study revealed a difference in prevalence in faeces as well as in internal organs between the clinical isolate and the food isolate, which was not reproduced in vitro. Dosage with monocultures of Listeria strains gave similar results as dosage with a mixture of the three strains; thus, the mixed infection approach was a feasible way to reduce the number of animals needed for determination of listerial virulence.


Immunologic tolerance in lymphatic filariasis. Diminished parasite-specific T and B lymphocyte precursor frequency in the microfilaremic state.
To explore the mechanisms of antigen-specific immune unresponsiveness seen in microfilaremic patients with bancroftian filariasis, T and B cell precursor frequency analysis was performed using PBMC from individuals with either asymptomatic microfilaremia (MF, n = 7) or chronic lymphatic obstruction (CP, n = 20). Highly purified CD3+ cells were partially reconstituted with adherent cells and their proliferative response to parasite antigens determined in cultures of T cells by limiting dilution analysis. A filter immunoplaque assay also assessed the frequency of both total and parasite-specific Ig-producing B cells. While the lymphocyte proliferation to mitogens and to a nonparasite antigen (Streptolysin-O, [SLO]) were similar in all groups of patients, the frequency of parasite-specific CD3+ T cells was significantly lower (geometric mean [GM], 1/3,757) in MF patients when compared to that in CP patients (GM 1/1,513; P less than 0.001). Similarly, the proportion of lymphocytes producing parasite-specific IgE or IgG was significantly lower in MF patients (IgE mean, 0.2%; IgG mean, 0.33%) compared with CP patients (IgE mean, 3.2%; IgG mean, 1.76%; P less than 0.05 for both comparisons). These observations imply that low numbers of parasite-specific T and B lymphocytes may be partially responsible for the severely diminished capacity of lymphocytes from patients with MF to produce parasite-specific antibody and to proliferate to parasite antigen in vitro. Such differences in parasite-specific lymphocyte responses suggest that tolerance by clonal anergy may be a critical mechanism for maintaining the microfilaremic state.


Fatty acid-regulated transcription factors in the liver.
Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population.


Cost-effectiveness of the non-laboratory based Framingham algorithm in primary prevention of cardiovascular disease: A simulated analysis of a cohort of African American adults.
The non-lab Framingham algorithm, which substitute body mass index for lipids in the laboratory based (lab-based) Framingham algorithm, has been validated among African Americans (AAs). However, its cost-effectiveness and economic tradeoffs have not been evaluated. This study examines the incremental cost-effectiveness ratio (ICER) of two cardiovascular disease (CVD) prevention programs guided by the non-lab versus lab-based Framingham algorithm. We simulated the World Health Organization CVD prevention guidelines on a cohort of 2690 AA participants in the Atherosclerosis Risk in Communities (ARIC) cohort. Costs were estimated using Medicare fee schedules (diagnostic tests, drugs & visits), Bureau of Labor Statistics (RN wages), and estimates for managing incident CVD events. Outcomes were assumed to be true positive cases detected at a data driven treatment threshold. Both algorithms had the best balance of sensitivity/specificity at the moderate risk threshold (>10% risk). Over 12years, 82% and 77% of 401 incident CVD events were accurately predicted via the non-lab and lab-based Framingham algorithms, respectively. There were 20 fewer false negative cases in the non-lab approach translating into over $900,000 in savings over 12years. The ICER was -$57,153 for every extra CVD event prevented when using the non-lab algorithm. The approach guided by the non-lab Framingham strategy dominated the lab-based approach with respect to both costs and predictive ability. Consequently, the non-lab Framingham algorithm could potentially provide a highly effective screening tool at lower cost to address the high burden of CVD especially among AA and in resource-constrained settings where lab tests are unavailable.


Preventive Anti-inflammatory Diet to Reduce Gastrointestinal Inflammation in Familial Adenomatous Polyposis Patients: A Prospective Pilot Study.
Familial adenomatous polyposis (FAP) is an autosomal-dominant hereditary condition associated with germline mutations in the adenomatous polyposis coli gene. Patient management involves prophylactic surgery and intensive life-long endoscopic surveillance. Diet is a major concern for patients with FAP, who are generally free of symptoms before surgery but tend to have issues related to bowel function postoperatively. We hypothesized that a low-inflammatory diet based on the principles and recipes of the Mediterranean diet would reduce markers of local and systemic inflammation. Twenty-eight patients with FAP over 18 years of age who underwent rectum-sparing prophylactic colectomy and were included in our surveillance program participated in a pilot dietary intervention study. Blood and stool samples at baseline (T0), at the end of the dietary intervention (T1, three months), and at the end of the study (T2, six months after T0) were collected. Gastrointestinal inflammation markers including fecal calprotectin, cyclooxygenase-2, and 15-hydroxyprostaglandin dehydrogenase were evaluated. Serum calprotectin, insulin, insulin-like growth factor-1, C-reactive protein, and glycated hemoglobin were also assessed. Significant changes in serum calprotectin, insulin, and insulin-like growth factor-1 levels occurred over time. Borderline significant changes were observed in the neutrophil-lymphocyte ratio. These changes were noticeable immediately at the end of the 3-month active dietary intervention (T1). A significant increase in 15-hydroxyprostaglandin dehydrogenase expression in the normal crypts of matched samples was also observed between T0 and T2. This pilot study supports the hypothesis that a low-inflammatory diet can modulate gastrointestinal markers of inflammation in individuals with FAP. PREVENTION RELEVANCE: Cancer is known to be related to inflammatory conditions. This study suggests that anti-inflammatory dietary intervention may potentially prevent adenomas and cancer in FAP patients by reducing systemic and tissue inflammatory indices.


Endoscopic submucosal dissection for the diagnosis and treatment of a gastric submucosal tumor: initial experience in Greece.
Gastric submucosal tumors (GSMTs) are frequently found incidentally on routine upper endoscopy. Definitive diagnosis based on histological confirmation is relatively difficult. Even without accurate diagnosis before treatment, open or laparoscopic surgery is considered the standard of care for most GSMTs. Alternatively, endoscopic resection of GSMTs using different techniques has been reported in a limited number of papers. We describe a case of an antral submucosal tumor, more specifically a leiomyoma of muscularis mucosa origin, in a 78-year-old woman, that was completely resected en bloc using an endoscopic submucosal technique with a TT-knife. It is suggested that ESD is a feasible option for the diagnosis and treatment of GSTMs.


Tactile soft-sparse mean fluid-flow imaging with a robotic whisker array.
An array of whiskers is critical to many mammals to survive in their environment. However, current engineered systems generally employ vision, radar or sonar to explore the surroundings, not having sufficiently benefited from tactile perception. Inspired by the whisking animals, we present here a novel tomography-based tactile fluid-flow imaging technique for the reconstruction of surroundings with an artificial whisker array. The moment sensed at the whisker base is the weighted integral of the drag force per length, which is proportional to the relative velocity squared on a whisker segment. We demonstrate that the 2D cross-sectional mean fluid-flow velocity-field can be successfully mapped out by collecting moment measurements at different angular positions with the whisker array. We use a regularized version of the FOCal underdetermined system solver algorithm with a smoothness constraint to obtain soft-sparse static estimates of the 2D cross-sectional velocity-squared distribution. This new proposed approach has the strong potential to be an alternative environmental sensing technology, particularly in dark or murky environments.


Neurodevelopmental outcome for offspring of women treated for antenatal depression: a systematic review.
The aim of this systematic review is to appraise existing literature on the effects of treatments for antenatal depression on the neurodevelopment outcomes of the offspring. We conducted a systematic review of the literature to identify studies on different kinds of treatments for antenatal depression (antidepressants and alternative therapies) and their effects on infants' neurodevelopment. After reading the title, abstract, or full text and applying exclusion criteria, a total of 22 papers were selected. Nineteen papers studied the effects of antidepressant drugs, one on docosahexanoic acid (DHA) (fish oil capsules) and two on massage therapy; however, no studies used a randomized controlled design, and in most studies, the control group comprise healthy women not exposed to depression. Comparisons between newborns exposed to antidepressants in utero with those not exposed showed significant differences in a wide range of neurobehavioral outcomes, although in many cases, these symptoms were transient. Two studies found a slight delay in psychomotor development, and one study found a delay in mental development. Alternative therapies may have some benefits on neurodevelopmental outcomes. Our review suggests that antidepressant treatment may be associated with some neurodevelopmental changes, but we cannot exclude that some of these effects may be due to depression per se.


Electric-Field-Assisted Anion-π Catalysis.
This report focuses on the remote control of anion-π catalysis by electric fields. We have synthesized and immobilized anion-π catalysts to explore the addition reaction of malonic acid half thioesters to enolate acceptors on conductive indium tin oxide surfaces. Exposed to increasing electric fields, anion-π catalysts show an increase in activity and an inversion of selectivity. These changes originate from a more than 100-fold rate enhancement of the disfavored enolate addition reaction that coincides with an increase in selectivity of transition-state recognition by up to -14.8 kJ mol-1. The addition of nitrate with strong π affinity nullified (IC50 = 2.2 mM) the responsiveness of anion-π catalysts to electric fields. These results support that the polarization of the π-acidic naphthalenediimide surface in anion-π catalysts with electric fields increases the recognition of anionic intermediates and transition states on this polarized π surface, that is, the existence and relevance of electric-field-assisted anion-π catalysis.


Occurrence and Molecular Characterization of Recombinant Potato virus YNTN Isolates from Sulawesi, Indonesia.
The importance of potato has increased dramatically in Indonesia over the last three decades. During this period, 'Granola', a potato cultivar originally from Germany, has become the most common cultivar for fresh consumption in Indonesia. In August 2014, a survey was conducted in Sulawesi, where potato fields cultivated with Granola and its selection, 'Super John', were sampled for Potato virus Y (PVY) presence. PVY was found in Sulawesi for the first time. Samples determined to be positive for PVY were subsequently typed to strain using reverse-transcription polymerase chain reaction assays. All PVY isolates sampled were identified as PVYNTN recombinants, with three recombination junctions in P3, VPg, and CP regions of the genome. Three local PVY isolates were subjected to whole-genome sequencing and subsequent sequence analysis. The whole genomes of the Indonesian PVYNTN isolates I-6, I-16, and I-17 were found to be closely related to the European PVYNTN-A. This recombinant type was shown previously to cause potato tuber necrotic ringspot disease (PTNRD) in susceptible potato cultivars. The dependence of potato farmers on mostly a single cultivar, Granola, may have given a competitive advantage to PVYNTN over other PVY strains, resulting in the predominance of the PVYNTN recombinant. The dominance of PVYNTN in Sulawesi, and possibly in Indonesia as a whole, represents a potential risk to any newly introduced potato cultivar to the country, especially cultivars susceptible to PTNRD.