Cardiovascular Effects of Continuous Positive Airway Pressure Treatment in Patients With Obstructive Sleep Apnea: A Meta-Analysis.
Continuous positive airway pressure (CPAP) is the first-line treatment of obstructive sleep apnea (OSA). Obstructive sleep apnea is a predictor of cardiovascular (CV) events. In this meta-analysis, we evaluated the effect of CPAP on left ventricular ejection fraction (LVEF), CV events, CV mortality, and all-cause mortality in patients with OSA. Nine articles (n = 9610 patients) were analyzed. Four different meta-analyses were performed: evaluation of LVEF, assessment of all-cause mortality, CV mortality, and CV events. Continuous positive airway pressure treatment was associated with a significant increase in LVEF (mean difference: 2.1%, 95% confidence interval [CI]: 0.8%-3.4%). There was a nonsignificant reduction in all-cause mortality (hazard ratio [HR]: 0.92, 95% CI: 0.73-1.15) but a significant reduction of 66% in the risk of CV mortality associated with the CPAP treatment (HR: 0.34, 95% CI: 0.17-0.68, P = .002). There was a nonsignificant reduction in the risk of CV events in the CPAP-treated patients (HR: 0.84, 95% CI: 0.60-1.18, P = .31). Our meta-analyses showed that CPAP treatment improves LVEF and could have a beneficial effect on CV mortality.


Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness: a meta-analysis.
Many studies have investigated the association between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and carotid artery intima-media thickness (IMT); however, most studies were small and conducted in selective samples. The aim of this study was to evaluate this association by performing a meta-analysis on published articles. We searched Medline for articles studying the association between the ACE I/D polymorphism and carotid IMT. Twenty-six studies were found; 23 articles containing 9833 subjects were qualified to enter the meta-analysis. We classified those articles on the basis of their samples into high-risk and low-risk populations and white and Asian ethnic groups. IMT was used as a continuous variable, and data were analyzed with the Cochrane Review Manager. A significant positive association was present between the D allele and common carotid IMT (weighted mean difference between DD and II genotypes, 0.23 mm x 10(-1); P<0.01). The association was stronger among high-risk populations. The point estimates of DD versus II were higher than those of ID versus II. Our meta-analysis showed evidence of a positive association between the D allele of the ACE gene and common carotid IMT. The overall results were concordant in both ethnic groups.


Comparison between manual and computer-assisted measurements of hallux valgus parameters.
The aim of this study was to determine if there are intraobserver and interobserver differences in reliability when measuring hallux valgus angles (HVA), 1-2 intermetatarsal angles (IMA), and distal metatarsal articular angles (DMAA) manually compared to computer-assisted means. Our hypothesis was that the measurements taken by computer-assisted methods of these three forefoot angles would be superior in consistency and accuracy compared to manual measurements. Four examiners studied 20 weightbearing anteroposterior radiographs of patients with hallux valgus. Manual measurements were taken on photographic prints using a goniometer and a fine point pen. Computer-assisted measurements were taken on digitized images using computer software. Three sets of measurements by both of these methods were taken 1 week apart. There was no statistically significant difference between digital and manual measurements for any of the three angles measured (p .05). However, the reliability of measurements within a range of 5 degrees for both methods was 70.6% for HVA, 84% for 1-2 IMA, and 59% for DMAA. There were no significant differences in interobserver and intraobserver reliability in measuring 1-2 IMA and HVA, regardless of the method of measurement; however, there was a significant difference in interobserver reliability when measuring the DMAA either on computer or manually (p = <.05).


Impact of peroxydisulfate in the presence of zero valent iron on the oxidation of cyclohexanoic acid and naphthenic acids from oil sands process-affected water.
Large volumes of oil sands process-affected water (OSPW) are produced during the extraction of bitumen from oil sands in Alberta, Canada. The degradation of a model naphthenic acid, cyclohexanoic acid (CHA), and real naphthenic acids (NAs) from OSPW were investigated in the presence of peroxydisulfate (S(2)O(8)(2-)) and zerovalent iron (ZVI). For the model compound CHA (50 mg/L), in the presence of ZVI and 500 mg/L S(2)O(8)(2-), the concentration decreased by 45% after 6 days of treatment at 20 °C, whereas at 40, 60, and 80 °C the concentration decreased by 20, 45 and 90%, respectively, after 2 h of treatment. The formation of chloro-CHA was observed during ZVI/S(2)O(8)(2-) treatment of CHA in the presence of chloride. For OSPW NAs, in the presence of ZVI alone, a 50% removal of NAs was observed after 6 days of exposure at 20 °C. The addition of 100 mg/L S(2)O(8)(2-) to the solution increased the removal of OSPW NAs from 50 to 90%. In absence of ZVI, a complete NAs removal from OSPW was observed in presence of 2000 mg/L S(2)O(8)(2-) at 80 °C. The addition of ZVI increased the efficiency of NAs oxidation by S(2)O(8)(2-) near room temperature. Thus, ZVI/S(2)O(8)(2-) process was found to be a viable option for accelerating the degradation of NAs present in OSPW.


Identification of a Novel Oligosaccharide in Maple Syrup as a Potential Alternative Saccharide for Diabetes Mellitus Patients.
The incidence of diabetes mellitus (DM) is increasing rapidly and is associated with changes in dietary habits. Although restrictions in the use of sweeteners may prevent the development of DM, this might reduce the quality of life of patients with DM. Therefore, there has been a great deal of research into alternative sweeteners. In the search for such sweeteners, we analyzed the carbohydrate content of maple syrup and identified a novel oligosaccharide composed of fructose and glucose, linked at the C-4 of glucose and the C-6 of fructose. This oligosaccharide inhibited the release of fructose from sucrose by invertase (IC50: 1.17 mmol/L) and the decomposition of maltose by α-(1-4) glucosidase (IC50: 1.72 mmol/L). In addition, when orally administered together with sucrose to rats with DM, the subsequent plasma glucose concentrations were significantly lower than if the rats had been administered sucrose alone, without having any effect on the insulin concentration. These findings suggest that this novel oligosaccharide might represent a useful alternative sweetener for inclusion in the diet of patients with DM and may also have therapeutic benefits.


Evolutionary forces affecting synonymous variations in plant genomes.
Base composition is highly variable among and within plant genomes, especially at third codon positions, ranging from GC-poor and homogeneous species to GC-rich and highly heterogeneous ones (particularly Monocots). Consequently, synonymous codon usage is biased in most species, even when base composition is relatively homogeneous. The causes of these variations are still under debate, with three main forces being possibly involved: mutational bias, selection and GC-biased gene conversion (gBGC). So far, both selection and gBGC have been detected in some species but how their relative strength varies among and within species remains unclear. Population genetics approaches allow to jointly estimating the intensity of selection, gBGC and mutational bias. We extended a recently developed method and applied it to a large population genomic dataset based on transcriptome sequencing of 11 angiosperm species spread across the phylogeny. We found that at synonymous positions, base composition is far from mutation-drift equilibrium in most genomes and that gBGC is a widespread and stronger process than selection. gBGC could strongly contribute to base composition variation among plant species, implying that it should be taken into account in plant genome analyses, especially for GC-rich ones.


National trends in exposure to and experiences of violence on the Internet among children.
To examine rates of technology-based violent experiences (eg, bullying, harassment, unwanted sexual experiences [USEs] perpetration, and victimization) and exposures (eg, hate sites) from 2006 to 2008 among US children. One thousand five-hundred eighty-eight youth aged 10 to 15 years were surveyed nationally online in 2006, 2007 (76% follow-up rate), and 2008 (73% follow-up rate). All other things equal, rates of Internet-based violent exposures and experiences were stable. Of exception, harassment perpetration and exposure to violent cartoon sites reduced by 26% and 36% over the 2 year period (P < 0.05), respectively. In contrast, several rates of violent experiences via text messaging increased over time, specifically: harassment victimization (aOR = 1.6, p = 0.001) and perpetration (aOR = 1.4, p = 0.03), and USE victimization (aOR = 1.9, p = 0.02). Increases in bullying victimization were suggested (aOR = 1.5, p = 0.06). Text messaging USE perpetration did not significantly change, however. General technology use (i.e., intensity and frequency of Internet and text messaging) was consistently influential in explaining the odds of almost all violent experiences and exposures both online and via text messaging; as was age for many exposures and experiences online. Ongoing surveillance of text-messaging-based experiences is needed to understand trends as population usage rates begin to stabilize. General technology use is a predictive factor for almost all technology-based violent experiences and exposures. Age is also influential in explaining involvement in Internet-based experiences and exposures. Prevention programs should focus on reducing risk as youth age into later adolescence and to help heavy technology users manage their risk for violence involvement.


Is there a gender difference of somatostatin-receptor density in the human brain?
Animal experiments and observations in human brains have convincingly shown that sexual differentiation not only concerns the genitalia but also the brain. This has been investigated also in the light of a possible explanation of a presumed biological aetiology of transsexuality. The volume of the central subdivision of the bed nucleus of the stria terminalis, a brain area that is essential for sexual behaviour, has been reported to be larger in men than in women. Additionally, the number of somatostatin expressing neurons in this region was shown to be higher in men than in women. As neuronal production of somatostatin is involved the idea is striking whether somatostatin-receptor density in the cortex of cerebral hemispheres might be related to gender identity. We investigated in vivo the density of somatostatin-receptors in selected regions of the human brain in both sexes by means of receptor scintigraphy. Basal ganglia tracer uptake of 111-In-Pentreotide was equally low in both genders at 0,80% +/ 0,26 (related to tracer uptake of the whole brain layer). Temporal cortex accumulated at 2,9% +/ 1,1 in men and at 2,3% +/ 0,76 in women. Frontal brain region had an uptake of 3,0% +/ 1,4 in male and of 2,5% +/ 1,3 in female. This shows a tendency in males for relatively augmented uptake indicating higher somatostatin receptor density in temporal and frontal cerebral cortex.


Quiet about pain: experiences of Aboriginal people in two rural communities.
This study explores communications experienced by Aboriginal people in health care encounters about pain. It examines barriers that can impact upon effective pain management for Aboriginal patients. (This article refers to Aboriginal people, as these were the study participants. It is not intended to exclude Torres Strait Islander people.) A qualitative study using focus groups. Two Aboriginal communities in South East Queensland. The participants were 20 men and 20 women who identified a health condition with associated pain for which they had sought health care, including pain relief. Their conditions included arthritis, orthopaedic injuries, back pain and coronary artery disease. Physical pains associated with participants' health conditions were accorded a second place to deep emotional pain attributed to dispossession, dislocation and loss. At health facilities, prominent perceptions were that health professionals held a negative attitude towards them, and lacked respect and caring. Participants experienced that the language used by health professionals in consultations was complex. Aboriginal people often do not report pain, on the basis of previous negative encounters with the health system. Other perceived barriers to effective pain management included discriminatory attitudes of health professionals and communication problems.


First Report of Sarocladium oryzae Causing Sheath Rot on Rice (Oryza sativa) in Western Australia.
Rice (Oryza sativa L.) has been grown in the Ord River Irrigation Area (ORIA) in northern Western Australia since 1960. In 2011, a sheath rot of rice was observed in the ORIA. Symptoms were variable, appearing as either (i) oblong pale to dark brown lesions up to 3 cm length, (ii) lesions with pale grey/brown centers and with dark brown margins, or (iii) diffuse dark or reddish brown streaks along the sheath. Lesions enlarged and coalesced, often covering the majority of the leaf sheath, disrupting panicle emergence. Isolations from small pieces of infested tissues from plants showing sheath rot symptoms were made onto water agar, subcultured onto potato dextrose agar, cultures maintained at 20°C, and a representative culture lodged both in the Western Australian Culture Collection maintained at the Department of Agriculture and Food Western Australia (as WAC 13481) and in the culture collection located at the DAFF Plant Pathology Herbarium (as BRIP 54763). Amplification of the internal transcribed spacer (ITS)1 and (ITS)2 regions flanking the 5.8S rRNA gene were carried out with universal primers ITS1 and ITS4 according to the published protocol (4). The DNA PCR products from a single isolate were sequenced and BLAST analyses used to compare sequences with those in GenBank. The sequence had 99% nucleotide identity with the corresponding sequence in GenBank for Sarocladium oryzae (Sawada) W. Gams & D. Hawksworth. Isolates showed morphological (e.g., conidiophore and conidia characteristics) (2) and molecular (1) similarities with S. oryzae as described in other reports. The relevant sequence information for a representative isolate was lodged in GenBank (GenBank Accession No. JQ965668). Spores of S. oryzae were produced on rice agar under "black light" at 22°C to induce sporulation over 4 weeks. Under conditions of 30/28°C (day/night), 14/12 h (light/dark), rice cv. Quest, grown for 11 weeks until plants reached the tillering stage, was inoculated by spraying a suspension 5 × 107 spores/ml of the same single isolate onto foliage until runoff occurred. Inoculated plants were placed under a dark plastic cover for 72 h to maximize humidity levels around leaves and subsequently maintained under >90% relative humidity conditions. Symptoms of sheath rot as described in (i) and (ii) above appeared by 14 days after inoculation, with lesions up to 23 cm long by 15 days post-inoculation. Severe disease prevented young panicles from emerging. Infection studies were successfully repeated and S. oryzae was reisolated from leaf lesions 1 week after lesion appearance. No disease was observed on water-inoculated control rice plants. There have been records of S. oryzae on rice in New South Wales in the early 1980s (3) and in 2006 to 2007 (Australian Plant Pest Database), but to our knowledge, this is the first report of this pathogen in Western Australia. References: (1) N. Ayyadurai et al. Cur. Microbiol. Mycologia 50:319, 2005. (2) B. L. K. Brady. No. 673 in: IMI Descriptions of Fungi and Bacteria, 1980. (3) D. Phillips et al. FAO Plant Prot. Bull. 40:4, 1992. (4) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA, 1990.


Heterogeneity of myoglobin distribution in the locomotory muscles of five cetacean species.
Myoglobin is an important storage site for oxygen in the swimming muscles of diving marine mammals. However, little is known about its distribution within muscles since previous studies have relied on single samples. The goal of this study was to determine the distribution of myoglobin within the swimming muscles of five species of cetacean: dusky dolphin, false killer whale, striped dolphin, humpbacked dolphin and bottlenose dolphin. The entire dorsal (epaxial) and ventral (hypaxial) swimming muscles were removed from each animal and weighed. Transverse sections were taken from the cranial, middle and caudal regions of each muscle and sampled along a circular grid with a minimum of 30 sites per section. Spectrophotometric analysis was used to measure the myoglobin concentration of each sample. Contour maps of myoglobin concentration were made for each transverse section. Myoglobin concentration was found to be non-uniformly distributed within the muscle. The interior of the muscle lying closest to the vertebrae showed a significantly higher (11 %) mean myoglobin concentration than the exterior of the muscle for all five species. In the epaxial muscles, the mean myoglobin concentration was significantly higher in the caudal region closest to the flukes. The two deep-water species (false killer whale and striped dolphin) had significantly higher myoglobin concentrations than the three species (dusky, humpbacked and bottlenose dolphins) that occur in shallow, coastal waters. These results show that myoglobin is not homogeneously distributed in the locomotory muscle of cetaceans and that levels may be highest in those areas that produce greater force and consume more oxygen during aerobic swimming. Enhancing oxygen stores in those areas of the muscle that work the hardest would theoretically lengthen the aerobic dive limit of the animal during submerged swimming.


High Prevalence of Humoral and Cellular Immunity to Influenza Viruses in Preschool Children Living in Addis Ababa, Ethiopia.
Influenza in children who reside in tropical and subtropical regions has until recently been regarded as insignificant. However, new evidence suggests that it significantly impacts hospitalization and promotes secondary bacterial coinfections. Ethiopia is situated in a subtropical area where influenza viruses are likely to circulate year round. Clinical data were recorded in a cohort of 103 healthy preschool children recruited in Addis Ababa, Ethiopia. Humoral and cellular immune responses to influenza virus were determined by hemagglutination inhibition (HI) and interferon-γ enzyme-linked immunospot assays. Ninety-six percent of the children (2-5 years old) had pre-existing HI antibody responses to 1 or more of the circulating influenza A subtypes, H1N1 (51%), H3N2 (86%), or influenza B (51%) strains. At the age of 4, all children had been infected with at least 1 strain, and 75% had been infected with 2-4 different viral strains. CD4+ and CD8+ T-cell responses against conserved viral antigens increased with repeated exposures, indicating boosting of cross-reactive cellular immunity. Malnutrition did not seem to affect these immune responses to influenza. Influenza is highly prevalent among children in this area of Ethiopia. Due to the risk of secondary bacterial pneumonia, increased influenza awareness might benefit child health.


The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF).
Acute heart failure syndromes (AHFS) are related to several diseases affecting not only the heart but also the kidneys and blood vessels. Emerging evidence indicates that myocardial injury may also play a role in the pathophysiology of AHFS, as suggested by increased levels of markers of injury, such as cardiac troponin (cTn). Although cTn is a known prognostic marker, the release of cTn during hospitalization has not been evaluated prospectively with serial measures. We prospectively evaluated patterns of cTn release by conducting serial measures of cTnI and cTnT in patients hospitalized for AHFS. This study enrolled 51 patients with AHFS who were admitted with worsening heart failure (HF) and a history of coronary artery disease (CAD) in whom an acute coronary event was not suspected. Levels of cTnI and cTnT were measured at 8, 32, 56, and 80 hours after study entry. At baseline, 73.9% of patients had detectable cTnI, and 43.5% had detectable cTnT levels. The median concentrations of cTnI and cTnT were unchanged from 0 to 32 hours, increased from 32 to 56 hours, then either plateaued (cTnT) or decreased to baseline (cTnI). Of the 26 patients who had no detectable cTn levels at baseline, 2 (7.7%) developed detectable cTnT and 5 (41.7%) developed detectable cTnI release during hospitalization. Detectable levels of cTn at baseline were related to short-term clinical events. In this study of patients with CAD in whom an acute coronary event was not suspected, most had detectable levels of cTn present at admission, and some patients developed cTn release during hospitalization. Because cTn release may be a marker for myocardial injury, this study raises the possibility that injury occurred in most patients admitted with AHFS. Therefore, the goal of therapy for AHFS should be not only to improve symptoms and hemodynamics but also to salvage myocardium. Accordingly, therapies for AHFS that are aimed at improving hemodynamics may affect long-term prognosis by either injuring or salvaging myocardium.


A framework for evaluating and utilizing medical terminology mappings.
Use of medical terminologies and mappings across them are considered to be crucial pre-requisites for achieving interoperable eHealth applications. Built upon the outcomes of several research projects, we introduce a framework for evaluating and utilizing terminology mappings that offers a platform for i) performing various mappings strategies, ii) representing terminology mappings together with their provenance information, and iii) enabling terminology reasoning for inferring both new and erroneous mappings. We present the results of the introduced framework from SALUS project where we evaluated the quality of both existing and inferred terminology mappings among standard terminologies.


Early decrease in α-fetoprotein, but not des-γ-carboxy prothrombin, predicts sorafenib efficacy in patients with advanced hepatocellular carcinoma.
The aim of this study was to investigate the relationships between early changes in the tumor markers α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), and antitumor response in the early period following administration of sorafenib in patients with advanced hepatocellular carcinoma (HCC). Forty-eight advanced HCC patients were evaluated. AFP and DCP were measured at baseline, and after 2 and 4 weeks, and the antitumor responses were evaluated according to the RECIST criteria 4 weeks after starting sorafenib therapy. The ratios of each tumor marker were compared by stratifying the patients into the partial response (PR) + stable disease (SD) group or the progressive disease (PD) group. Both 2 and 4 weeks after starting sorafenib therapy, the AFP ratio in the PR + SD group (n = 32) was significantly lower than in the PD group (n = 16; p = 0.002, p = 0.002). DCP was elevated in both the PR + SD group and the PD group 2 weeks and 4 weeks after starting sorafenib therapy. Evaluation of AFP ratios 2 and 4 weeks after starting sorafenib therapy may be useful for predicting antitumor response. On the other hand, early elevation of DCP does not necessarily suggest treatment failure by sorafenib, as DCP elevation can occur despite therapeutic efficacy.


Persistence of natural mineral fibers in human lungs: an overview.
Virtually all available data on persistence of naturally occurring mineral fibers in human lungs have been derived from studies of asbestos fiber loads. These studies indicate that, although both amphibole and chrysotile asbestos fibers are found in the lungs of the general population and exposed workers, amphibole fibers are universally present in disproportionately large and chrysotile fibers in disproportionately small amounts compared to their known abundance in the original inhaled dusts. Why this should be remains unclear. Most reports have shown that fiber accumulation is proportional to measured exposure for amphiboles, but this is not generally true for chrysotile. Very little information is available on actual fiber clearance rates from human lungs. For amosite and crocidolite, estimated clearance half-times are measured in years to decades, whereas for chrysotile the available, rather indirect, data suggest that the vast majority of fibers are cleared within months, although some fibers may be sequestered and very slowly cleared. Overall these studies suggest that the differences between amphibole and chrysotile fiber burdens in man reflect much faster clearance of chrysotile fibers, rather than a failure of chrysotile deposition. A variety of other naturally occurring fibers are commonly found in human lungs, but there are no data on their rates of accumulation or disappearance.


Identifying success on the process level reduces negative effects of prior weight loss on subsequent weight loss during a low-calorie diet.
Dieters often show weight cycling, i.e. prior successful weight loss is followed by weight gain. The current study examined how goal progress during a diet (i.e. weight loss) impacts subsequent weight loss depending on whether success is identified on the process level or the outcome level of dieting. A short-term longitudinal study examined lagged effects of weight loss and identifications of success in one week on weight loss in the subsequent week. Across 6 weeks, N = 126 overweight women reported their weekly weight and the degree to which they considered themselves as successful regarding the process of dieting (e.g. changing eating behavior) and the desired dieting outcomes (e.g. improving appearance). Successful weight loss in one week negatively affected weight loss in the subsequent week. However, identifying success on the process level reduced this negative effect. Although people might feel generally that goal progress licenses subsequent goal-inconsistent behavior, identifying successful goal-pursuit on the process rather than the outcome level of a goal may counteract the subsequent loss of dieting motivation.


Stopover and fat deposition by North American wood-warblers (Parulinae) following spring migration over the Gulf of Mexico.
Length of stopover and rate of weight gain (fat deposition) were studied in several species of passerine birds that stopped in southwestern Louisiana along the northern coast of the Gulf of Mexico after a trans-Gulf flight. Fatdepleted birds were more common among the birds that arrived at our study site in southwest Louisiana, though variability characterized our samples. Migrants that landed after encountering opposing winds or rain over the northern Gulf of Mexico were, on average, fatter than migrants that landed when weather was favorable for continued migration. Some of the variation in the energetic condition of arrivals may be explained by the location where migrants initiated crossings. Our simulation of flight over the Gulf of Mexico showed that with following winds a warbler can cross the Gulf of Mexico from Yucatan with fat reserves to spare, and stronger tailwinds make flights from as far south as Honduras energetically permissible. The length of stay after a trans-Gulf flight was related to the extent of fat-depletion upon arrival: lean birds stayed longer than fat migrants. Migrants stopped over for 1-7 days and replenished energy reserves at rates that varied from 0.19 g/d for Hooded Warblers (Wilsonia citrina) to 0.87 g/d for Ovenbirds (Seiurus aurocapillus). Within each species, most individuals gained weight at a rapid rate, though a few individuals lost or maintained weight during their stay.


Identification and deletion of sequences required for feline leukemia virus RNA packaging and construction of a high-titer feline leukemia virus packaging cell line.
Sequences required for specific encapsidation of feline leukemia virus (FeLV) genomic RNA have not yet been defined. Deletion of 107 nucleotides between the splice donor (SD) and the gag coding region of a prototypic subgroup A FeLV, 61E, resulted in an approximately 200-fold reduction of packaged viral RNA. Virus particle production was not disrupted by the deletion, although viral infectivity was dramatically reduced. These data indicate that the 107-nucleotide sequence comprises a portion of the FeLV packaging signal. FeLV particles expressed from the deleted genome were able to efficiently package murine leukemia virus vectors, resulting in high-titer G418R virus production. This system can be easily adapted to produce FeLV particles that contain envelope proteins from other feline leukemia virus subgroups and will be broadly useful for studies of FeLV envelope/receptor interactions.


The Use of Commercially Available Alpha-Amylase Compounds to Inhibit and Remove Staphylococcus aureus Biofilms.
Staphylococcus aureus, a versatile human pathogen, is commonly associated with medical device infections. Its capacity to establish and maintain these infections is thought to be related to its ability to form adherent biofilms. In this study, commercially available α-amylase compounds from various biological sources were evaluated for their ability to reduce and prevent biofilm formation of several S. aureus isolates. Our data demonstrates that α-amylase compounds can rapidly detach biofilms of S. aureus, as well as inhibit biofilm formation. Our data also demonstrates that α-amylase compounds have an ability to reduce and disassociate S. aureus cell-aggregates grown in liquid suspension. These findings suggest that commercially available α-amylase compounds could be used in the future to control S. aureus biofilm-related infections.


Unraveling the dose-response puzzle of L. monocytogenes: A mechanistic approach.
Food-borne disease outbreaks caused by Listeria monocytogenes continue to impose heavy burdens on public health in North America and globally. To explore the threat L. monocytogenes presents to the elderly, pregnant woman and immuno-compromised individuals, many studies have focused on in-host infection mechanisms and risk evaluation in terms of dose-response outcomes. However, the connection of these two foci has received little attention, leaving risk prediction with an insufficient mechanistic basis. Consequently, there is a critical need to quantifiably link in-host infection pathways with the dose-response paradigm. To better understand these relationships, we propose a new mathematical model to describe the gastro-intestinal pathway of L. monocytogenes within the host. The model dynamics are shown to be sensitive to inoculation doses and exhibit bi-stability phenomena. Applying the model to guinea pigs, we show how it provides useful tools to identify key parameters and to inform critical values of these parameters that are pivotal in risk evaluation. Our preliminary analysis shows that the effect of gastro-environmental stress, the role of commensal microbiota and immune cells are critical for successful infection of L. monocytogenes and for dictating the shape of the dose-response curves.


Molecular Mechanisms behind Free Radical Scavengers Function against Oxidative Stress.
Accumulating evidence shows that oxidative stress is involved in a wide variety of human diseases: rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, cancers, etc. Here, we discuss the significance of oxidative conditions in different disease, with the focus on neurodegenerative disease including Parkinson's disease, which is mainly caused by oxidative stress. Reactive oxygen and nitrogen species (ROS and RNS, respectively), collectively known as RONS, are produced by cellular enzymes such as myeloperoxidase, NADPH-oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) and nitric oxide synthase (NOS). Natural antioxidant systems are categorized into enzymatic and non-enzymatic antioxidant groups. The former includes a number of enzymes such as catalase and glutathione peroxidase, while the latter contains a number of antioxidants acquired from dietary sources including vitamin C, carotenoids, flavonoids and polyphenols. There are also scavengers used for therapeutic purposes, such as 3,4-dihydroxyphenylalanine (L-DOPA) used routinely in the treatment of Parkinson's disease (not as a free radical scavenger), and 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) that acts as a free radical detoxifier frequently used in acute ischemic stroke. The cell surviving properties of L-DOPA and Edaravone against oxidative stress conditions rely on the alteration of a number of stress proteins such as Annexin A1, Peroxiredoxin-6 and PARK7/DJ-1 (Parkinson disease protein 7, also known as Protein deglycase DJ-1). Although they share the targets in reversing the cytotoxic effects of H₂O₂, they seem to have distinct mechanism of function. Exposure to L-DOPA may result in hypoxia condition and further induction of ORP150 (150-kDa oxygen-regulated protein) with its concomitant cytoprotective effects but Edaravone seems to protect cells via direct induction of Peroxiredoxin-2 and inhibition of apoptosis.


Transcriptomics of two evolutionary novelties: how to make a sperm-transfer organ out of an anal fin and a sexually selected "sword" out of a caudal fin.
Swords are exaggerated male ornaments of swordtail fishes that have been of great interest to evolutionary biologists ever since Darwin described them in the Descent of Man (1871). They are a novel sexually selected trait derived from modified ventral caudal fin rays and are only found in the genus Xiphophorus. Another phylogenetically more widespread and older male trait is the gonopodium, an intromittent organ found in all poeciliid fishes, that is derived from a modified anal fin. Despite many evolutionary and behavioral studies on both traits, little is known so far about the molecular mechanisms underlying their development. By investigating transcriptomic changes (utilizing a RNA-Seq approach) in response to testosterone treatment in the swordtail fish, Xiphophorus hellerii, we aimed to better understand the architecture of the gene regulatory networks underpinning the development of these two evolutionary novelties. Large numbers of genes with tissue-specific expression patterns were identified. Among the "sword genes" those involved in embryonic organ development, sexual character development and coloration were highly expressed, while in the gonopodium rather more morphogenesis-related genes were found. Interestingly, many genes and genetic pathways are shared between both developing novel traits derived from median fins: the sword and the gonopodium. Our analyses show that a larger set of gene networks was co-opted during the development and evolution of the "older" gonopodium than in the "younger," and morphologically less complex trait, the sword. We provide a catalog of candidate genes for future efforts to dissect the development of those sexually selected exaggerated male traits in swordtails.


The Netherlands Arrhythmogenic Cardiomyopathy Registry: design and status update.
Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website ( www.acmregistry.nl ) and patient conferences.


On the accuracy of language trees.
Historical linguistics aims at inferring the most likely language phylogenetic tree starting from information concerning the evolutionary relatedness of languages. The available information are typically lists of homologous (lexical, phonological, syntactic) features or characters for many different languages: a set of parallel corpora whose compilation represents a paramount achievement in linguistics. From this perspective the reconstruction of language trees is an example of inverse problems: starting from present, incomplete and often noisy, information, one aims at inferring the most likely past evolutionary history. A fundamental issue in inverse problems is the evaluation of the inference made. A standard way of dealing with this question is to generate data with artificial models in order to have full access to the evolutionary process one is going to infer. This procedure presents an intrinsic limitation: when dealing with real data sets, one typically does not know which model of evolution is the most suitable for them. A possible way out is to compare algorithmic inference with expert classifications. This is the point of view we take here by conducting a thorough survey of the accuracy of reconstruction methods as compared with the Ethnologue expert classifications. We focus in particular on state-of-the-art distance-based methods for phylogeny reconstruction using worldwide linguistic databases. In order to assess the accuracy of the inferred trees we introduce and characterize two generalizations of standard definitions of distances between trees. Based on these scores we quantify the relative performances of the distance-based algorithms considered. Further we quantify how the completeness and the coverage of the available databases affect the accuracy of the reconstruction. Finally we draw some conclusions about where the accuracy of the reconstructions in historical linguistics stands and about the leading directions to improve it.


Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson's disease.
The molecular mechanisms mediating degeneration of midbrain dopamine neurons in Parkinson's disease (PD) are poorly understood. Here, we provide evidence to support a role for the involvement of the calcium-dependent proteases, calpains, in the loss of dopamine neurons in a mouse model of PD. We show that administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes an increase in calpain-mediated proteolysis in nigral dopamine neurons in vivo. Inhibition of calpain proteolysis using either a calpain inhibitor (MDL-28170) or adenovirus-mediated overexpression of the endogenous calpain inhibitor protein, calpastatin, significantly attenuated MPTP-induced loss of nigral dopamine neurons. Commensurate with this neuroprotection, MPTP-induced locomotor deficits were abolished, and markers of striatal postsynaptic activity were normalized in calpain inhibitor-treated mice. However, behavioral improvements in MPTP-treated, calpain inhibited mice did not correlate with restored levels of striatal dopamine. These results suggest that protection against nigral neuron degeneration in PD may be sufficient to facilitate normalized locomotor activity without necessitating striatal reinnervation. Immunohistochemical analyses of postmortem midbrain tissues from human PD cases also displayed evidence of increased calpain-related proteolytic activity that was not evident in age-matched control subjects. Taken together, our findings provide a potentially novel correlation between calpain proteolytic activity in an MPTP model of PD and the etiology of neuronal loss in PD in humans.


Optical and acoustical interrogation of submicron contrast agents.
Unlike conventional ultrasound contrast agents with a diameter of several microns, in this paper we explore the use of submicron contrast agents for the detection and localization of lymph nodes. The submicron agents are gas-filled, double-walled microspheres that rupture when exposed to ultrasound energy at megahertz frequencies. In this study, three experimental systems are combined with model predictions to assist in understanding the response of these unique agents to a range of signal transmission parameters. Optical experimental results for each agent delineate the relative expansion as a function of acoustical peak negative pressure, pulse length, and center frequency. The optical images demonstrate an order of magnitude expansion in radius during the pulse rarefaction, in which the expansion magnitude is dependent on the transmitted pressure and frequency. Simulations using a modified Rayleigh-Plesset model predict an increasing relative expansion for the microbubbles (initial bubble radius ranging from 0.3-1.3 microm) with increasing pressure and decreasing initial radius. Acoustically recorded frequency spectra reveal the presence of harmonics for a range of transmitted pulses. In addition, in-vivo results from a normal canine model demonstrate marked contrast enhancement of first order lymph nodes. We hope to offer an alternative to present intra-operative procedures for sentinel node detection.


Development and distribution of a human B cell subpopulation identified by the HB-4 monoclonal antibody.
Monoclonal antibodies have been successfully used to identify B cell differentiation antigens, few of which mark discrete B cell subpopulations. We have produced a monoclonal antibody, HB-4, against a cell surface antigen on the human B cell line, BJAB, which has an unusual distribution on normal lymphoid cells. HB-4, an IgM antibody, was found to react with an antigen that is expressed by a subpopulation of B cells, approximately 50% of natural killer cells, and not by other types of cells in bone marrow, blood, and lymphoid tissues. In two-color immunofluorescence assays, the HB-4-reactive antigen was found on less than 5% of immature IgM+ B cells in fetal liver and bone marrow and on 25% of B cells in fetal spleen. The HB-4 antibody reacted with 40% of IgM+ cells in newborn blood and 60% of B cells in adult blood. In contrast, only 2 to 26% of IgM+ B cells in the peripheral lymphoid tissues of adults were HB-4+. HB-4+ B cells could be induced to proliferate by cross-linkage of their surface immunoglobulins but not by T cell-derived growth factors. The subpopulation of activated B cells that is responsive to T cell-derived differentiation factors was HB-4-, as were plasma cells. The HB-4 antibody was reactive with some but not all B cell malignancies and cell lines, and not with malignancies or cell lines of other lineages. The HB-4 antigen may therefore serve as a useful nonimmunoglobulin marker for the identification of a subpopulation of mature resting B cells that are present in the highest frequency in the circulation.


Regulation of hypoxia-inducible factor 2-a is essential for integrity of the glomerular barrier.
Deletion of the von Hippel-Lindau tumor suppressor (Vhl) gene from renal podocytes of mice (podVhl KO) leads to rapidly progressive glomerulonephritis (RPGN), a clinical syndrome characterized by rapid loss of renal function and crescents on renal biopsy. Genomic profiling of glomeruli isolated from podVhl knockout (KO) mice and from patients with RPGN identified a fingerprint of genes regulated by hypoxia-inducible factors (HIF), important substrates of the product of the VHL gene. Here, we show that stabilization of Hifs in podocytes is both required and sufficient for the glomerular phenotype observed in podVhl KO mice. Genetic deletion of the obligate dimerization partner Arnt/Hif1b that is essential for Hif transcriptional function rescues the phenotype. Conversely, stabilization of HIF2A alone in podocytes results in crescentic glomerular disease. Together, our results show that the Hif pathway and Hif2a in particular are key players in maintenance of the glomerular barrier.


Multifunctional Gadolinium-Doped Mesoporous TiO2 Nanobeads: Photoluminescence, Enhanced Spin Relaxation, and Reactive Oxygen Species Photogeneration, Beneficial for Cancer Diagnosis and Treatment.
Materials with controllable multifunctional abilities for optical imaging (OI) and magnetic resonant imaging (MRI) that also can be used in photodynamic therapy are very interesting for future applications. Mesoporous TiO2 sub-micrometer particles are doped with gadolinium to improve photoluminescence functionality and spin relaxation for MRI, with the added benefit of enhanced generation of reactive oxygen species (ROS). The Gd-doped TiO2 exhibits red emission at 637 nm that is beneficial for OI and significantly improves MRI relaxation times, with a beneficial decrease in spin-lattice and spin-spin relaxation times. Density functional theory calculations show that Gd3+ ions introduce impurity energy levels inside the bandgap of anatase TiO2 , and also create dipoles that are beneficial for charge separation and decreased electron-hole recombination in the doped lattice. The Gd-doped TiO2 nanobeads (NBs) show enhanced ability for ROS monitored via • OH radical photogeneration, in comparison with undoped TiO2 nanobeads and TiO2 P25, for Gd-doping up to 10%. Cellular internalization and biocompatibility of TiO2 @xGd NBs are tested in vitro on MG-63 human osteosarcoma cells, showing full biocompatibility. After photoactivation of the particles, anticancer trace by means of ROS photogeneration is observed just after 3 min irradiation.


Optoelectronic wavelet processors based on Smartt interferometry.
Optoelectronic wavelet-processor implementations based on Smartt interferometry are described for both one-dimensional (1-D) and two-dimensional (2-D) wavelet transforms. The 1-D processor study focuses on the processor's capability to perform the wavelet transform when the wavelets are defined in the time domain. The experimental results indicate that the system preserves all the phase information of the selected mother wavelets and thus delivers the true wavelet transform. The 2-D version of the processor is designed for the implementation of the complex wavelet transform. This processor will be valuable for applications, such as image coding-decoding, for which the preservation of phase information is necessary. A pair of prototype processors that incorporates.the 1-D and the 2-D systems has been built and tested to mechanical vibrations. High-quality reconstructed images were also obtained from the experimental data. The proposed systems have great potential for many practical applications.


The alpha-latrotoxin mutant LTXN4C enhances spontaneous and evoked transmitter release in CA3 pyramidal neurons.
Alpha-latrotoxin (LTX) stimulates vesicular exocytosis by at least two mechanisms that include (1) receptor binding-stimulation and (2) membrane pore formation. Here, we use the toxin mutant LTX(N4C) to selectively study the receptor-mediated actions of LTX. LTX(N4C) binds to both LTX receptors (latrophilin and neurexin) and greatly enhances the frequency of spontaneous and miniature EPSCs recorded from CA3 pyramidal neurons in hippocampal slice cultures. The effect of LTX(N4C) is reversible and is not attenuated by La3+ that is known to block LTX pores. On the other hand, LTX(N4C) action, which requires extracellular Ca2+, is inhibited by thapsigargin, a drug depleting intracellular Ca2+ stores, by 2-aminoethoxydiphenyl borate, a blocker of inositol(1,4,5)-trisphosphate-induced Ca2+ release, and by U73122, a phospholipase C inhibitor. Furthermore, measurements using a fluorescent Ca2+ indicator directly demonstrate that LTX(N4C) increases presynaptic, but not dendritic, free Ca2+ concentration; this Ca2+ rise is blocked by thapsigargin, suggesting, together with electrophysiological data, that the receptor-mediated action of LTX(N4C) involves mobilization of Ca2+ from intracellular stores. Finally, in contrast to wild-type LTX, which inhibits evoked synaptic transmission probably attributable to pore formation, LTX(N4C) actually potentiates synaptic currents elicited by electrical stimulation of afferent fibers. We suggest that the mutant LTX(N4C), lacking the ionophore-like activity of wild-type LTX, activates a presynaptic receptor and stimulates Ca2+ release from intracellular stores, leading to the enhancement of synaptic vesicle exocytosis.


Validity of the computer science and applications (CSA) activity monitor in children.
The purpose of this study was to evaluate the validity of the CSA activity monitor as a measure of children's physical activity using energy expenditure (EE) as a criterion measure. Thirty subjects aged 10 to 14 performed three 5-min treadmill bouts at 3, 4, and 6 mph, respectively. While on the treadmill, subjects wore CSA (WAM 7164) activity monitors on the right and left hips. VO2 was monitored continuously by an automated system. EE was determined by multiplying the average VO2 by the caloric equivalent of the mean respiratory exchange ratio. Repeated measures ANOVA indicated that both CSA monitors were sensitive to changes in treadmill speed. Mean activity counts from each CSA unit were not significantly different and the intraclass reliability coefficient for the two CSA units across all speeds was 0.87. Activity counts from both CSA units were strongly correlated with EE (r = 0.86 and 0.87, P < 0.001). An EE prediction equation was developed from 20 randomly selected subjects and cross-validated on the remaining 10. The equation predicted mean EE within 0.01 kcal.min-1. The correlation between actual and predicted values was 0.93 (P < 0.01) and the SEE was 0.93 kcal.min-1. These data indicate that the CSA monitor is a valid and reliable tool for quantifying treadmill walking and running in children.


Solid-state sensors based on Eu3+-containing supramolecular polymers with luminescence colour switching capability.
Polymers that exhibit changes of their luminescence colour in response to external stimuli are attractive candidates for sensing systems. We herein report the preparation of europium-based metallosupramolecular polymers, which can be processed into films and coatings that display readily detectable luminescence colour changes in response to various types of analytes.


Outcome of medial hamstring lengthening in children with spastic paresis: A biomechanical and morphological observational study.
To improve gait in children with spastic paresis due to cerebral palsy or hereditary spastic paresis, the semitendinosus muscle is frequently lengthened amongst other medial hamstring muscles by orthopaedic surgery. Side effects on gait due to weakening of the hamstring muscles and overcorrections have been reported. How these side effects relate to semitendinosus morphology is unknown. This study assessed the effects of bilateral medial hamstring lengthening as part of single-event multilevel surgery (SEMLS) on (1) knee joint mechanics (2) semitendinosus muscle morphology and (3) gait kinematics. All variables were assessed for the right side only. Six children with spastic paresis selected for surgery to counteract limited knee range of motion were measured before and about a year after surgery. After surgery, in most subjects popliteal angle decreased and knee moment-angle curves were shifted towards a more extended knee joint, semitendinosus muscle belly length was approximately 30% decreased, while at all assessed knee angles tendon length was increased by about 80%. In the majority of children muscle volume of the semitendinosus muscle decreased substantially suggesting a reduction of physiological cross-sectional area. Gait kinematics showed more knee extension during stance (mean change ± standard deviation: 34±13°), but also increased pelvic anterior tilt (mean change ± standard deviation: 23±5°). In most subjects, surgical lengthening of semitendinosus tendon contributed to more extended knee joint angle during static measurements as well as during gait, whereas extensibility of semitendinosus muscle belly was decreased. Post-surgical treatment to maintain muscle belly length and physiological cross-sectional area may improve treatment outcome of medial hamstring lengthening.


Diversity by race, Hispanic ethnicity, and sex of the United States medical oncology physician workforce over the past quarter century.
To assess the medical oncology (MO) physician workforce diversity by race, Hispanic ethnicity, and sex, with attention to trainees. Public registries were used to assess 2010 differences among MO practicing physicians, academic faculty, and fellows; internal medicine (IM) residents; and the US population, using binomial tests with P < .001 significance adjusting for multiple comparisons. Significant changes in fellow representation from 1986 to 2011 were assessed. Female representation as MO fellows (45.0%) was significantly increased compared with faculty (22.4%) and practicing physicians (27.4%); was no different than IM residents (44.7%, P = .853); and increased significantly, by 1.0% per year. Women were significantly underrepresented as practicing physicians, faculty, and fellows compared with the US population (50.8%). Traditionally underrepresented minorities in medicine (URM) were significantly underrepresented as practicing physicians (7.8%), faculty (5.7%), and fellows (10.9%), versus US population (30.0%). Hispanic MO fellows (7.5%) were increased compared with faculty (3.9%) and practicing physicians (4.1%); Black fellows (3.1%) were no different than faculty (1.8%, P = .0283) or practicing physicians (3.5%, P = .443). When comparing MO fellows versus IM residents, there were no differences for American Indians/Alaska Natives/Native Hawaiians/Pacific Islanders (0.3%, 0.6%, respectively, P = .137) and Hispanics (7.5%, 8.7%, P = .139), unlike Blacks (3.1%, 5.6%, P < .001). There has been no significant change in URM representation, with negligible changes every 5 years for American Indians/Alaska Natives/Native Hawaiians/Pacific Islanders (-0.1%), Blacks (-0.3%), and Hispanics (0.3%). Female fellow representation increased 1% per year over the quarter century indicating historical gains, whereas URM diversity remains unchanged. For Blacks alone, representation as MO fellows is decreased compared with IM residents, suggesting greater disparity in MO training.


Patched 1 Expression Correlates with Biochemical Relapse in High-Risk Prostate Cancer Patients.
There is an unmet clinical need for adequate biomarkers to aid risk stratification and management of prostate cancer (PCa) patients. Even within the high-risk PCa category, not all patients will invariably have a poor prognosis, and improved stratification of this heterogeneous group is needed. In this context, components of the hedgehog (Hh) pathway may have promise as biomarkers, because the available evidence suggests increased Hh pathway activity may confer a poorer outcome in advanced and castrate-resistant PCa. In this study, potential associations between Hh pathway protein expression and clinicopathological factors, including time to biochemical recurrence (BCR), were investigated using a tissue microarray constructed from benign and malignant prostate samples from 75 predominantly high-risk PCa patients who underwent radical prostatectomy. Hh signaling activity was found to differ between benign and malignant prostate tissue, with a greater amount of active Hh signaling present in malignant than benign prostate epithelium. High expression of Patched 1 in malignant prostate epithelium was found to be an independent predictor of BCR in high-risk PCa patients. Glioma-associated oncogene 1 may potentially represent a clinically useful biomarker of an aggressive tumor phenotype. Evaluation of Hh signaling activity in PCa patients may be useful for risk stratification, and epithelial Patched 1 expression, in particular, may be a prognostic marker for BCR in high-risk PCa patients.


Economic value in the Brain: A meta-analysis of willingness-to-pay using the Becker-DeGroot-Marschak auction.
Forming and comparing subjective values (SVs) of choice options is a critical stage of decision-making. Previous studies have highlighted a complex network of brain regions involved in this process by utilising a diverse range of tasks and stimuli, varying in economic, hedonic and sensory qualities. However, the heterogeneity of tasks and sensory modalities may systematically confound the set of regions mediating the SVs of goods. To identify and delineate the core brain valuation system involved in processing SV, we utilised the Becker-DeGroot-Marschak (BDM) auction, an incentivised demand-revealing mechanism which quantifies SV through the economic metric of willingness-to-pay (WTP). A coordinate-based activation likelihood estimation meta-analysis analysed twenty-four fMRI studies employing a BDM task (731 participants; 190 foci). Using an additional contrast analysis, we also investigated whether this encoding of SV would be invariant to the concurrency of auction task and fMRI recordings. A fail-safe number analysis was conducted to explore potential publication bias. WTP positively correlated with fMRI-BOLD activations in the left ventromedial prefrontal cortex with a sub-cluster extending into anterior cingulate cortex, bilateral ventral striatum, right dorsolateral prefrontal cortex, right inferior frontal gyrus, and right anterior insula. Contrast analysis identified preferential engagement of the mentalizing-related structures in response to concurrent scanning. Together, our findings offer succinct empirical support for the core structures participating in the formation of SV, separate from the hedonic aspects of reward and evaluated in terms of WTP using BDM, and show the selective involvement of inhibition-related brain structures during active valuation.


De novo synthesis of steroids and oxysterols in adipocytes.
Local production and action of cholesterol metabolites such as steroids or oxysterols within endocrine tissues are currently recognized as an important principle in the cell type- and tissue-specific regulation of hormone effects. In adipocytes, one of the most abundant endocrine cells in the human body, the de novo production of steroids or oxysterols from cholesterol has not been examined. Here, we demonstrate that essential components of cholesterol transport and metabolism machinery in the initial steps of steroid and/or oxysterol biosynthesis pathways are present and active in adipocytes. The ability of adipocyte CYP11A1 in producing pregnenolone is demonstrated for the first time, rendering adipocyte a steroidogenic cell. The oxysterol 27-hydroxycholesterol (27HC), synthesized by the mitochondrial enzyme CYP27A1, was identified as one of the major de novo adipocyte products from cholesterol and its precursor mevalonate. Inhibition of CYP27A1 activity or knockdown and deletion of the Cyp27a1 gene induced adipocyte differentiation, suggesting a paracrine or autocrine biological significance for the adipocyte-derived 27HC. These findings suggest that the presence of the 27HC biosynthesis pathway in adipocytes may represent a defense mechanism to prevent the formation of new fat cells upon overfeeding with dietary cholesterol.


Tunable structure priors for Bayesian rule learning for knowledge integrated biomarker discovery.
To develop a framework to incorporate background domain knowledge into classification rule learning for knowledge discovery in biomedicine. Bayesian rule learning (BRL) is a rule-based classifier that uses a greedy best-first search over a space of Bayesian belief-networks (BN) to find the optimal BN to explain the input dataset, and then infers classification rules from this BN. BRL uses a Bayesian score to evaluate the quality of BNs. In this paper, we extended the Bayesian score to include informative structure priors, which encodes our prior domain knowledge about the dataset. We call this extension of BRL as BRLp. The structure prior has a λ hyperparameter that allows the user to tune the degree of incorporation of the prior knowledge in the model learning process. We studied the effect of λ on model learning using a simulated dataset and a real-world lung cancer prognostic biomarker dataset, by measuring the degree of incorporation of our specified prior knowledge. We also monitored its effect on the model predictive performance. Finally, we compared BRLp to other state-of-the-art classifiers commonly used in biomedicine. We evaluated the degree of incorporation of prior knowledge into BRLp, with simulated data by measuring the Graph Edit Distance between the true data-generating model and the model learned by BRLp. We specified the true model using informative structure priors. We observed that by increasing the value of λ we were able to increase the influence of the specified structure priors on model learning. A large value of λ of BRLp caused it to return the true model. This also led to a gain in predictive performance measured by area under the receiver operator characteristic curve (AUC). We then obtained a publicly available real-world lung cancer prognostic biomarker dataset and specified a known biomarker from literature [the epidermal growth factor receptor (EGFR) gene]. We again observed that larger values of λ led to an increased incorporation of EGFR into the final BRLp model. This relevant background knowledge also led to a gain in AUC. BRLp enables tunable structure priors to be incorporated during Bayesian classification rule learning that integrates data and knowledge as demonstrated using lung cancer biomarker data.


[Atypical hemolytic uremic syndrome. Report of two cases treated with Eculizumab].
Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy where organic damage predominates in the kidney. Atypical HUS (aHUS) is a rare disease that affects young adults and causes terminal chronic renal failure ending in dialysis, in most cases. It also recurs after kidney transplantation. aHUS is associated with genetic defects of the alternative complement pathway or its activation by other factors such as drugs, autoimmune diseases, infections, malignant hypertension and ischemia-reperfusion. We report two women aged 17 and 25 years old with catastrophic aHUS. In both cases, complement amplifying factors (drugs and infections) were added and acted on a genetic vulnerability to precipitate complement activation and produce aHUS. Both patients developed terminal renal failure and had to undergo hemodialysis. Fortunately, after a broad etiological study, it was possible to make the diagnosis of aHUS and start treatment with Eculizumab, a monoclonal antibody that changed the natural history of aHUS. It inhibits complement activity controlling microangiopathy and preventing the development of end-stage renal disease. It also improves the success rate in kidney transplantation. In the case of our patients, both discontinued dialysis after chronic treatment with Eculizumab.


Early volumetric changes of hippocampus and medial prefrontal cortex following medial temporal lobe resection.
Previous studies have shown that cognitive demands and physical exercise stimulate adult neurogenesis in the dentate gyrus and hippocampus. Recent observations in healthy humans and patients with mild cognitive impairment moreover suggest that training-induced increases in hippocampal volume may be associated with improved memory performance. The corresponding plasticity processes in hippocampal volume may occur on timescales of months to years. For patients with focal lesions in this region, previous functional imaging studies suggest that increased recruitment of the contralateral hippocampus and extratemporal regions may be an important part of the reorganization of episodic memory. However, it is currently unclear whether focal damage to the medial temporal lobe (MTL) induces gray matter (GM) volume changes in the intact contralateral hippocampus and in connected network regions on a shorter timescale. We therefore investigated whether unilateral resection of the MTL, including the hippocampus, induces measurable volumetric changes in the contralateral hippocampus and in the default mode network (DMN). We recruited 31 patients with unilateral left (N = 19) or right (N = 12) hippocampal sclerosis undergoing MTL resection for treatment of drug-resistant epilepsy. Structural MRI was acquired immediately before and 3 months after surgery. Longitudinal voxel-based morphometry (VBM) analysis revealed a significant increase of right hippocampal volume following resection of the left anterior MTL. Furthermore, this patient group showed GM volume increases in the DMN. These results demonstrate significant structural plasticity of the contralateral hippocampus, even in patients with a long-standing unilateral hippocampal dysfunction and structural reorganization processes extending to distant, but functionally connected brain regions.


Darwin and Fisher meet at biotech: on the potential of computational molecular evolution in industry.
Today computational molecular evolution is a vibrant research field that benefits from the availability of large and complex new generation sequencing data - ranging from full genomes and proteomes to microbiomes, metabolomes and epigenomes. The grounds for this progress were established long before the discovery of the DNA structure. Specifically, Darwin's theory of evolution by means of natural selection not only remains relevant today, but also provides a solid basis for computational research with a variety of applications. But a long-term progress in biology was ensured by the mathematical sciences, as exemplified by Sir R. Fisher in early 20th century. Now this is true more than ever: The data size and its complexity require biologists to work in close collaboration with experts in computational sciences, modeling and statistics. Natural selection drives function conservation and adaptation to emerging pathogens or new environments; selection plays key role in immune and resistance systems. Here I focus on computational methods for evaluating selection in molecular sequences, and argue that they have a high potential for applications. Pharma and biotech industries can successfully use this potential, and should take the initiative to enhance their research and development with state of the art bioinformatics approaches. This review provides a quick guide to the current computational approaches that apply the evolutionary principles of natural selection to real life problems - from drug target validation, vaccine design and protein engineering to applications in agriculture, ecology and conservation.


Trans-hydrogen bond deuterium isotope effects of A:T base pairs in DNA.
The chemical shifts of (13)C2 of adenosine residues of DNA were observed to experience a through-space or trans-hydrogen bond isotope effect as a result of deuterium substitution at the imino hydrogen site of base-paired thymidine residues. NMR measurements of several self-complementary DNA duplexes at natural abundance (13)C in 50% H(2)O, 50% D(2)O solvent mixtures yielded an average trans-hydrogen bond isotope effect, (2h)Delta(13)C2, of -47 ppb. The data suggest that stronger hydrogen bonds have more negative (2h)Delta(13)C2 values, which means that A:T N1.H3 hydrogen bonds increase the anharmonicity of the effective vibrational potential of H3. However, (2h)Delta(13)C2 values do not correlate with intra-residue (2)Delta(13)C4 values of thymidine observed here and earlier (Vakonakis et al., 2003), which suggests that (2h)Delta(13)C2 is not determined entirely by hydrogen bond strength. Instead, the variations observed in (2h)Delta(13)C2 values suggest that they may also be sensitive to base pair geometry.


Genetic loci associated with heart rate variability and their effects on cardiac disease risk.
Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74<rg<-0.55) and blood pressure (-0.35<rg<-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.


A selective calix[6]arene-based fluorescent chemosensor for phosphatidylcholine type lipids.
The development of chemosensors that can selectively detect phosphatidylcholines (PCs) in biological samples is of medical relevance considering the importance of these phospholipids in cell growth and survival. Their selective sensing over phosphatidylethanolamines (PEs) is however a challenging task. We report here on the chemosensing capacities of calix[6]tris-pyrenylurea 1, which is able to selectively interact with phosphatidylcholine-type lipids in organic media. Host 1 also binds them in a biphasic chloroform/water solution, opening the way to the design of selective chemosensors for these lipids in biological media. The results obtained by NMR, fluorescence spectroscopy and modelling studies show that the selectivity is the result of the high degree of complementarity between the lipids' zwitterionic phosphatidylcholine headgroup and the receptor's H-bonding donor site and hydrophobic pocket. The mode of recognition is reminiscent of natural systems, such as human phosphatidylcholine transfer proteins (PC-TPs), validating the biomimetic approach adopted in our work.


Microarray analysis of gene expression in soybean roots susceptible to the soybean cyst nematode two days post invasion.
Soybean root cells undergo dramatic morphological and biochemical changes during the establishment of a feeding site in a compatible interaction with the soybean cyst nematode (SCN). We constructed a cDNA microarray with approximately 1,300 cDNA inserts targeted to identify differentially expressed genes during the compatible interaction of SCN with soybean roots 2 days after infection. Three independent biological replicates were grown and inoculated with SCN, and 2 days later RNA was extracted for hybridization to microarrays and compared to noninoculated controls. Statistical analysis indicated that approximately 8% of the genes monitored were induced and more than 50% of these were genes of unknown function. Notable genes that were more highly expressed 2 days after inoculation with SCN as compared to noninoculated roots included the repetitive proline-rich glycoprotein, the stress-induced gene SAM22, ss-1,3-endoglucanase, peroxidase, and those involved in carbohydrate metabolism, plant defense, and signaling.


An analysis of the relative and absolute incidence of somatic morbidity in patients with affective disorders-A nationwide cohort study.
Patients with affective disorder seem to experience higher risks of several somatic diseases, but no studies have provided estimates of both absolute and relative risks for these diseases in the same population. A prospective cohort of all patients age ≥18 years old with a hospital contact with affective disorder between 1997-2014 (n=246,282) and a random sample from the background population (n=167,562) was followed for hospitalizations with cardiovascular disease, diabetes, cancers, chronic obstructive pulmonary disease (COPD), asthma, inflammatory bowel disease, hip fracture, psoriasis, migraine, or dementia. Adjusted absolute and relative risk estimates were calculated using multivariable adjusted Aalen's additive and Cox proportional hazard regression models. After adjustments, the absolute risk difference was 130.6 (95% confidence interval [CI] 125.5-135.7) additional cases per 10,000 person-years among affective disorder patients compared to the reference population. The corresponding hazard ratio for any somatic disease was 1.50 (95% CI 1.48-1.52). The strongest associations were found for dementia, hip fracture, COPD, and stroke on both the relative and absolute scale. The patients did not have higher risk of cancers except for lung cancer and brain tumors. Risk estimates tended to be slightly higher for individuals with depression or other affective disorder compared to bipolar disorder. Limitations include use of register-based data, risk of reverse causation and Berkson's bias. Patients with affective disorder have both higher absolute and relative risk of most somatic diseases except for cancers. Further identification of the shared mechanisms will facilitate the development of targeted interventions.


A Descriptive Study of Hospital- and Community-acquired Pressure Ulcers/Injuries.
Hospital-acquired pressure ulcers/injuries (HAPU/I) have been a major focus of research, but information about community-acquired pressure ulcer/injuries (CAPU/I) is limited. The aim of this study was to compare HAPU/I and CAPU/I in a 620-bed academic medical center in the western United States. This descriptive study involved prospective/retrospective data collected from the National Data for Nursing Quality Indicators, including pressure ulcer stage (January 1, 2015, through December 31, 2017); the hospital's incident reporting system (January 1, 2017, through December 31, 2017); electronic medical records (EMR) as needed for verification; and the hospital's pressure ulcer registry (January 1, 2012, through December 31, 2017), developed by both EMR and manual extraction. Data regarding point prevalence, length of stay (LOS), source of admission, ulcer stage, and frequency of hospital encounters from patients at least 18 years of age with a pressure ulcer/injury documented in their records were abstracted. Data from pregnant or incarcerated persons and persons with missing or incomplete information on staging or origin of admission were excluded. Variables were analyzed using descriptive statistics. The number of patients with data reviewed for point prevalence was 1787 for 2015, 1989 for 2016, and 1917 for 2017. For 2015, the average CAPU/I and HAPU/I point prevalence was 6.6% and 0.8%, respectively; for 2016, 6.0% and 1.5%, respectively; and for 2017, 6.9% and 0.9%, respectively. The average LOS for patients analyzed for 2017 admitted with a CAPU/I or HAPU/I was 10.5 days and 38.9 days, respectively. Hospital encounters were more frequent in the CAPU/I than in the HAPU/I group, with 821 CAPU/encounters compared to 45 HAPU/I encounters. The majority of patients with a HAPU/I (80%) or CAPU/I (65.4%) were admitted from home. In this study, CAPU/I were more prevalent than HAPU/I and most patient encounters originated from home. More descriptive research that includes staging and source of admission is needed to document the rate of CAPU/I and characteristics of HAPU/I compared to CAPU/I in order to optimize pressure ulcer/injury practices across the continuum of care.


First Report of Botryosphaeria dothidea Causing White Rot of Apple Fruit in Serbia.
Botryosphaeria dothidea (Moug.: Fr.) Ces. & De Not has a worldwide distribution infecting species from over 80 genera of plants (1). Apart from being an important pathogen of apple trees in many countries, B. dothidea can cause pre- and postharvest decay on apple fruit (2). It has been known to cause canker and dieback of forest trees in Serbia (3), but has not been recorded either on apple trees or apple fruit. In December 2010, apple fruit cv. Idared (Malus × domestica Borkh.) with symptoms of white rot were collected from one storage in the area of Svilajnac in Serbia. The incidence of the disease was low but the symptoms were severe. Affected fruit were brown, soft, and almost completely decayed, while the internal decayed tissue appeared watery and brown. A fungus was isolated from symptomatic tissue of one fruit after surface sterilization with 70% ethanol (without rinsing) and aseptic removal of the skin. Small fragments of decayed tissue were placed on potato dextrose agar (PDA) and incubated in a chamber at 22°C under alternating light and dark conditions (12/12 h). Fungal colonies were initially whitish, but started turning dark gray to black after 5 to 6 days. Pycnidia were produced after 20 to 25 days of incubation at 22°C and contained one-celled, elliptical, hyaline conidia. Conidia were 17.19 to 23.74 μm (mean 18.93) × 3.72 to 4.93 μm (mean 4.45) (n = 50). These morphological characteristics are in accordance with those described for the fungus B. dothidea (4). Genomic DNA was isolated from the fungus and internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced. The nucleotide sequence has been assigned to GenBank Accession No. KC994640. BLAST analysis of the 528-bp segment showed a 100% similarity with several sequences of B. dothidea deposited in NCBI GenBank, which confirmed morphological identification. Pathogenicity was tested by wound inoculation of five surface-sterilized, mature apple fruit cv. Idared with mycelium plugs (5 mm in diameter) of the isolate grown on PDA. Five control fruit were inoculated with sterile PDA plugs. After 5 days of incubation in plastic containers, under high humidity (RH 90 to 95%) at 22°C, typical symptoms of white rot developed on inoculated fruit, while wounded, uninoculated, control fruit remained symptomless. The isolate recovered from symptomatic fruit showed the same morphological features as original isolate. To the best of our knowledge, this is the first report of B. dothidea on apple fruit in Serbia. Apple is widely grown in Serbia and it is important to further investigate the presence of this pathogen in apple storage, as well as in orchards since B. dothidea may cause rapid disease outbreaks that result in severe losses. References: (1) G. H. Hapting Agriculture Handbook 386, USDA, Forest Service, 1971. (2) A. L. Jones and H. S. Aldwinckle Compendium of Apple and Pear Diseases. APS Press, St. Paul, MN, 1990. (3) D. Karadžic et al. Glasnik Šumarskog Fakulteta 83:87, 2000. (4) B. Slippers et al. Mycologia 96:83, 2004.


Hyperspectral image representation and processing with binary partition trees.
The optimal exploitation of the information provided by hyperspectral images requires the development of advanced image-processing tools. This paper proposes the construction and the processing of a new region-based hierarchical hyperspectral image representation relying on the binary partition tree (BPT). This hierarchical region-based representation can be interpreted as a set of hierarchical regions stored in a tree structure. Hence, the BPT succeeds in presenting: 1) the decomposition of the image in terms of coherent regions, and 2) the inclusion relations of the regions in the scene. Based on region-merging techniques, the BPT construction is investigated by studying the hyperspectral region models and the associated similarity metrics. Once the BPT is constructed, the fixed tree structure allows implementing efficient and advanced application-dependent techniques on it. The application-dependent processing of BPT is generally implemented through a specific pruning of the tree. In this paper, a pruning strategy is proposed and discussed in a classification context. Experimental results on various hyperspectral data sets demonstrate the interest and the good performances of the BPT representation.


Drunken-cell footprints: nuclease treatment of ethanol-permeabilized bacteria reveals an initiation-like nucleoprotein complex in stationary phase replication origins.
The nucleoprotein complex formed on oriC, the Escherichia coli replication origin, is dynamic. During the cell cycle, high levels of the initiator DnaA and a bending protein, IHF, bind to oriC at the time of initiation of DNA replication, while binding of Fis, another bending protein, is reduced. In order to probe the structure of nucleoprotein complexes at oriC in more detail, we have developed an in situ footprinting method, termed drunken-cell footprinting, that allows enzymatic DNA modifying reagents access to intracellular nucleoprotein complexes in E.coli, after a brief exposure to ethanol. With this method, we observed in situ binding of Fis to oriC in exponentially growing cells, and binding of IHF to oriC in stationary cells, using DNase I and Bst NI endonuclease, respectively. Increased binding of DnaA to oriC in stationary phase was also noted. Because binding of DnaA and IHF results in unwinding of oriC in vitro, P1 endonuclease was used to probe for intracellular unwinding of oriC. P1 cleavage sites, localized within the 13mer unwinding region of oriC ', were dramatically enhanced in stationary phase on wild-type origins, but not on mutant versions of oriC unable to unwind. These observations suggest that most oriC copies become unwound during stationary phase, forming an initiation-like nucleoprotein complex.


Depression and Incident HIV in Adolescent Girls and Young Women in HIV Prevention Trials Network 068: Targets for Prevention and Mediating Factors.
The human immunodeficiency virus (HIV) epidemic among adolescent girls and young women (AGYW) in sub-Saharan Africa is a critical public health problem. We assessed whether depressive symptoms in AGYW were longitudinally associated with incident HIV, and identified potential social and behavioral mediators. Data came from a randomized trial of a cash transfer conditional on school attendance among AGYW (ages 13-21 years) in rural Mpumalanga Province, South Africa, during 2011-2017. We estimated the relationship between depressive symptoms and cumulative HIV incidence using a linear probability model, and we assessed mediation using inverse odds ratio weighting. Inference was calculated using the nonparametric bootstrap. AGYW with depressive symptoms had higher cumulative incidence of HIV compared with those without (risk difference = 3.5, 95% confidence interval (CI): 0.1, 7.0). The strongest individual mediators of this association were parental monitoring and involvement (indirect effect = 1.6, 95% CI: 0.0, 3.3) and reporting a partner would hit her if she asked him to wear a condom (indirect effect = 1.5, 95% CI: -0.3, 3.3). All mediators jointly explained two-thirds (indirect effect = 2.4, 95% CI: 0.2, 4.5) of the association between depressive symptoms and HIV incidence. Interventions addressing mental health might reduce risk of acquiring HIV among AGYW.


[Basic aspects of the potential toxicity of anesthetic drugs].
Brain development is a complex phenomenon in which several stages of production, maturation, and organization of neural cells in a network succeed each other. Various environmental factors can disrupt these stages. During the last decade, numerous in vitro and in vivo experimental studies in newborn animal models have established the neurotoxic effects of most anesthetic and sedative drugs used in pediatrics. These effects are essentially responsible for neuronal apoptosis and have been associated with learning disorders in adulthood. This neurotoxicity is time-varying: there is a vulnerability period during synaptogenesis. These toxic effects were attributed to agonist properties on GABA receptors or antagonist properties on NMDA receptors, which are characteristics of all implicated anesthetics. Excessive activation of the GABA pathway and/or excessive inhibition of the NMDA pathway activate cellular mechanisms leading to apoptosis. The intensity of neurotoxic effects is dose- and time-exposure-dependent. These numerous experimental data must be interpreted with caution with regard to their validity in humans, mainly because of interspecies differences as well as differences between experimental conditions and clinical practice. Today, these data are insufficient to change our practices, taking into account the indisputable benefits of the use of anesthetics and sedative drugs. However, progress in experimental research will help us identify the safest therapeutic strategies and neuroprotective treatments.


The role of vasopressin in blood pressure control and in experimental hypertension.
1. The role of vasopressin in blood pressure control and in the pathogenesis of one-kidney Goldblatt hypertension in the conscious dog was investigated. 2. Infusion of synthetic arginine vasopressin to elevate plasma levels approximately five-fold caused bradycardia in normal dogs and increase in mean arterial blood pressure in dogs with pharmacological autonomic blockade. 3. A similar degree of elevation of plasma vasopressin concentration was observed after mild non-hypotensive haemorrhage. 4. Renal artery constriction in unilaterally-nephrectomized dogs caused a rise in plasma renin activity and only a doubling of plasma vasopressin concentration, but a marked rise in mean arterial blood pressure. 5. Vasopressin may play a role in normal cardiovascular homeostatic responses, but its role in the pathogenesis of this form of hypertension is unlikely to be significant.


Effects of tailored neck-shoulder pain treatment based on a decision model guided by clinical assessments and standardized functional tests. A study protocol of a randomized controlled trial.
A major problem with rehabilitation interventions for neck pain is that the condition may have multiple causes, thus a single treatment approach is seldom efficient. The present study protocol outlines a single blinded randomised controlled trial evaluating the effect of tailored treatment for neck-shoulder pain. The treatment is based on a decision model guided by standardized clinical assessment and functional tests with cut-off values. Our main hypothesis is that the tailored treatment has better short, intermediate and long-term effects than either non-tailored treatment or treatment-as-usual (TAU) on pain and function. We sub-sequentially hypothesize that tailored and non-tailored treatment both have better effect than TAU. 120 working women with minimum six weeks of nonspecific neck-shoulder pain aged 20-65, are allocated by minimisation with the factors age, duration of pain, pain intensity and disability in to the groups tailored treatment (T), non-tailored treatment (NT) or treatment-as-usual (TAU). Treatment is given to the groups T and NT for 11 weeks (27 sessions evenly distributed). An extensive presentation of the tests and treatment decision model is provided. The main treatment components are manual therapy, cranio-cervical flexion exercise and strength training, EMG-biofeedback training, treatment for cervicogenic headache, neck motor control training. A decision algorithm based on the baseline assessment determines the treatment components given to each participant of T- and NT-groups. Primary outcome measures are physical functioning (Neck Disability Index) and average pain intensity last week (Numeric Rating Scale). Secondary outcomes are general improvement (Patient Global Impression of Change scale), symptoms (Profile Fitness Mapping neck questionnaire), capacity to work in the last 6 weeks (quality and quantity) and pressure pain threshold of m. trapezius. Primary and secondary outcomes will be reported for each group with effect size and its precision. We have chosen not to include women with psychological ill-health and focus on biomedical aspects of neck pain. Future studies should aim at including psychosocial aspects in a widened treatment decision model. No important adverse events or side-effects are expected.


Current status of esophageal cancer treatment.
Esophageal cancer (EC) remains one of the most common and aggressive diseases worldwide. This review discusses some debates in the modern management of the disease. Endoscopic procedures for early cancer (T1a-b) are now embedded in routine care and the challenge will be to more accurately select patients for endoscopic resection with or without adjuvant therapy. Perioperative multimodal therapies are associated with improved survival compared to surgery alone for locally advanced esophageal cancer. However, there is no global consensus on the optimal regimen. Furthermore, histological subtype (adenocarcinomavs. squamous cell cancer) plays a role in the choice for treatment. New studies are underway to resolve some issues. The extent of the lymphadenectomy during esophagectomy remains controversial especially after neoadjuvant chemoradiation. The ideal operation balances between limiting surgical trauma and optimizing survival. Minimally invasive esophagectomy and enhanced recovery pathways are associated with decreased morbidity and faster recovery albeit there is no consensus yet what approach should be used. Finally, immune checkpoint inhibitors present promising preliminary results in the novel treatment of advanced or metastatic EC but their widespread application in clinical practice is still awaited.


Coping in normal pregnancy.
In high-risk populations (e.g., adolescents, substance abusers), coping strategies in pregnancy have been studied. Avoidance of the stressful situation and aggressive coping are frequently used and related to postnatal depression and other negative outcomes. Little is known about coping strategies in nulliparous normal-risk pregnancy. To examine the factor structure of the 19-item Utrecht Coping List (UCL-19) in a sample of nulliparous normal-risk pregnant women and to explore the stability, change, and correlates of coping strategies throughout pregnancy. The associations between a particular coping strategy and the reported pregnancy complaints and experienced distress were examined. The UCL-19 was filled out and self-report data were collected about neuroticism, locus of control, depression, general anxiety, perceived stress, and physical pregnancy complaints in nulliparous women in early, mid-, and late pregnancy. Confirmatory factor analysis on the UCL-19 revealed 2 coping strategies: emotion-focused coping and problem-focused coping. The factor structure of the UCL-19 had a good stability throughout pregnancy. Some changes in emotion-focused coping and problem-focused coping scores were found, although the absolute differences were rather small. High educational level and low internal locus of control predicted a high score on emotion-focused coping in the early period of pregnancy, F(2, 228) = 11.49, p < .005, R2 = .22. High educational level also predicted a high score on problem-focused coping in early pregnancy, F(1, 229) = 4.80, p < .05, R2 = .06. Emotion-focused coping was negatively and problem-focused coping was positively related to pregnancy complaints (r = -.23, p < .05 and r = .25, p < .005, respectively). Emotion-focused coping in early pregnancy and problem-focused coping in mid-pregnancy were negatively related to experienced distress in early and mid pregnancy, respectively (r = -.27, p < .0005 and r = -.18, p < .01). Two coping strategies were consistently found throughout pregnancy: emotion-focused coping and problem-focused coping. Coping in nulliparous normal-risk pregnancy is a process with small temporal variations. Emotion-focused coping was negatively related to the number of reported pregnancy complaints and to experienced distress.


Fractal and stochastic geometry inference for breast cancer: a case study with random fractal models and Quermass-interaction process.
Fractals are models of natural processes with many applications in medicine. The recent studies in medicine show that fractals can be applied for cancer detection and the description of pathological architecture of tumors. This fact is not surprising, as due to the irregular structure, cancerous cells can be interpreted as fractals. Inspired by Sierpinski carpet, we introduce a flexible parametric model of random carpets. Randomization is introduced by usage of binomial random variables. We provide an algorithm for estimation of parameters of the model and illustrate theoretical and practical issues in generation of Sierpinski gaskets and Hausdorff measure calculations. Stochastic geometry models can also serve as models for binary cancer images. Recently, a Boolean model was applied on the 200 images of mammary cancer tissue and 200 images of mastopathic tissue. Here, we describe the Quermass-interaction process, which can handle much more variations in the cancer data, and we apply it to the images. It was found out that mastopathic tissue deviates significantly stronger from Quermass-interaction process, which describes interactions among particles, than mammary cancer tissue does. The Quermass-interaction process serves as a model describing the tissue, which structure is broken to a certain level. However, random fractal model fits well for mastopathic tissue. We provide a novel discrimination method between mastopathic and mammary cancer tissue on the basis of complex wavelet-based self-similarity measure with classification rates more than 80%. Such similarity measure relates to Hurst exponent and fractional Brownian motions. The R package FractalParameterEstimation is developed and introduced in the paper.


Incidental Finding of Gastric Schwannoma in a Renal Failure Patient - Managed by a Minimally Invasive Procedure: Report of a Rare Case.
BACKGROUND Schwannomas are benign tumors originating from any nerve with a Schwann cell sheath. It is an extremely rare tumor, accounting for 0.2% of all gastrointestinal tumors and 4% of all benign tumors of the stomach. Clinical differentiation of gastrointestinal mesenchymal tumors is challenging and confirmatory diagnosis requires biopsy. Surgical resection is the treatment of choice when tumor size is less than 30 mm or when it is located within the muscularis propria. Here, we present a case of a large (>50 mm) gastric Schwannoma that was resected using a new laparoscopic technique suitable for larger tumors. CASE REPORT A 69-year-old woman with past medical history of hypertension, diabetes mellitus, and stroke, and CKD stage 4, presented to the Emergency Department (ED) with persistent nausea, vomiting, and weakness. She was found to have uremia requiring emergent hemodialysis. Eventually, she underwent peritoneal catheter insertion for peritoneal dialysis. A mass on the gastric antrum was found incidentally during the procedure. Biopsy confirmed the diagnosis of gastric Schwannoma. The tumor was removed successfully using a minimally invasive procedure via robotic-assisted laparoscopy. CONCLUSIONS Gastric Schwannoma is a rare submucosal tumor arising from Auerbach's plexus in the muscularis propria. It is usually asymptomatic, but can present with symptoms such as epigastric pain, or upper gastrointestinal bleeding. Tissue biopsy and immunohistochemical staining are the criterion standard for diagnosis. It has no tendency for malignant transformation. Tumors smaller than 30 mm are removed endoscopically, while tumors larger than 30 mm can be removed surgically. In this case, the tumor was removed successfully by minimally invasive robotic-assisted laparoscopy.


Impaired osteoblastogenesis potential of progenitor cells in skeletal unloading is associated with alterations in angiogenic and energy metabolism profile.
Skeletal unloading provokes bone loss. These bone alterations have been shown to be associated with impairment of osteoblastic activity. In the present study, we evaluated the effect of skeletal unloading on bone marrow progenitor cells, for exploration of the underlying mechanism. Wistar rats were randomized to be either hindlimb unloaded for 9 days or to act as controls. Micro-CT was used to detect tibial trabecular architecture changes in response to skeletal unloading. Microgravity conditions for 9 days resulted in a decreased number and an increased spacing of the bone trabeculae in the proximal tibia. The proliferative capacity of the femoral bone marrow samples was assessed (fibroblast-colony-forming assay). By using qPCR, the expression of selected markers of vascularization (Vegfa; Hif1a; Angpt1), energy metabolism (Prkaa2; Mtor), bone formation (Runx2; Alp; Bglap; Bmp2; Bmp4; Bmp7) and bone resorption (Acp5; Tnfsf11; Tnfrsf11b) in these bone marrow suspensions was measured. We demonstrated a striking decrease in the number of fibroblastic progenitors in response to hindlimb unloading. This deficit in proliferation was shown to be accompanied by altered hindlimb perfusion and cellular energy homeostasis. Ex vivo culture assays of the bone marrow-derived progenitor cells screened for osteogenic (Runx2; Alp; Bglap) and adipogenic (Pparg; Fabp4) differentiation alterations in response to microgravity. Induced progenitor cells from unloaded rats showed a delay in osteogenic differentiation and impaired adipogenic differentiation compared to control. The data of this multi-level approach demonstrate that skeletal unloading significantly affects the bone tissue and its metabolism at the progenitor stage. The molecular expressions of the bone marrow population support a role of cellular metabolic stresses in skeletal alterations induced by inactivity.