How Does Severity of Aphasia Influence Individual Responsiveness to Rehabilitation? Using Big Data to Understand Theories of Aphasia Rehabilitation.
Our ability to make great progress in delivering, optimizing, and predicting rehabilitation outcomes for individuals with aphasia is challenged by factors that influence rehabilitation outcomes. These include patient demographic factors such as age, education, and neurologic factors such as time poststroke, the site and size of the lesion, and the resulting severity of language impairment. Also variable across individuals is the type of treatment and its duration and intensity. This article examines the utility of big data analysis for understanding one of these factors, severity of impairment, and how individual responsiveness to rehabilitation is influenced by a patient's severity of language and cognitive impairment(s). Using examples from two studies and a larger data set, we show that when rehabilitation is tailored to an individual's specific level of impairment, severe and mild patients both show improvements in accuracy and latency. Furthermore, more severe patients tend to show substantial gains on targeted rehabilitation tasks as well as on standardized tests. These results provide support for recent reviews of aphasia rehabilitation studies in concluding that systematic aphasia rehabilitation is indeed effective, and importantly, severity is not a negative prognostic indicator for successful outcomes.


Utilization of Quantitative EEG Trends for Critical Care Continuous EEG Monitoring: A Survey of Neurophysiologists.
Quantitative EEG (QEEG) can be used to assist with review of large amounts of data generated by critical care continuous EEG monitoring. This study aimed to identify current practices regarding the use of QEEG in critical care continuous EEG monitoring of critical care patients. An online survey was sent to 796 members of the American Clinical Neurophysiology Society (ACNS), instructing only neurophysiologists to participate. The survey was completed by 75 neurophysiologists that use QEEG in their practice. Survey respondents reported that neurophysiologists and neurophysiology fellows are most likely to serve as QEEG readers (97% and 52%, respectively). However, 21% of respondents reported nonneurophysiologists are also involved with QEEG interpretation. The majority of nonneurophysiologist QEEG data review is aimed to alert neurophysiologists to periods of concern, but 22% reported that nonneurophysiologists use QEEG to directly guide clinical care. Quantitative EEG was used most frequently for seizure detection (92%) and burst suppression monitoring (59%). A smaller number of respondents use QEEG for monitoring the depth of sedation (29%), ischemia detection (28%), vasospasm detection (28%) and prognosis after cardiac arrest (21%). About half of the respondents do not review every page of the raw critical care continuous EEG record when using QEEG. Respondents prefer a panel of QEEG trends displayed as hemispheric data, when applicable. There is substantial variability regarding QEEG trend preferences for seizure detection and ischemia detection. QEEG is being used by neurophysiologists and nonneurophysiologists for applications beyond seizure detection, but practice patterns vary widely. There is a need for standardization of QEEG methods and practices.


High Shedding Potential and Significant Individual Heterogeneity in Naturally-Infected Alpine ibex (Capra ibex) With Brucella melitensis.
Wildlife reservoirs of infectious diseases raise major management issues. In Europe, brucellosis has been eradicated in domestic ruminants from most countries and wild ruminants have not been considered important reservoirs so far. However, a high prevalence of Brucella melitensis infection has been recently identified in a French population of Alpine ibex (Capra ibex), after the emergence of brucellosis was confirmed in a dairy cattle farm and two human cases. This situation raised the need to identify the factors driving the persistence of Brucella infection at high prevalence levels in this ibex population. In the present paper, we studied the shedding pattern of B. melitensis in ibex from Bargy Massif, French Alps. Bacteriological examinations (1-15 tissues/samples per individual) were performed on 88 seropositive, supposedly infected and euthanized individuals. Among them, 51 (58%) showed at least one positive culture, including 45 ibex with at least one Brucella isolation from a urogenital sample or a lymph node in the pelvic area (active infection in organs in the pelvic area). Among these 45 ibex, 26 (30% of the total number of necropsied animals) showed at least one positive culture for a urogenital organ and were considered as being at risk of shedding the bacteria at the time of capture. We observed significant heterogeneity between sex-and-age classes: seropositive females were most at risk to excrete Brucella before the age of 5 years, possibly corresponding to abortion during the first pregnancy following infection such as reported in the domestic ruminants. The high shedding potential observed in young females may have contributed to the self-sustained maintenance of infection in this population, whereas males are supposed to play a role of transmission between spatial units through venereal transmission during mating. This heterogeneity in the shedding potential of seropositive individuals should be considered in the future to better evaluate management scenarios in this system as well as in others.


"Below their notice": exploring women's subjective experiences of cancer system exclusion.
The experiences that marginalized breast cancer populations have in common are rarely considered. The authors look across 3 qualitative studies to explore the experiences of older, lower-income, and Aboriginal women diagnosed with cancer and treated by the cancer care system in Ontario, Canada. The research examines critical moments in participants' narratives that parallel one another and are categorized within 2 themes: Not Getting Cancer Care and Not Getting Supportive Care. Although exploratory, the findings merit attention both for what they tell us about women's experiences, and because they suggest disparities in access to treatment and psychosocial support.


The child healthcare system in Azerbaijan.
The evolution of the child healthcare system in Azerbaijan is described herein. In particular, the article describes the development of child healthcare in the country, with particular focus on the Soviet and post-Soviet period. The organisation of healthcare (treatment and prophylaxis) for the general population, women and children in particular, and the current developing projects and programs are discussed. Finally, the article reports the current major priorities for child healthcare in Azerbaijan.


The current status and issues regarding hospital-based specialized palliative care service in Japanese Regional Cancer Centers: a nationwide questionnaire survey.
Palliative care consultation teams have become part of all Japanese regional cancer centers. However, the current status and issues regarding specialized palliative care service in the cancer centers have yet to be clarified. Therefore, we conducted a nationwide survey of the current status of palliative care service in all Japanese regional cancer centers in 2007. A self-reported cross-sectional survey questionnaire was mailed to all regional cancer centers in Japan. The structure and process of activities of palliative care service were included in the survey questions. A total of 242 of 288 institutions (84%) returned the questionnaires. Responses indicated that 99% had palliative care consultation teams. For the structure of palliative care consultation service, there were 73 ± 133 (mean ± standard deviation) referred patients per year and ∼ 90% had discharge and home care support for patients who needed palliative care; 31% had no available consultation service during the daytime on weekdays. For the process of palliative care consultation service, 90% defined the palliative care consultation request methods, 92% implemented seminars about palliative care for health-care workers in the hospital and 31% had joint meetings with the clinics and home nursing station in the community. Palliative care services have rapidly been developed and implemented in Japan. However, to improve the quality of palliative care services and provide more specialized palliative care within the limits of resources, it will be necessary to review the system in the future.


Helping patients master core conflictual relationship themes in psychotherapy.
An important component of case formulation is to understand the patient's difficulties in the context of their relationships. The Core Conflictual Relationship Theme (CCRT) method provides a clinical guide for understanding the narratives of relationship conflicts told during therapy. We follow the case of Barbara, a 60 year old with a long history of chronic shyness. Her narratives follow a common CCRT: she wishes to feel safe, but fears that others are out to get her, which makes her withdraw. These patterns have pervasively repeated themselves in the past, present, and across different relationships (self, family, partners, colleagues). The therapist responds carefully by creating safety, tolerating her fears, and working to overcome these CCRT patterns, thus reducing her impulse to withdraw from treatment. Psychotherapists from many theoretical orientations can learn how patients mastering these repetitive negative CCRTs can lead to more adaptive relationship patterns that improve their mental health.


[Cará-de-rama (Dioscorea bulbifera, L) fried processing].
The present study examined the influence of density of the aerial bulbs in the variables: fat absorption, fry time and yield of the cara-de-rama chips and french fries, as well as organoleptic analysis of fried products. The results showed that there was no differences between the bulbs densities, in the variables examined, except for the moisture of cara-de-rama chips. In the organoleptical analysis, the samples did not show significant differences in relation to similar potato products.


Proper chromatin condensation and maintenance of histone H3 phosphorylation during mouse oocyte meiosis requires protein phosphatase activity.
We have shown okadaic acid (OA) and calyculin-A (CLA) inhibition of mouse oocyte phosphoprotein phosphatase 1 (PPP1C) and/or phosphoprotein phosphatase 2A (PPP2CA) results in aberrant chromatin condensation, as evidenced by the inability to resolve bivalents. Phosphorylation of histone H3 at specific residues is thought to regulate chromatin condensation. Therefore, we examined changes in histone H3 phosphorylation during oocyte meiosis and the potential regulation by protein PPPs. Western blot and immunocytochemical analysis revealed histone H3 phosphorylation changed during mouse oocyte meiosis, with changes in chromatin condensation. Germinal vesicle-intact (GV-intact; 0 h) oocytes had no phospho-Ser10 but did have phospho-Ser28 histone H3. Oocytes that had undergone germinal vesicle breakdown (GVBD; 2 h) and progressed to metaphase I (MI; 7 h) and MII (16 h) had phosphorylated Ser10 and Ser28 histone H3 associated with condensed chromatin. To determine whether OA-induced aberrations in chromatin condensation were due to alterations in levels of histone H3 phosphorylation, we assessed phosphorylation of Ser10 and Ser28 residues following PPP inhibition. Oocytes treated with OA (1 microM) displayed increased phosphorylation of histone H3 at both Ser10 and Ser28 compared with controls. To begin to elucidate which OA-sensitive PPP is responsible for regulating chromatin condensation and histone H3 phosphorylation, we examined spatial and temporal localization of OA-sensitive PPPs, PPP1C, and PPP2CA. PPPC2A did not localize to condensed chromatin, whereas PPP1beta (PPP1CB) associated with condensing chromatin in GVBD, MI, and MII oocytes. Additionally, Western blot and immunocytochemistry confirmed presence of the PPP1C regulatory inhibitor subunit 2 (PPP1R2) in oocytes at condensed chromatin during meiosis and indicated a change in PPP1R2 phosphorylation. Inhibition of oocyte glycogen synthase kinase 3 (GSK3) appeared to regulate phosphorylation of PPP1R2. Furthermore, inhibition of GSK3 resulted in aberrant oocyte bivalent formation similar to that observed following PPP inhibition. These data suggest that PPP1CB is the OA/CLA-sensitive PPP that regulates oocyte chromatin condensation through regulation of histone H3 phosphorylation. Furthermore, GSK3 inhibition results in aberrant chromatin condensation and appears to regulate phosphorylation of PPP1R2.


An environmentally friendly and cost effective technique for the commercial cultivation of oyster mushroom [Pleurotus florida (Mont.) Singer].
The existing protocol for the cultivation of oyster mushroom (Pleurotus florida) in polyethylene bags leads to environmental pollution amounting to 18 g of polyethylene per 450 g of mushroom, which is the average biological efficiency achieved from a bag. Thus the projected annual global pollution amounts to 2 million tones, corresponding to the production of 48 million tones. Experiments were conducted at Kerala Agricultural University, India, to formulate an oyster mushroom cultivation strategy that reduces this pollution level. Pooled results of experiments at the institute's and farmers' units have shown that reusable plastic buckets having perforations of 1.5 cm × 1.0 cm throughout the side walls could be used to substitute polyethylene bags, while following the standard cultivation protocols. Cultivation in perforated buckets has recorded a biological efficiency of 435.69 ± 56.75 g in 47.07 ± 5.22 days against 459.11 ± 53.52 g in 38.05 ± 4.54 days in polyethylene bags. The rate of contamination in buckets was significantly lower than that in bags: 9.28 ± 2.12 and 12.60 ± 3.73% respectively. Reusable plastic buckets with perforations on the side walls could be used to substitute the conventional polyethylene bags in oyster mushroom cultivation, with no significant difference in yield. Losses due to slight increase in crop duration in buckets will be compensated with a lower rate of contamination. For a unit having a daily output of 100 kg, it was estimated that during 10 years of permanent cultivation following this technique, the cost of cultivation could be reduced to one-tenth and the environmental pollution reduced by at least 730 000 non-degradable polyethylene bags.


Opioid use in patients with rheumatoid arthritis 2005-2014: a population-based comparative study.
Opioid prescriptions have seen an increase across the USA, Canada, Europe, and the UK. In the USA, they have quadrupled from 1999 to 2010. Opioid use among patients with rheumatoid arthritis (RA) over time is not well described. This study examined trends of opioid use in patients with RA. Retrospective prescription data was examined from 2005 to 2014 in a population-based incidence cohort of patients with RA by 1987 ACR criteria and comparable non-RA subjects. Differences in opioid use were examined with Poisson models. A total of 501 patients with RA (71 % female) and 532 non-RA subjects (70 % female) were included in the study. Total and chronic opioid use in 2014 was substantial in both cohorts 40 % RA vs 24 % non-RA and 12 % RA vs. 4 % non-RA, respectively. Opioid use increased by 19 % per year in both cohorts during the study period (95 % confidence interval [CI] 1.15, 1.25). Relative risk (RR) of chronic opiate use for RA patients compared to non-RA subjects was highest in adults aged 50-64 years (RR 2.82; 95 % CI 1.43-6.23). RA disease characteristics, biologic use at index, treated depression/fibromyalgia, education, and smoking status were not significantly associated with chronic opiate use. Over a third of patients with RA use opioids in some form, and in more than a tenth use is chronic. Use has increased in recent years. Patients aged 50-64 with RA use substantially more opioids than their non-RA counterparts.


Covalent Labeling Denaturation Mass Spectrometry for Sensitive Localized Higher Order Structure Comparisons.
Protein higher order structure (HOS) describes the three-dimensional folding arrangement of a given protein and plays critical roles in structure/function relationships. As such, it is a key product quality attribute that is monitored during biopharmaceutical development. Covalent labeling of surface residues, combined with mass spectrometry analysis, has increasingly played an important role in characterizing localized protein HOS. Since the label can potentially induce conformation changes, protocols generally use a small amount of label to ensure that the integrity of the protein HOS is not disturbed. The present study, however, describes a method that purposely uses high amounts of isobaric label (levels that induce denaturation) to enhance the sensitivity and resolution for detecting localized structural differences between two or more biological products. The method proved to be highly discriminative, detecting differences in HOS affecting as little as 2.5-5% of the molecular population, levels at which circular dichroism and nuclear magnetic resonance spectroscopy fingerprinting, both gold standard HOS techniques, were unable to adequately differentiate. The methodology was shown to have comparable sensitivity to differential scanning calorimetry for detecting HOS differences. In addition, the workflow presented herein can also quantify other product attributes such as post-translational modifications and site-specific glycosylation, using a single liquid chromatography-tandem mass spectrometry (LC-MS/MS) run with automated data analysis. We applied this technique to characterize a large (>90 kDa), multiply glycosylated therapeutic protein under different heat stress conditions and aggregation states.


Prosthetic Valve Endocarditis Caused by ST8 SCCmecIVl Type Community-associated Methicillin-resistant Staphylococcus aureus.
The emergence of a Japan-intrinsic community associated methicillin-resistant Staphylococcus aureus strain (CA-MRSA/J) has been reported. A 70-year-old man with recurrent colon cancer and a history of mitral valve replacement was admitted to the hospital in a state of shock. He was diagnosed with prosthetic valve endocarditis (PVE) caused by MRSA and underwent cardiac surgery. The MRSA isolates belonged to multilocus sequence type 8 and carried staphylococcal cassette chromosome mec IVl and the genes of toxic shock syndrome toxin-1, enterotoxin C, and enterotoxin L. These characteristics indicated a CA-MRSA/J clone. This is the first reported case of PVE caused by CA-MRSA/J.


Development of a vaccine of cross-linked heat-stable and heat-labile enterotoxins that protects against Escherichia coli producing either enterotoxin.
A vaccine of cross-linked heat-stable (ST) and heat-labile (LT) toxins that protects against heterologous serotypes of strains of Escherichia coli which produce either the LT or ST enterotoxin was developed by conjugating ST to LT by the carbodiimide reaction. Three interrelated factors were found to affect the composition and properties of the final conjugate: (i) the amount of carbodiimide added to the toxins, (ii) the initial ratio of ST to LT, and (iii) the duration of the conjugation reaction. Optimal conjugation conditions were identified as a carbodiimide-to-toxin ratio of 10:1 by weight, an initial molar ratio of ST to LT of 100:1, and a conjugation reaction time of 96 h. This approach yielded a conjugate that contained 96% by moles and 36% by weight pure ST, determined with radioiodinated pure ST, and 34% by weight semi-pure ST, determined by the Lowry protein method. The retained antigenicities of the conjugated toxins, as determined by enzyme-linked immunosorbent assays, was greater than or equal to 82%, and their toxicities, as determined by the Y1 adrenal cell assay for LT and by the suckling mouse assay for ST, were reduced to less than or equal to 0.15%. Immunization of rats with this cross-linked ST-LT vaccine provided strong protection against challenge with either the LT or the ST toxin or with viable heterologous strains which produce these toxins, either singly or together. These observations indicate that conjugation of ST to LT results in a unique new immunogen in that ST acquires immunogenicity as a function of the reaction, LT retains most of its antigenicity, and the toxic properties of each individual toxin are greatly reduced.


[Image quality of thin- and thick-slice MSCT reconstructions in low-contrast objects (liver lesions) with equal doses].
To evaluate the image quality of thin-section MSCT examinations of low-contrast objects such as liver lesions, and to find out whether a thin slice technique requires an increase in radiation dose. MSCT examinations of the liver were performed in the portal venous phase on a Volume Zoom Scanner (Siemens, Erlangen) with a collimation of 4 x 2.5 mm, 120 kV, 125 mAs and table speed of 12.5 mm. Forty small hypodense liver lesions with a mean size of 3 mm (1 to 8 mm) were reconstructed using a slice thickness of 3, 5, 7, and 10 mm. All lesions were evaluated for each slice thickness by 3 independent radiologists using a 5-point scale (excellent to poor) for the following 7 criteria: contrast, demarcation and contour of the lesion, image noise and quality, demarcation of liver veins and liver contour. The mean values of the reviewers' scores were calculated. The correlation of the three observers in the evaluation of the criteria was determined using the Kendall's Tau coefficient. The 3-mm thin sections were excellent in the evaluation of lesion detection, lesion contrast and lesion contour with a mean score of 1.4 compared to 4.1 for 10-mm sections. Concerning the criteria image quality and liver contour, thin sections achieved the best results in our series. Image noise was pronounced in thin sections but did not affect negatively the image analysis. Interrater agreement was 0.53 for the criterium image noise. Thin sections in MSCT examinations of low contrast objects such as liver lesions do not require an increase in radiation dose because the increase in image noise is compensated by improved lesion contrast.


Morphologic changes of the ascending colon during experimental ischemia and reperfusion in ponies.
The morphologic changes following ascending colon volvulus result from the interaction of inflammatory and coagulation mediators. The objective of this study was to establish a quantifiable histopathologic scoring system to evaluate the serial pathomorphologic changes during ischemia and reperfusion. Such a scoring system could then be applied to subsequent studies designed to attenuate bowel lesions by regulating activity of individual mediators. Ten normal, healthy adult ponies were randomly divided into two equal groups. Following anesthesia and a 30-minute stabilization period, the colon of ponies in the experimental group was twisted 720 degrees for 2 hours of ischemia and then untwisted for 2 hours of reperfusion. The control ponies underwent 4 hours of anesthesia. Full-thickness colonic biopsy specimens were obtained from the antimessenteric border of the pelvic flexure and prepared for light and transmission electron microscopy at 0, 1, 2, 3, and 4 hours after twisting. The mean histopathology score at 0 hours for control ponies was 1.2 and remained unchanged; the score for the experimental ponies was 1.8 and progressed to 4.2 by 4 hours. At 2 hours of ischemia, there was edema of the submucosa and lamina propria attributable to accumulation of platelets, fibrin, and neutrophils in capillaries of the lamina propria. The morphologic changes in experimental ponies progressed to complete destruction of the mucosa with congestion, hemorrhage, and microvascular thrombosis. Mean histopathology scores of control and experimental ponies were significantly different at 1 hour of ischemia, and lesions progressively worsened through the reperfusion period.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparison of manual and ultrasound measurements of fundal height.
Uterine fundal height has long been used to assess fetal growth. The common prediction rule states that the distance in centimeters between the pubic symphysis and the top of the fundus equals the gestational age in weeks. The correlation holds best between weeks 18 and 32. This study compares manual and ultrasound measurements of fundal height. We compared palpated and ultrasound symphysis-fundal height. We then compared both measurements with gestational age as determined by usual ultrasound measurements. Patients were statistically separated by weight into two groups: normal and obese. We hypothesized that manual measurements of fundal height would be affected by obesity and race. Ultrasound fundal height and manual fundal height were equivalent (P < or = .01, R2 = .92). Regression analysis in normal weight and obese patients showed that both methods have the same predictive power in determining fetal age. Manual measurements are still a reliable and inexpensive means of evaluating the course of pregnancy. Ultrasound is needed when there is a size-vs-date discrepancy. Ultrasound is also useful for teaching the measurement of fundal height.


Achieving quality assurance through clinical audit.
Audit is a crucial component of improvements to the quality of patient care. Clinical audits are undertaken to help ensure that patients can be given safe, reliable and dignified care, and to encourage them to self-direct their recovery. Such audits are undertaken also to help reduce lengths of patient stay in hospital, readmission rates and delays in discharge. This article describes the stages of clinical audit and the support required to achieve organisational core values.


A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine.
Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the age-related diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.


The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy.
Pulmonary hypertension (PH) is characterized by increased pulmonary arterial pressure caused by the accumulation of mesenchymal-like cells in the pulmonary vasculature. PH can lead to right ventricular hypertrophy (RVH) and, ultimately, heart failure and death. In PH etiology, endothelial-to-mesenchymal transition (EndMT) has emerged as a critical process governing the conversion of endothelial cells into mesenchymal cells, and S100A4, EGF, and EGFR are implicated in EndMT. However, a potential role of S100A4, EGF, and EGFR in PH has to date not been elucidated. We therefore quantified S100A4, EGF, and EGFR in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH). To determine specificity for unilateral heart disease, the EndMT biomarker signature was further compared between PH patients presenting with RVH and patients suffering from aortic valve stenosis (AVS) with left ventricular hypertrophy. Reduced S100A4 concentrations were found in CTEPH and iPAH patients with RVH. Systemic EGF was increased in CTEPH but not in iPAH, while AVS patients displayed slightly diminished EGF levels. EGFR was downregulated in all patient groups when compared to healthy controls. Longitudinal data analysis revealed no effect of surgical therapies on EndMT markers. Pulmonary thrombo-endarterectomized samples were devoid of S100A4, while S100A4 tissue expression positively correlated with higher grades of Heath-Edwards histopathological lesions of iPAH-derived lung tissue. Histologically, EGFR was not detectable in CTEPH lungs or in iPAH lesions. Together, our data suggest an intricate role for S100A4 and EGF/EGFR in PH with right heart pathology.


Promoter regulation by distinct mechanisms of functional interplay between lysine acetylase Rtt109 and histone chaperone Asf1.
The promoter activity of yeast genes can depend on lysine 56 (K56) acetylation of histone H3. This modification of H3 is performed by lysine acetylase Rtt109 acting in concert with histone chaperone Asf1. We have examined the contributions of Rtt109, Asf1, and H3 K56 acetylation to nutrient regulation of a well-studied metabolic gene, ARG1. As expected, Rtt109, Asf1, and H3 K56 acetylation are required for maximal transcription of ARG1 under inducing conditions. However, Rtt109 and Asf1 also inhibit ARG1 under repressing conditions. This inhibition requires Asf1 binding to H3-H4 and Rtt109 KAT activity, but not tail acetylation of H3-H4 or K56 acetylation of H3. These observations suggest the existence of a unique mechanism of transcriptional regulation by Rtt109. Indeed, chromatin immunoprecipitation and genetic interaction studies support a model in which promoter-targeted Rtt109 represses ARG1 by silencing a pathway of transcriptional activation that depends on ASF1. Collectively, our results show that ARG1 transcription intensity at its induced and repressed set points is controlled by different mechanisms of functional interplay between Rtt109 and Asf1.


[Airway metal stents removal by rigid bronchoscopy].
To explore the techniques and related complication management of airway metal stents removal with rigid bronchoscope under general anesthesia. We reviewed 20 patients who had received rigid bronchoscopic stents removal under general anesthesia from Jan. 2008 to Jan. 2015. The clinical data were analyzed retrospectively. The indications for stents removal and potential difficulties encountered, the relationship between techniques and related complications of stents removal were discussed and analyzed, and our experiences were summarized. The indications for airway metal stents removal included stent migration, fracture, and granulation related in-stent restenosis. Nineteen airway metal stents were removed from 20 patients, which included 9 covered metal stents, 6 without fragmentation and 3 with fragmentation. The average duration of stenting before removal was (7.4±6.9)months (5 days-24 months). Of the 11 uncovered metal stents, which had stayed in the airway for (10.2±7.0) months (20 days-24 months), 10 were removed successfully and 1 failed. Three of them were removed intact and 7 fragmented. Complications were as follows: airway bleeding requiring management (n=11), airway collapse (n=6), re-obstruction requiring temporary stent placement (n=5), postoperative tracheal intubation (n=1), mucosal tear with tracheoesophageal fistula (n=1), airway firing (n=1), airway obstruction, and death as a result of attempted stent removal (n=1). Airway metal stent removal is a high-risk operation. Indications for stents removal should be evaluated thoroughly and all the advantages and disadvantages should be evaluated. Once stent removal is decided, the type of the metal stent, the position of the stent implanted, the duration of stenting, and the extent of the stent embedded in granulation tissue should be carefully considered to assess the difficulty of the procedure. Dissection of the stent from the airway wall before extracting it can reduce complications such as airway bleeding, mucosal tear and airway obstruction. At the same time, a standby stent is needed to deal with possible airway collapse after stent removal. Removal of metal airway stents should only be performed by a proficient and experienced interventional pulmonology team to ensure successful operation and to improve patient safety.


Structural inhomogeneity of water by complex network analysis.
There is still an open debate regarding the structure forming capabilities of water at ambient conditions. To probe the presence of such inhomogeneities, we apply complex network analysis methods to a molecular dynamics simulation at room temperature. This study provides both a structural and quantitative characterization of kinetically homogeneous substates present in bulk water. We find that the conformation-space network is highly modular, and that structural properties of water molecules are spatially correlated over at least two solvation shells. From a kinetic point of view, the free energy surface is characterized by multiple heterogeneous metastable regions with different populations and marginal barriers separating them. The typical time scale of hopping between them is 200-400 fs. A scanning in temperature reveals that those substates can be stabilized either entropically or enthalpically. The latter resembles an icelike domain that extends for at least two solvation shells.


Chemoreceptor gene loss and acquisition via horizontal gene transfer in Escherichia coli.
Chemotaxis allows bacteria to more efficiently colonize optimal microhabitats within their larger environment. Chemotaxis in Escherichia coli is the best-studied model system, and a large number of E. coli strains have been sequenced. The Escherichia/Shigella genus encompasses a great variety of commensal and pathogenic strains, but the role of chemotaxis in their association with the host remains poorly understood. Here we show that the core chemotaxis genes are lost in many, but not all, nonmotile strains but are well preserved in all motile strains. The genes encoding the Tar, Tsr, and Aer chemoreceptors, which mediate chemotaxis to a broad spectrum of chemical and physical cues, are also nearly uniformly conserved in motile strains. In contrast, the clade of extraintestinal pathogenic E. coli strains apparently underwent an ancestral loss of Trg and Tap chemoreceptors, which sense sugars, dipeptides, and pyrimidines. The broad range of time estimated for the loss of these genes (1 to 3 million years ago) corresponds to the appearance of the genus Homo.


Magnetic resonance imaging characteristics in patients with psoriatic arthritis and axial manifestations from the MAXIMISE cohort.
The current analysis of the MAXIMISE trial was conducted to investigate the presence of post-inflammatory and degenerative spinal changes and inflammatory changes in spinal processes identified in baseline magnetic resonance images (MRIs) and their potential for predicting differential treatment effects in a cohort of psoriatic arthritis (PsA) patients with axial manifestations. Baseline spinal MRIs from MAXIMISE trial were re-read to identify additional inflammatory (spinal process), post-inflammatory, and degenerative changes, and investigate the differential treatment effect of these imaging features using logistic regression modelling. In addition to bone marrow oedema (BME) assessed at primary analysis, spinal process inflammation (SPi) and post-inflammatory changes evaluated by FAt Spondyloarthritis Spine Score were documented in 11.1% and 20.2% patients, respectively. At least one type of degenerative change was noted in 64% patients with Pfirrmann grade ≥3 (51.1%) being the most common. Combining primary and re-read MRI findings 67.1% of patients presented with inflammatory or post-inflammatory changes while 21.2% had degenerative changes alone. Although not statistically significant, post-inflammatory changes were associated with a trend for better efficacy outcomes in terms of ASAS20, ASAS40, and BASDAI50 responses; a trend for worse outcomes was observed in the presence of degenerative changes. The current analysis revealed the occurrence of additional inflammatory and post-inflammatory changes suggestive of axial PsA (axPsA) and a trend for better clinical outcomes for patients treated with secukinumab. These results elucidate the imaging characteristics and improve our current understanding of axPsA thereby supporting the interpretation of future trials. ClinicalTrials.gov, NCT02721966.


Results of treatment of stage 3A Hodgkin's disease.
From 1975 to 1981, 38 patients with Stage 3A Hodgkin's disease (35 patients pathologically staged) underwent mantle and para-aortic irradiation, and in 36 patients this was preceded or followed by at least six cycles of multiagent chemotherapy. Both the 5-year actuarial survival and disease-free survival for all 38 patients were 83%. There have been six treatment failures: two patients have relapsed within irradiated nodal groups, one patient in apical pericardial lymph nodes as a marginal recurrence, one patient concurrently infield and in unirradiated nodal groups, and two patients systemically (concurrently in unirradiated nodal groups). Of these six relapses, three patients have died of Hodgkin's disease, one patient has been salvaged, and two patients currently are under treatment for salvage. One patient has developed acute nonlymphocytic leukemia and died of this disease. Extensive disease, as estimated by the number of sites of involvement at presentation, degree of splenic involvement, extent of intra-abdominal disease or mediastinal involvement, did not reveal statistically significant prognostic subgroups for relapse. It is currently recommended that patients with Stage 3A Hodgkin's disease receive six cycles of multiagent chemotherapy and mantle and para-aortic irradiation.


Light and dark adaptation in Phycomyces phototropism.
Light and dark adaptation of the phototropism of Phycomyces sporangiophores were analyzed in the intensity range of 10(-7)-6 W X m-2. The experiments were designed to test the validity of the Delbrück-Reichardt model of adaptation (Delbrück, M., and W. Reichardt, 1956, Cellular Mechanisms in Differentiation and Growth, 3-44), and the kinetics were measured by the phototropic delay method. We found that their model describes adequately only changes of the adaptation level after small, relatively short intensity changes. For dark adaptation, we found a biphasic decay with two time constants of b1 = 1-2 min and b2 = 6.5-10 min. The model fails for light adaptation, in which the level of adaptation can overshoot the actual intensity level before it relaxes to the new intensity. The light adaptation kinetics depend critically on the height of the applied pulse as well as the intensity range. Both these features are incompatible with the Delbrück-Reichardt model and indicate that light and dark adaptation are regulated by different mechanisms. The comparison of the dark adaptation kinetics with the time course of the dark growth response shows that Phycomyces has two adaptation mechanisms: an input adaptation, which operates for the range adjustment, and an output adaptation, which directly modulates the growth response. The analysis of four different types of behavioral mutants permitted a partial genetic dissection of the adaptation mechanism. The hypertropic strain L82 and mutants with defects in the madA gene have qualitatively the same adaptation behavior as the wild type; however, the adaptation constants are altered in these strains. Mutation of the madB gene leads to loss of the fast component of the dark adaptation kinetics and to overshooting of the light adaptation under conditions where the wild type does not overshoot. Another mutant with a defect in the madC gene shows abnormal behavior after steps up in light intensity. Since the madB and madC mutants have been associated with the receptor pigment, we infer that at least part of the adaptation process is mediated by the receptor pigment.


[Investigation of a foodborne intoxication in a high-density penitentiary center].
On September 25 2005, more than 100 inmates (almost 5% of the 1,800 prison population) experienced sudden onset gastroenteritis. This outbreak was the largest foodborne outbreak described in a prison population in Spain. Our objective was to confirm the outbreak, identify risk factors, implement control measures, and provide recommendations. We conducted a cohort analysis of a stratified random sample of all the inmates, a cohort analysis of the one of the prison blocks, and an environmental investigation. A total of 221 inmates were selected, of which 196 were interviewed. Twenty-eight percent had gastroenteritis and the main symptoms were abdominal pain (85%) and diarrhea (71%). All foods consumed caused similar attack rates. Factors associated with the risk of illness were eating the entire portion of seafood cocktail at lunch or all of the fried shrimp at dinner on September 24 (RR = 2; 95% CI, 1.1-3.8, and RR = 1.8; 95% CI, 1.1-3.1). Analysis of one of the prison blocks yielded results similar to those of the random sample. Clostridium perfringens, Bacillus cereus and Escherichia coli were isolated from a sample of the seafood cocktail. A gastroenteritis outbreak caused by several pa-thogens was confirmed. Both the reported symptoms and the calculated incubation periods corresponded to the pathogens isolated. Preparation of food in prison facilities should meet minimum safety standards, including refrigeration and training of food handlers.


The REBOA Dissipation Curve: Training Starts to Wane at 6 Months in the Absence of Clinical REBOA Cases.
Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a low-frequency, high-acuity intervention. We hypothesized that REBOA-specific knowledge and comfort deteriorate significantly within 6 months of a formal training course if REBOA is not performed in the interim. A comprehensive REBOA course was developed including didactics and hands-on practical simulation training. Baseline knowledge and comfort were assessed with a precourse objective test and a subjective self-assessment. REBOA knowledge and comfort were then re-assessed immediately postcourse and again at 6 months and 1 year. Performance trends were measured using paired Student's t and Wilcoxon signed-rank tests. Thirteen participants were evaluated including trauma faculty (n = 10) and fellows (n = 3). Test scores improved significantly from precourse (72% ± 10% correct) to postcourse (88% ± 8%, p < 0.001). At 6 months, scores remained no different from postcourse (p = 0.126); at 1 year, scores decreased back to baseline (p = 0.024 from postcourse; 0.285 from precourse). Subjective comfort with femoral arterial line placement and REBOA improved with training (p = 0.044 and 0.003, respectively). Femoral arterial line comfort remained unchanged from postcourse at 6 months (p = 0.898) and 1 year (p = 0.158). However, subjective comfort with REBOA decreased relative to postcourse levels at 6 months (p = 0.009), driven primarily by participants with no clinical REBOA cases in the interim. A formal REBOA curriculum improves knowledge and comfort with critical aspects of this procedure. This knowledge persists at 6 months, though subjective comfort deteriorated among those without REBOA placement in the interim. REBOA refresher training should be considered at 6-month intervals in the absence of clinical REBOA cases. Level III, prognostic.


Prediction of Multidrug-Resistant TB from CT Pulmonary Images Based on Deep Learning Techniques.
While tuberculosis (TB) disease was discovered more than a century ago, it has not been eradicated yet. Quite contrary, at present, TB constitutes one of the top 10 causes of death and has shown signs of increasing. To complement the conventional diagnostic procedure of applying microbiological culture that takes several weeks and remains expensive, high resolution computer tomography (CT) of pulmonary images has been resorted to not only for aiding clinicians to expedite the process of diagnosis but also for monitoring prognosis when administering antibiotic drugs. This research undertakes the investigation of predicting multidrug-resistant (MDR) patients from drug-sensitive (DS) ones based on CT lung images to monitor the effectiveness of treatment. To contend with smaller data sets (i.e., hundreds) and the characteristics of CT TB images with limited regions capturing abnormities, patch-based deep convolutional neural network (CNN) allied to support vector machine (SVM) classifier is implemented on a collection of data sets from 230 patients obtained from the ImageCLEF 2017 competition. As a result, the proposed architecture of CNN + SVM + patch performs the best with classification accuracy rate at 91.11% (79.80% in terms of patches). In addition, a hand-crafted SIFT based approach accomplishes 88.88% in terms of subject and 83.56% with reference to patches, the highest in this study, which can be explained away by the fact that the data sets are in small numbers. Significantly, during the Tuberculosis Competition at ImageCLEF 2017, the authors took part in the task of classification of 5 types of TB disease and achieved the top one with regard to averaged classification accuracy (i.e., ACC = 0.4067), which is also premised on the approach of CNN + SVM + patch. On the other hand, when the whole slices of 3D TB data sets are applied to train a CNN network, the best result is achieved through the application of CNN coupled with orderless pooling and SVM at 64.71% accuracy rate.


Dietary fat and semen quality among men attending a fertility clinic.
The objective of this study was to examine the relation between dietary fats and semen quality parameters. Data from 99 men with complete dietary and semen quality data were analyzed. Fatty acid levels in sperm and seminal plasma were measured using gas chromatography in a subgroup of men (n = 23). Linear regression was used to determine associations while adjusting for potential confounders. Men were primarily Caucasian (89%) with a mean (SD) age of 36.4 (5.3) years; 71% were overweight or obese; and 67% were never smokers. Higher total fat intake was negatively related to total sperm count and concentration. Men in the highest third of total fat intake had 43% (95% confidence interval (CI): 62-14%) lower total sperm count and 38% (95% CI: 58-10%) lower sperm concentration than men in the lowest third (P(trend) = 0.01). This association was driven by intake of saturated fats. Levels of saturated fatty acids in sperm were also negatively related to sperm concentration (r= -0.53), but saturated fat intake was unrelated to sperm levels (r = 0.09). Higher intake of omega-3 polyunsaturated fats was related to a more favorable sperm morphology. Men in the highest third of omega-3 fatty acids had 1.9% (0.4-3.5%) higher normal morphology than men in the lowest third (P(trend) = 0.02). In this preliminary cross-sectional study, high intake of saturated fats was negatively related to sperm concentration whereas higher intake of omega-3 fats was positively related to sperm morphology. Further, studies with larger samples are now required to confirm these findings.


Limited detection of small (≤ 10 mm) colorectal liver metastasis at preoperative CT in patients undergoing liver resection.
To retrospectively determine the sensitivity of preoperative CT in the detection of small (≤ 10 mm) colorectal liver metastasis (CRLM) nodules in patients undergoing liver resection. The institutional review board approved the study and waived informed consent. We included 461 pathologically confirmed CRLM nodules in 211 patients (including 71 women; mean age, 66.4 years) who underwent 229 liver resections following abdominal CT. Prior to 163 resections, gadoxetic acid-enhanced liver MR imaging was also performed. Nodules were matched between pathology reports and prospective CT reports following a predefined algorithm. Per-nodule sensitivity of CT was calculated by nodule-size category. Generalized estimating equations were used to adjust for within-case correlation. Fourteen nodule sizes were missing in the pathology report. Nodules of 1-5 mm and 6-10 mm accounted for 8.1% (n = 36) and 23.5% (n = 105) of the remaining 447 nodules, and the number of nodules gradually decreased as nodule size increased beyond 10 mm. The overall sensitivity of CT was 81.2% (95% confidence interval, 77.1%, 85.2%; 365/461). The sensitivity was 8% (0%, 17%; 3/36), 55% (45%, 65%; 59/105), 91%, 95%, and 100% for nodules of 1-5 mm, 6-10 mm, 11-15 mm, 16-20 mm, and >20 mm, respectively. The nodule-size distribution was similar between resections undergoing gadoxetic acid-enhanced MR imaging and those not undergoing the MR imaging. CT has limited sensitivity for nodules of ≤ 10 mm and particularly of ≤ 5 mm.


Expression of the fusion protein of human respiratory syncytial virus from recombinant vaccinia virus vectors and protection of vaccinated mice.
Vaccinia virus (VV) recombinants were constructed that contained full-length cDNA copies of the fusion (F) protein gene of human respiratory syncytial (RS) virus. The F protein gene was placed next to the strong early-late VV 7.5-kilodalton promoter and was located within the VV thymidine kinase (tk) gene. Full-length recombinant transcripts that initiated at both the tk and the 7.5-kilodalton promoters accumulated in cells early in infection, and one or more of these transcripts was translated to yield a glycoprotein which comigrated with Fo, the fusion protein precursor. This precursor was processed by proteolytic cleavage to produce the two disulfide-linked subunits F1 and F2, which were both glycosylated and of the same electrophoretic mobility as authentic F1 and F2. Immunofluorescence studies demonstrated that the mature F protein was transported to and expressed on the surface of recombinant VV-infected cells. Inoculation of rabbits with a recombinant vector expressing F resulted in the production of antiserum specific for the RS virus F protein. This antiserum neutralized virus infectivity and was capable of preventing fusion in RS virus-infected cells. Mice were vaccinated with recombinants expressing the F protein. At 3 weeks postinoculation, these animals had serum antibody against RS virus F protein. At 5 days after intranasal challenge with RS virus, the lungs of the mice previously vaccinated with recombinants expressing F protein were free of detectable RS virus, whereas the lungs of unvaccinated mice contained 10(4.2) PFU of virus per g.


Selective biliary lipid secretion at low bile-salt-output rates in the isolated perfused rat liver. Effects of phalloidin.
At high bile-salt-secretion rates the biliary secretion of phospholipids and cholesterol is dependent on that of the bile salts. However, at low bile-salt outputs some secretion remains. Isolated perfused rat livers were used in these experiments in order to study the bile-salt-independent secretion of biliary lipids. The livers were isolated and saline (0.9% NaCl), or phalloidin dissolved in saline, was added to the perfusion fluid after 1 h of liver isolation. The concentration and output of cholesterol was significantly decreased in phalloidin-treated livers compared with the controls, whereas there was no significant decrease in phospholipids; the secretion of cholesterol and phospholipids can thus be uncoupled from each other by the action of phalloidin. These experiments suggest that a proportion of cholesterol gets into bile independently of bile salts and phospholipids. These findings are discussed in relation to the supersaturation of some biles with cholesterol and its relationship to the bile-salt-independent fraction of cholesterol.


Delayed open reduction and fixation of ankle fractures.
Because of clinical circumstances in the period from 1970-1980, 26 consecutive ankle fractures were treated by delayed (14-31 days after injury) open reduction and internal fixation. Follow-up examination (two to 12 years) was obtained in 25 patients. Based on clinical performance index, outcome was judged satisfactory in 17 patients (68%). Seventeen (68%) had an anatomic reduction, and 15 (88%) of these 17 had a satisfactory result. Compared to a group of 26 similar patients treated within 24 hours after injury, the major effect of delay was an adverse influence on the probability of achieving an anatomic reduction (p less than 0.08). When anatomic reduction was obtained, the performance index in the delayed-treatment group (78.8) was comparable to that in the immediate-treatment group (78.4%). Thus, when immediate fixation is not possible, delayed reduction and fixation of displaced ankle fractures is a reasonable option in some instances and can be seriously considered by the surgeon. Displaced fractures should not be left in a malreduced position because this provides virtually no opportunity for a satisfactory result.


Rod cell activity in retinal degenerative rats.
The Royal College of Surgeons (RCS) rat is a good model for the study of the early onset of retinal degenerative disorders. RCS retinal disease is often associated with the loss of rhodopsin in outer segment membranes and the progressive degeneration of photoreceptor cells. This study was conducted to investigate the possible mechanisms of the loss of photoreceptor sensitivity. The electroretinographic responses were recorded in RCS and control rats, age 15, 25 and 35 days, as well as in adult control rats. The a-waves were analyzed using the Hood and Birch model of activation of photoresponse. Photoresponse latency in the RCS rats was prolonged as the disease progressed. The maximum recorded a-wave amplitudes were significantly lower for the RCS rats compared to the control rats. The sensitivity of a-waves as indicated by Ka, the semi-saturation constant, varied and depended on the age of the rats and degenerative stage of the disease. The model's time to peak response increased more than twofold as the degeneration advanced. The changes in a-waves indicate that RCS disease causes progressive impairment of the rod photoresponse. It also suggests that in addition to the phagocytic defect of the retinal pigment epithelium, the abnormal composition of the membrane lipids and the interphotoreceptor matrix and the rhodopsin loss may also cause abnormal photoresponses in RCS rats.


Automatic identification and validation of planar collagen organization in the aorta wall with application to abdominal aortic aneurysm.
Arterial physiology relies on a delicate three-dimensional (3D) organization of cells and extracellular matrix, which is remarkably altered by vascular diseases like abdominal aortic aneurysms (AAA). The ability to explore the micro-histology of the aorta wall is important in the study of vascular pathologies and in the development of vascular constitutive models, i.e., mathematical descriptions of biomechanical properties of the wall. The present study reports and validates a fast image processing sequence capable of quantifying collagen fiber organization from histological stains. Powering and re-normalizing the histogram of the classical fast Fourier transformation (FFT) is a key step in the proposed analysis sequence. This modification introduces a powering parameter w, which was calibrated to best fit the reference data obtained using classical FFT and polarized light microscopy (PLM) of stained histological slices of AAA wall samples. The values of w = 3 and 7 give the best correlation (Pearson's correlation coefficient larger than 0.7, R 2 about 0.7) with the classical FFT approach and PLM measurements. A fast and operator independent method to identify collagen organization in the arterial wall was developed and validated. This overcomes severe limitations of currently applied methods like PLM to identify collagen organization in the arterial wall.


The clinical significance of antiphospholipid antibodies in COVID-19 infection.
One of the factors that may aggravate the clinical presentation in COVID-19 is the increased level of antiphospholipid antibodies (aPLs) and thrombotic events that can be seen with the disease. In our retrospective study, we aimed to evaluate the effect of aPLs on the clinical findings in patients with a diagnosis of COVID-19. Seventy-three patients diagnosed with COVID-19 and examined for aPLs were included in the study. Patients were divided into two groups according to the test results of aPLs. Clinical and laboratory parameters were compared in both groups to reveal whether there was any difference between the groups. There were 15 patients with a positive aPLs test. Dyspnea, nausea, vomiting, myalgia, and abdominal pain were significantly higher in the aPLs positive group than those with negative aPLs. The duration of hospital stays and the need for oxygen therapy of the patients in the aPLs positive group were significantly higher than the aPLs negative group. However, no difference was found between the two groups in terms of mechanical ventilation need, intensive care admission rate, thrombosis and mortality. In terms of laboratory findings, those with positive aPLs have higher median C-reactive protein (CRP) and ferritin values than those with negative aPLs. In our study group, we could not find a relationship between aPLs positivity and critical complications. According to our hypothesis, it may not be necessary to routinely examine aPLs in patients with a diagnosis of COVID-19 to determine the risk of thromboembolic complications.


The accumulation rate of tau aggregates is higher in females and younger amyloid-positive subjects.
The development of tau-PET allows paired helical filament tau pathology to be visualized in vivo. Increased knowledge about conditions affecting the rate of tau accumulation could guide the development of therapies halting the progression of Alzheimer's disease. However, the factors modifying the rate of tau accumulation over time in Alzheimer's disease are still largely unknown. Large-scale longitudinal cohort studies, adjusting for baseline tau load, are needed to establish such risk factors. In the present longitudinal study, 419 participants from four cohorts in the USA (Avid 05e, n = 157; Expedition-3, n = 82; ADNI, n = 123) and Sweden (BioFINDER, n = 57) were scanned repeatedly with tau-PET. The study participants were cognitively unimpaired (n = 153), or patients with mild cognitive impairment (n = 139) or Alzheimer's disease dementia (n = 127). Participants underwent two to four tau-PET (18F-flortaucipir) scans with a mean (± standard deviation) of 537 (±163) days between the first and last scan. The change in tau-PET signal was estimated in temporal meta- and neocortical regions of interest. Subject specific tau-PET slopes were predicted simultaneously by age, sex, amyloid status (determined by amyloid-β PET), APOE ε4 genotype, study cohort, diagnosis and baseline tau load. We found that accelerated increase in tau-PET signal was observed in amyloid-β-positive mild cognitive impairment (3.0 ± 5.3%) and Alzheimer's disease dementia (2.9 ± 5.7%), respectively, when compared to either amyloid-β-negative cognitively unimpaired (0.4 ± 2.7%), amyloid-β-negative mild cognitive impairment (-0.4 ± 2.3%) or amyloid-β-positive cognitively unimpaired (1.2 ± 2.8%). Tau-PET uptake was accelerated in females (temporal region of interest: t = 2.86, P = 0.005; neocortical region of interest: t = 2.90, P = 0.004), younger individuals (temporal region of interest: t = -2.49, P = 0.013), and individuals with higher baseline tau-PET signal (temporal region of interest: t = 3.83, P < 0.001; neocortical region of interest: t = 5.01, P < 0.001). Tau-PET slopes decreased with age in amyloid-β-positive subjects, but were stable by age in amyloid-β-negative subjects (age × amyloid-β status interaction: t = -2.39, P = 0.018). There were no effects of study cohort or APOE ε4 positivity. In a similar analysis on longitudinal amyloid-β-PET (in ADNI subjects only, n = 639), we found significant associations between the rate of amyloid-β accumulation and APOE ε4 positivity, older age and baseline amyloid-β positivity, but no effect of sex. In conclusion, in this longitudinal PET study comprising four cohorts, we found that the tau accumulation rate is greater in females and younger amyloid-β-positive individuals, while amyloid-β accumulation is greater in APOE ε4 carriers and older individuals. These findings are important considerations for the design of clinical trials, and might improve our understanding of factors associated with faster tau aggregation and spread.


Surface complexation modeling of proton and Cd adsorption onto an algal cell wall.
This study quantifies Cd adsorption onto the cell wall of the algal species Pseudokirchneriella subcapitata by applying a surface complexation approach to model the observed adsorption behavior. We use potentiometric titrations to determine deprotonation constants and site concentrations for the functional groups on the algal cell wall. Adsorption and desorption kinetics experiments illustrate that adsorption of Cd onto the cell wall is rapid and reversible, except under low pH conditions. Adsorption experiments conducted as a function of pH and total Cd concentration yield the stoichiometry and site-specific stability constants for the important Cd-algal surface complexes. We model the acid/base properties of the algal cell wall by invoking four discrete surface functional group types, with pKa values of 3.9 +/- 0.3, 5.4 +/- 0.1, 7.6 +/- 0.3, and 9.6 +/- 0.4. The results of the Cd adsorption experiments indicate that the first, third, and fourth sites contribute to Cd adsorption under the experimental conditions, with calculated log stability constant values of 4.1 +/- 0.5, 5.4 +/- 0.5, and 6.1 +/- 0.4, respectively. Our results suggest that the stabilities of the Cd-surface complexes are high enough for algal adsorption to affect the fate and transport of Cd under some conditions and that on a per gram basis, algae and bacteria exhibit broadly similar extents of Cd adsorption.


Glucocorticoid receptor mRNA and protein in fetal rat lung in vivo: modulation by glucocorticoid and androgen.
Pulmonary glucocorticoid receptor (GR) is essential to timely preparation for the onset of breathing air at birth. We have previously used primary culture of late-gestation fetal rat lung cells to demonstrate differential regulation of GR by glucocorticoid depending on cell type. In this study, we hypothesized that the action of glucocorticoid on GR mRNA expression and protein elaboration in lung cells might be modulated by interactions present in vivo but not in primary culture. Given that male sex hormone (androgen) has an inhibitory effect on antenatal lung development, we also postulated that androgen would decrease antenatal lung GR. We report that antenatal maternal injection of the glucocorticoid dexamethasone (1 mg/kg) enhanced fetal lung cellular levels of GR mRNA and protein as assessed by in situ hybridization and immunocytochemistry (ICC), respectively. ICC was performed using polyclonal rabbit anti-human antibody that reacts with rat GR whether bound to ligand or not and does not interfere with GR binding to DNA. Levels of GR mRNA and protein were enhanced in cells throughout all areas of the lung tissue, suggesting that interactions occurring in intact tissue may override the previously reported direct inhibition by glucocorticoid of GR protein elaboration in isolated fetal rat lung epithelial cells. Furthermore, antenatal administration of the androgen 5alpha-dihydrotestosterone (0.2 mg/kg) reduced tissue levels of GR mRNA and protein, consistent with androgenic inhibition of antenatal lung development by decreasing GR. We conclude that glucocorticoids and androgens exert opposite effects on fetal lung GR.


Formation by aggregation of viable chimaeras between ICM and eight-cell mouse embryos with different genetic backgrounds.
The author studied the difference between immunosurgical and microsurgical isolation of inner cell masses (ICMs) from fully expanding blastocysts. The stage after which no further cell exchange between ICM and trophoblast can take place may involve the closure of certain gene pathways. The process of the aggregation of ICMs and eight-cell embryos with different genetic backgrounds was also studied. The results seem to lend strong support to the opinion that the microsurgical technique for isolating the differentiating ICM from the trophoblast is better than immunosurgery. The author also supports the view that the cells of the ICM become committed in the fully expanding blastocyst, while the cells of the eight-cell embryo are still labile and can differentiate to either ICM or trophoblast cells. Cell position during the aggregation process plays a role in cell determination and differentiation.


Why episodic memory may not be for communication.
Three serious challenges to Mahr & Csibra's (M&C's) proposal are presented. First, we argue that the epistemic attitude that they claim is unique to remembering also applies to some forms of imaginative simulations that aren't memories. Second, we argue that their account cannot accommodate critical neuropsychological evidence. Finally, we argue that their proposal looks unconvincing when compared to more parsimonious evolutionary accounts.


Improving the Reporting of Primary Care Research: Consensus Reporting Items for Studies in Primary Care-the CRISP Statement.
Primary care (PC) is a unique clinical specialty and research discipline with its own perspectives and methods. Research in this field uses varied research methods and study designs to investigate myriad topics. The diversity of PC presents challenges for reporting, and despite the proliferation of reporting guidelines, none focuses specifically on the needs of PC. The Consensus Reporting Items for Studies in Primary Care (CRISP) Checklist guides reporting of PC research to include the information needed by the diverse PC community, including practitioners, patients, and communities. CRISP complements current guidelines to enhance the reporting, dissemination, and application of PC research findings and results. Prior CRISP studies documented opportunities to improve research reporting in this field. Our surveys of the international, interdisciplinary, and interprofessional PC community identified essential items to include in PC research reports. A 2-round Delphi study identified a consensus list of items considered necessary. The CRISP Checklist contains 24 items that describe the research team, patients, study participants, health conditions, clinical encounters, care teams, interventions, study measures, settings of care, and implementation of findings/results in PC. Not every item applies to every study design or topic. The CRISP guidelines inform the design and reporting of (1) studies done by PC researchers, (2) studies done by other investigators in PC populations and settings, and (3) studies intended for application in PC practice. Improved reporting of the context of the clinical services and the process of research is critical to interpreting study findings/results and applying them to diverse populations and varied settings in PC.Annals "Online First" article.


Exploring the Journey of Zinc Oxide Nanoparticles (ZnO-NPs) toward Biomedical Applications.
The field of nanotechnology is concerned with the creation and application of materials having a nanoscale spatial dimensioning. Having a considerable surface area to volume ratio, nanoparticles have particularly unique properties. Several chemical and physical strategies have been used to prepare zinc oxide nanoparticles (ZnO-NPs). Still, biological methods using green or natural routes in various underlying substances (e.g., plant extracts, enzymes, and microorganisms) can be more environmentally friendly and cost-effective than chemical and/or physical methods in the long run. ZnO-NPs are now being studied as antibacterial agents in nanoscale and microscale formulations. The purpose of this study is to analyze the prevalent traditional method of generating ZnO-NPs, as well as its harmful side effects, and how it might be addressed utilizing an eco-friendly green approach. The study's primary focus is on the potential biomedical applications of green synthesized ZnO-NPs. Biocompatibility and biomedical qualities have been improved in green-synthesized ZnO-NPs over their traditionally produced counterparts, making them excellent antibacterial and cancer-fighting drugs. Additionally, these ZnO-NPs are beneficial when combined with the healing processes of wounds and biosensing components to trace small portions of biomarkers linked with various disorders. It has also been discovered that ZnO-NPs can distribute and sense drugs. Green-synthesized ZnO-NPs are compared to traditionally synthesized ones in this review, which shows that they have outstanding potential as a potent biological agent, as well as related hazardous properties.


[Effect of aminazin and haloperidol on the content of glial fibrillar acid protein in the rat brain].
The immune-enzyme analysis was used to determine the quantity of glial fibrillar acid protein in the water-soluble extracts of frontal and limbic cortex, caudate nucleus, medulla oblongata of rats before and after administration of aminazin and haloperidol. The obtained results testify to a decrease of the protein content under the action of both neuroleptics only in the limbic brain cortex of rats.


Oxidative Damage and Antioxidant Defense in Ferroptosis.
Many new types of regulated cell death have been recently implicated in human health and disease. These regulated cell deaths have different morphological, genetic, biochemical, and functional hallmarks. Ferroptosis was originally described as a carcinogenic RAS-dependent non-apoptotic cell death, and is now defined as a type of regulated necrosis characterized by iron accumulation, lipid peroxidation, and the release of damage-associated molecular patterns (DAMPs). Multiple oxidative and antioxidant systems, acting together autophagy machinery, shape the process of lipid peroxidation during ferroptosis. In particular, the production of reactive oxygen species (ROS) that depends on the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and the mitochondrial respiratory chain promotes lipid peroxidation by lipoxygenase (ALOX) or cytochrome P450 reductase (POR). In contrast, the glutathione (GSH), coenzyme Q10 (CoQ10), and tetrahydrobiopterin (BH4) system limits oxidative damage during ferroptosis. These antioxidant processes are further transcriptionally regulated by nuclear factor, erythroid 2-like 2 (NFE2L2/NRF2), whereas membrane repair during ferroptotic damage requires the activation of endosomal sorting complexes required for transport (ESCRT)-III. A further understanding of the process and function of ferroptosis may provide precise treatment strategies for disease.


Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
P450 oxidoreductase (POR) is the obligatory flavoprotein intermediate that transfers electrons from reduced nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 enzymes. Although mouse Por gene ablation causes embryonic lethality, POR missense mutations cause disordered steroidogenesis, ambiguous genitalia, and Antley-Bixler syndrome (ABS), which has also been attributed to fibroblast growth factor receptor 2 (FGFR2) mutations. We sequenced the POR gene and FGFR2 exons 8 and 10 in 32 individuals with ABS and/or hormonal findings that suggested POR deficiency. POR and FGFR2 mutations segregated completely. Fifteen patients carried POR mutations on both alleles, 4 carried mutations on only one allele, 10 carried FGFR2 or FGFR3 mutations, and 3 patients carried no mutations. The 34 affected POR alleles included 10 with A287P (all from whites) and 7 with R457H (four Japanese, one African, two whites); 17 of the 34 alleles carried 16 "private" mutations, including 9 missense and 7 frameshift mutations. These 11 missense mutations, plus 10 others found in databases or reported elsewhere, were recreated by site-directed mutagenesis and were assessed by four assays: reduction of cytochrome c, oxidation of NADPH, support of 17alpha-hydroxylase activity, and support of 17,20 lyase using human P450c17. Assays that were based on cytochrome c, which is not a physiologic substrate for POR, correlated poorly with clinical phenotype, but assays that were based on POR's support of catalysis by P450c17--the enzyme most closely associated with the hormonal phenotype--provided an excellent genotype/phenotype correlation. Our large survey of patients with ABS shows that individuals with an ABS-like phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct new disease: POR deficiency.


[Should comparison be made between survival of responding vs. non-responding patients?].
In oncology trials, it is not uncommon to compare the survival of the patients who responded to therapy to the survival of the non-responders, while choosing the beginning of therapy as time 0. This comparison is biased because part of the survival time of the responders is the time between the start of therapy and response, which is guaranteed by the observation of the response. The survival experience of responders must be studied starting from the observation of response. A significant difference between the survival experiences of responders and non-responders is often considered as evidence of a causal relation between response and better survival, or even as demonstrating the efficacy of the treatment. A causal relation between response and survival is certainly biologically plausible but the response may as well be associated with some prognostic factors, the selection of responders leading to the selection of patients with a better prognosis, independently of the treatment. The conclusion that the efficacy of the treatment is demonstrated assumes that the non responders, which represent treatment failures, are a control group which can be compared to the responders. This is absolutely untenable, because the two groups are likely to be very different.


Leveraging Multimedia Patient Engagement to Address Minority Cerebrovascular Health Needs: Prospective Observational Study.
Social inequities affecting minority populations after Hurricane Katrina led to an expansion of environmental justice literature. In August 2017, Hurricane Harvey rainfall was estimated as a 3000- to 20,000-year flood event, further affecting minority populations with disproportionate stroke prevalence. The Stomp Out Stroke initiative leveraged multimedia engagement, creating a patient-centered cerebrovascular health intervention. This study aims to address social inequities in cerebrovascular health through the identification of race- or ethnicity-specific health needs and the provision of in-person stroke prevention screening during two community events (May 2018 and May 2019). Stomp Out Stroke recruitment took place through internet-based channels (websites and social networking). Exclusively through web registration, Stomp Out Stroke participants (aged >18 years) detailed sociodemographic characteristics, family history of stroke, and stroke survivorship. Participant health interests were compared by race or ethnicity using Kruskal-Wallis or chi-square test at an α=.05. A Bonferroni-corrected P value of .0083 was used for multiple comparisons. Stomp Out Stroke registrants (N=1401) were 70% (973/1390) female (median age 45 years) and largely self-identified as members of minority groups: 32.05% (449/1401) Hispanic, 25.62% (359/1401) African American, 13.63% (191/1401) Asian compared with 23.63% (331/1401) non-Hispanic White. Stroke survivors comprised 11.55% (155/1401) of our population. A total of 124 stroke caregivers participated. Approximately 36.81% (493/1339) of participants had a family history of stroke. African American participants were most likely to have Medicare or Medicaid insurance (84/341, 24.6%), whereas Hispanic participants were most likely to be uninsured (127/435, 29.2%). Hispanic participants were more likely than non-Hispanic White participants to obtain health screenings (282/449, 62.8% vs 175/331, 52.9%; P=.03). Asian (105/191, 54.9%) and African American (201/359, 55.9%) participants were more likely to request stroke education than non-Hispanic White (138/331, 41.6%) or Hispanic participants (193/449, 42.9%). African American participants were more likely to seek overall health education than non-Hispanic White participants (166/359, 46.2% vs 108/331, 32.6%; P=.002). Non-Hispanic White participants (48/331, 14.5%) were less likely to speak to health care providers than African American (91/359, 25.3%) or Asian participants (54/191, 28.3%). During the 2018 and 2019 events, 2774 health screenings were completed across 12 hours, averaging four health screenings per minute. These included blood pressure (1031/2774, 37.16%), stroke risk assessment (496/2774, 17.88%), bone density (426/2774, 15.35%), carotid ultrasound (380/2774, 13.69%), BMI (182/2774, 6.56%), serum lipids (157/2774, 5.65%), and hemoglobin A1c (102/2774, 3.67%). Twenty multimedia placements using the Stomp Out Stroke webpage, social media, #stompoutstroke, television, iQ radio, and web-based news reached approximately 849,731 people in the Houston area. Using a combination of internet-based recruitment, registration, and in-person assessments, Stomp Out Stroke identified race- or ethnicity-specific health care needs and provided appropriate screenings to minority populations at increased risk of urban flooding and stroke. This protocol can be replicated in Southern US Stroke Belt cities with similar flood risks.


Whole-exome sequencing identified mutational profiles of squamous cell carcinomas of anus.
Anal squamous cell carcinoma (ASCC), either with human papillomavirus (+) or (-), is a neoplastic disease with frequent recurrence and metastasis. To characterize ASCC genomes, we attempted to disclose novel alterations of ASCC genomes and other genetic features including mutation signatures. We performed whole-exome sequencing and copy number alteration (CNA) profiling for 8 ASCC samples from 6 patients (2 cases with primary and recurrent/metastatic tumors). We found known ASCC mutations (TP53, CDKN2A, and PIK3CA) and CNAs (gains on 3q and 19q and losses on 11q and 13q). In addition, we discovered novel mutations in HRAS and ARID1A and CNAs (gain on 8q and losses 5q, 9p, 10q, and 19p) that had not been reported in ASCCs. We identified 4 signature patterns of the mutations (signatures 1 and 2 with deamination of 5-methyl-cytosin, signature 3 with APOBEC, and signature 4 with mismatch repair) in the ASCCs. Although signatures 1 to 3 have been detected in other SCCs, signature 4 was first identified in ASCCs. In addition, we first found that ASCCs harbored chromothripsis, copy-neutral losses of heterozygosity, and focal amplification of KLF5 super-enhancer. Analyses of primary and recurrent/metastatic pair genomes revealed that driver events in development and progression of ASCC might not be uniform. Our data indicate that ASCCs may have similar mutation and CNA profiles to other SCCs, but that there are unique genomic features of ASCCs as well. Our data may provide useful information for ASCC pathogenesis and for developing clinical strategies for ASCC.


Wrinkling of milk skin is mediated by evaporation.
Wrinkling of thin films and membranes can occur due to various mechanisms such as growth and/or mismatch between the mechanical properties of the film and substrate. However, the physical origins of dynamic wrinkling in soft membranes are still not fully understood. Here we use milk skin as a tractable experimental system to investigate the physics of wrinkle formation in a thin, poroelastic film. Upon heating milk, a micron-thick hydrogel of denatured proteins and fat globules forms at the air-water interface. Over time, we observe an increase in the total length of wrinkles. By confocal imaging and profilometry, we determine that the composition and thickness of the milk skin appears to be homogeneous over the length scale of the wrinkles, excluding differences in milk skin composition as a major contributor to wrinkling. To explain the physical origins of wrinkle growth, we describe theory that considers the milk skin as a thin, poroelastic film where pressure is generated by the evaporative-driven flow of solvent across the film; this imparts in-plane stresses in the milk skin, which cause wrinkling. Viscous effects can explain the time-dependent growth of wrinkles. Our theoretical predictions of the effects of relative humidity on the total length of wrinkles over time are consistent with our experimental results. Our findings provide insight into the physics of the common phenomenon of milk skin wrinkling, and identify hydration gradients as another physical mechanism that can drive morphological instabilities in soft matter.


TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation.
Aberrant expression of the TCL1 oncoprotein promotes malignant transformation of germinal center (GC) B cells. Repression of TCL1 in GC B cells facilitates FAS-mediated apoptosis and prevents lymphoma formation. However, the mechanism for this repression is unknown. Here we show that the CREB coactivator TORC2 directly regulates TCL1 expression independent of CREB Ser-133 phosphorylation and CBP/p300 recruitment. GC signaling through CD40 or the BCR, which activates pCREB-dependent genes, caused TORC2 phosphorylation, cytosolic emigration, and TCL1 repression. Signaling via cAMP-inducible pathways inhibited TCL1 repression and reduced apoptosis, consistent with a prosurvival role for TCL1 before GC selection and supporting an initiating role for aberrant TCL1 expression during GC lymphomagenesis. Our data indicate that a novel CREB/TORC2 regulatory mode controls the normal program of GC gene activation and repression that promotes B cell development and circumvents oncogenic progression. Our results also reconcile a paradox in which signals that activate pCREB/CBP/p300 genes concurrently repress TCL1 to initiate its silencing.


p120-catenin down-regulation and epidermal growth factor receptor overexpression results in a transformed epithelium that mimics esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis due to its highly invasive and metastatic potential. The molecular pathogenesis underlying the invasive mechanism of ESCC is not well known because of the lack of existing models to study this disease. p120-Catenin (p120ctn) and the epidermal growth factor receptor (EGFR) have each been implicated in several cancers, including ESCC. p120ctn is down-regulated in 60% of ESCC tumors, whereas EGFR is the most commonly overexpressed oncogene in ESCC. For these reasons, we investigated the cooperation between p120ctn and EGFR and its effect on ESCC invasion. We show that p120ctn down-regulation is commonly associated with EGFR overexpression. By using a three-dimensional culture system, we demonstrate that the inverse relationship between p120ctn and EGFR has biological implications. Specifically, p120ctn down-regulation coupled with EGFR overexpression in human esophageal keratinocytes (EPC1-PE) was required to promote invasion. Morphological comparison of EPC1-PE cells grown in three-dimensional culture and human ESCC revealed identical features, including significantly increased cellularity, nuclear grade, and proliferation. Molecular characteristics were measured by keratin expression patterns, which were nearly identical between EPC1-PE cells in three-dimensional culture and ESCC samples. Altogether, our analyses have demonstrated that p120ctn down-regulation and EGFR overexpression are able to mimic human ESCC in a relevant three-dimensional culture model.


Host response and dysfunction in the CNS during chronic simian immunodeficiency virus infection.
CNS abnormalities can be detected during chronic human immunodeficiency virus (HIV) infection, before the development of opportunistic infections or other sequelae of immunodeficiency. However, although end-stage dementia caused by HIV has been linked to the presence of infected and activated macrophages and microglia in the brain, the nature of the changes resulting in the motor and cognitive disorders in the chronic stage is unknown. Using simian immunodeficiency virus-infected rhesus monkeys, we sought the molecular basis for CNS dysfunction. In the chronic stable stage, nearly 2 years after infection, all animals had verified CNS functional abnormalities. Both virus and infiltrating lymphocytes (CD8+ T-cells) were found in the brain. Molecular analysis revealed that the expression of several immune response genes was increased, including CCL5, which has pleiotropic effects on neurons as well as immune cells. CCL5 was significantly upregulated throughout the course of infection, and in the chronic phase was present in the infiltrating lymphocytes. We have identified an altered state of the CNS at an important stage of the viral-host interaction, likely arising to protect against the virus but in the long term leading to damaging processes.


Exogenous tat protein activates human endothelial cells.
tat protein, a human immunodeficiency virus (HIV) gene product that functions as a transactivator for HIV replication, is known to be secreted extracellularly by infected cells. To determine the potential role of tat in the dissemination of HIV into extravascular tissue, this protein was examined for its ability to activate human endothelial cells. The results show that tat does indeed stimulate endothelial cells. This is evidenced by their expression of the endothelial-leukocyte adhesion molecules, E-selectin, critical for the initial binding of leukocytes to the blood vessel wall, and their increased synthesis of interleukin-6 (IL-6), a cytokine known to enhance endothelial cell permeability. Furthermore, tat acts synergistically with low concentrations of tumor necrosis factor-alpha to enhance IL-6 secretion. These data suggest that extracellular tat protein secreted or released into the microenvironment may contribute significantly to the determination of specific sites of leukocyte binding to blood vessels, to transmigration into tissue, and to eventual dissemination of HIV-infected cells or free virions into tissue.


Human growth hormone augmentation of epidermal growth factor binding sites on rat granulosa cells.
The effect of human GH (hGH) on the regulation of epidermal growth factor (EGF) receptor was investigated during differentiation of FSH-treated rat granulosa cells, which has been reported to be mediated by a cAMP-dependent mechanism. By measuring the binding of [125I]iodo-EGF to the intact cells, FSH was shown to cause increases in the number of EGF binding sites after culture for 72 h. When granulosa cells were cultured with hGH, the number of FSH-induced EGF binding sites was augmented, with a half-maximal effect at about 10 micrograms hGH/l and a maximal stimulatory concentration of 100 micrograms/l. The stimulatory effect of hGH was absolutely dependent on insulin which by itself showed stimulatory effects on EGF binding sites. Scatchard analysis of EGF binding sites indicated that treatment with hGH increased the number of EGF binding sites (17,200 sites/cell after treatment with FSH; 31,700 sites/cell after FSH plus hGH), but did not alter the binding affinity. The augmentation was observed after culturing for 48 h and increased progressively with time, reaching 280% of the level after FSH treatment by 120 h. Although progesterone synthesis was increased by hGH, the markers of cell differentiation such as cAMP synthesis and LH binding sites were suppressed, indicating hGH inhibition of the cAMP-mediated signal. The action of hGH on the EGF binding sites was not accompanied by cell proliferation. These findings indicate that hGH has a novel action on the regulation of rat granulosa cell EGF binding sites and that the granulosa cell may possess both cAMP-dependent and -independent mechanisms for expression of EGF binding sites.


Engineering cardiac microphysiological systems to model pathological extracellular matrix remodeling.
Many cardiovascular diseases are associated with pathological remodeling of the extracellular matrix (ECM) in the myocardium. ECM remodeling is a complex, multifactorial process that often contributes to declines in myocardial function and progression toward heart failure. However, the direct effects of the many forms of ECM remodeling on myocardial cell and tissue function remain elusive, in part because conventional model systems used to investigate these relationships lack robust experimental control over the ECM. To address these shortcomings, microphysiological systems are now being developed and implemented to establish direct relationships between distinct features in the ECM and myocardial function with unprecedented control and resolution in vitro. In this review, we will first highlight the most prominent characteristics of ECM remodeling in cardiovascular disease and describe how these features can be mimicked with synthetic and natural biomaterials that offer independent control over multiple ECM-related parameters, such as rigidity and composition. We will then detail innovative microfabrication techniques that enable precise regulation of cellular architecture in two and three dimensions. We will also describe new approaches for quantifying multiple aspects of myocardial function in vitro, such as contractility, action potential propagation, and metabolism. Together, these collective technologies implemented as cardiac microphysiological systems will continue to uncover important relationships between pathological ECM remodeling and myocardial cell and tissue function, leading to new fundamental insights into cardiovascular disease, improved human disease models, and novel therapeutic approaches.


Enteral tube feeding alters the oral indigenous microbiota in elderly adults.
Enteral tube feeding is widely used to maintain nutrition for elderly adults with eating difficulties, but its long-term use alters the environment of the oral ecosystem. This study characterized the tongue microbiota of tube-fed elderly adults by analyzing the 16S rRNA gene. The terminal restriction fragment length polymorphism (T-RFLP) profiles of 44 tube-fed subjects were compared with those of 54 subjects fed orally (average age, 86.4 ± 6.9 years). Bar-coded pyrosequencing data were also obtained for a subset of the subjects from each group (15 tube-fed subjects and 16 subjects fed orally). The T-RFLP profiles demonstrated that the microbiota of the tube-fed subjects was distinct from that of the subjects fed orally (permutational multivariate analysis of variance [perMANOVA], P < 0.001). The pyrosequencing data revealed that 22 bacterial genera, including Corynebacterium, Peptostreptococcus, and Fusobacterium, were significantly more predominant in tube-fed subjects, whereas the dominant genera in the subjects fed orally, such as Streptococcus and Veillonella, were present in much lower proportions. Opportunistic pathogens rarely detected in the normal oral microbiota, such as Corynebacterium striatum and Streptococcus agalactiae, were often found in high proportions in tube-fed subjects. The oral indigenous microbiota is disrupted by the use of enteral feeding, allowing health-threatening bacteria to thrive.


Bioconcentration pattern and induced apoptosis of bisphenol A in zebrafish embryos at environmentally relevant concentrations.
Bisphenol A (BPA) is a well-known endocrine-disrupting chemical that is ubiquitously present in the environment. In the present study, 4-h post-fertilization (hpf) zebrafish embryos were exposed to various environmentally relevant concentrations of BPA (0.1, 1, 10, 100, and 1000 μg/L) until 72 and 168 hpf, and the accumulation pattern of BPA and its potential to induce toxicity through apoptosis were determined. Compared to BPA concentrations in larvae at 168 hpf, BPA concentrations in embryos exposed until 72 hpf were at relatively higher levels (p < 0.05) with higher bioconcentration factor (BCF) values. The nonlinear fitting analysis indicated that the BCF values of BPA in fish embryos/larvae were significantly correlated to the log10-transformed BPA exposure concentrations in water in an inverse concentration-dependent manner. Fish accumulated more BPA as the exposure concentrations increased; however, their accumulation capacity of BPA declined and tended to be saturated in the high exposure groups of BPA. Moreover, caspase-3 activity was significantly induced upon BPA exposure at 0.1, 1, 10, and 100 μg/L BPA at 72 hpf, and also at 10 and 100 μg/L BPA at 168 hpf. Correspondingly, exposure to 10 and 100 μg/L of BPA significantly increased the DNA fragmentation in the extracted DNA at 168 hpf as determined by DNA ladder analysis. In addition, the expression patterns of four genes related to apoptosis including caspase-3, bax, p53, and c-jun were significantly up-regulated (p < 0.05) in fish embryos/larvae upon BPA exposure at 72 and 168 hpf. Our results revealed that low and environmentally relevant concentrations of BPA could be significantly accumulated in zebrafish and induced apoptosis with involvement of the regulation of caspase-3 and other apoptosis-related genes.


Healthy traditional Mediterranean diet: an expression of culture, history, and lifestyle.
The term Mediterranean diet refers to dietary patterns found in olive-growing areas of the Mediterranean region and described in the 1960s and beyond. There are several variants of the Mediterranean diet, but some common components can be identified: high monounsaturated/saturated fat ratio; ethanol consumption at moderate levels and mainly in the form of wine; high consumption of vegetables, fruits, legumes, and grains; moderate consumption of milk and dairy products, mostly in the form of cheese; and low consumption of meat and meat products. Growing evidence demonstrates that the Mediterranean diet is beneficial to health; the evidence is stronger for coronary heart disease, but it also applies to some forms of cancer. Results from recent investigations provide a strong biomedical foundation for the beneficial effects of the Mediterranean diet.


Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy.
Severe hemorrhagic events occur in a significant fraction of acute promyelocytic leukemia patients, either at presentation and/or early after starting therapy, leading to treatment failure and early deaths. However, identification of independent predictors for high-risk of severe bleeding at diagnosis, remains a challenge. Here, we investigated the immunophenotype of bone marrow leukemic cells from 109 newly diagnosed acute promyelocytic leukemia patients, particularly focusing on the identification of basophil-related features, and their potential association with severe bleeding episodes and patient overall survival.From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the occurrence and severity of bleeding (p ≤ 0.007); moreover, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was also more frequently found among patients with (mild and severe) bleeding at baseline and/or after starting treatment (p ≤ 0.009). Multivariate analysis showed that CD203c expression (hazard ratio: 26.4; p = 0.003) and older age (hazard ratio: 5.4; p = 0.03) were the best independent predictors for cumulative incidence of severe bleeding after starting therapy. In addition, CD203c expression on leukemic cells (hazard ratio: 4.4; p = 0.01), low fibrinogen levels (hazard ratio: 8.8; p = 0.001), older age (hazard ratio: 9.0; p = 0.002), and high leukocyte count (hazard ratio: 5.6; p = 0.02) were the most informative independent predictors for overall survival.In summary, our results show that the presence of basophil-associated phenotypic characteristics on leukemic cells from acute promyelocytic leukemia patients at diagnosis is a powerful independent predictor for severe bleeding and overall survival, which might contribute in the future to (early) risk-adapted therapy decisions.


Clinical, microbiological and immunological studies on recurrent periodontal disease.
The present study was performed to evaluate the clinical, microbiological and immunological aspects in the early stages of recurrent periodontal disease. After clinical monitoring of pockets with recent evidence of disease recurrence, microbiological samples for cultural analysis, serum and gingival crevicular fluid (GCF) samples were taken for IgG antibody analysis from 14 sites, 7 in 6 recurrent periodontitis patients and 7 in 7 periodontally healthy control subjects. IgG responses of serum antibody to 8 gram-negative bacterial strains were compared with those of GCF sampled from the recurrent site. The results clearly demonstrated the predominance of Bacteroides gingivalis in most subgingival plaque samples during the early stages of disease recurrence; the mean proportions of B. gingivalis were significantly different from those of the healthy sites (p less than 0.05). 4 out of 6 serum samples showed the elevated antibody responses to B. gingivalis 381; and this was closely correlated to homologous infection by this micro-organism in recurrent sites. Elevated serum antibody responses were also noted to Eikenella corrodens 1073 and Actinobacillus actinomycetemcomitans Y4. However, no relationship with homologous infection was found for A. actinomycetemcomitans. 3 out of 6 GCF samples had greater antibody titers than the serum, suggesting local antibody synthesis by the gingival cells in the recurrent pockets. The present study showed that B. gingivalis might play an important role in the pathogenesis of disease recurrence in its early stages.