Genetics, genomics and metabolomics: new insights into maternal metabolism during pregnancy.
Maternal glucose metabolism during pregnancy differs from the non-gravid state to allow the mother to meet her own and the growing fetus's energy needs. New insights into the mechanisms underlying maternal metabolism during pregnancy are being gained through the use of new 'omics' technologies. This review focuses on the application of genetics/genomics and metabolomics to the study of maternal metabolism during pregnancy. Following the identification of susceptibility genes for Type 2 diabetes through genome-wide association studies, association has been demonstrated of some Type 2 diabetes susceptibility genes with gestational diabetes mellitus, suggesting that the genetic architecture of Type 2 diabetes and gestational diabetes are, in part, similar. More recent genome-wide association studies examining maternal metabolism during pregnancy have demonstrated overlap of genes associated with metabolic traits in the gravid and non-gravid population, as well as genes that appear to be relatively unique to pregnancy. Metabolomics has also been used to profile the metabolic state of women during pregnancy through the multiplexed measurement of many low molecular weight metabolites. Measurement of amino acids and conventional metabolites have demonstrated changes in mothers with higher insulin resistance and glucose similar to changes in non-gravid, insulin-resistant populations, suggesting similarities in the metabolic profile characteristic of insulin resistance and hyperglycaemia in pregnant and non-pregnant populations. Metabolomics and genomics are but a few of the now available high-throughput 'omics' technologies. Future studies that integrate data from multiple technologies will allow an integrated systems biology approach to maternal metabolism during pregnancy.


[Comparison of quality of life and treatment efficacy in patients with chronic low back pain syndrome].
To test use of quality of life (QL) parameters for assessing treatment efficacy in patients with chronic low back pain syndrome (CLBPS). Clinical, device examinations, questionnaire survey were made in 100 patients, most of them females (77%) with CLBPS due to spinal osteochondrosis. Mean age of the patients was 45.69 +/- 7.61 years, mean duration of the disease 10.20 +/- 6.01 years, duration of the exacerbation 4.04 +/- 1.75 months. Most of the examinees had CLBPS x-ray stage II. QL was evaluated by questionning (general SF-36, HAQ and special Oswestry low back pain disability (OLBPD) questionnaires). The patients were divided into two groups by clinical and device findings and responses to the questionnaires. Group I patients had significant improvement of all the parameters studied, patients of group 2 had no improvement. A strong correlation was found between OLBPD responses and the patients' appraisal of the treatment efficacy. The effect value, standardized significance rates and factors intensity reflected high informative value of the questionnaire by assessment of efficacy of CLBPS treatment. SF-36 and OLBPD are recommended as adequate general and special questionnaires respectively, to estimate QL in patients with CLBPS. The treatment is effective if total parameters of physical and mental health by SF-36 rise significantly while vital activity disorders by OLBPD reduce more than 2-fold.


A severe case of Legionnaire's disease connected to the BBC outbreak in 1988.
On 1 May 1988 a senior Naval Officer, serving at HMS Warrior, was admitted to RAF Halton where a diagnosis of Legionnaire's disease was made. He suffered severe pneumonia and neurological symptoms, and although he eventually responded to treatment, he still suffers sequelae. On 19 April, he was in the vicinity of the BBC at the time of the outbreak of Legionnaire's disease. His clinical findings are reported in this article along with a brief history and discussion of the diagnosis and prevention of Legionnaire's disease.


The effect of pediatric orthopaedic experience on interobserver and intraobserver reliability of the herring lateral pillar classification of Perthes disease.
An analysis was done of the effect of surgeons' pediatric orthopaedic experience on the classification of Perthes disease according to the lateral pillar classification described by Herring. Five observers with varied pediatric orthopaedic experience reviewed anteroposterior (AP) pelvis radiographs of 33 patients in the fragmentation phase of Perthes disease and classified each case on three separate occasions at least 24 hours apart. Frog-leg lateral-view radiographs taken at the same time were also classified using the same criteria based on the femoral head anterior column. Kappa statistics showed good agreement for intra- and interobserver reliability of classification for both AP and frog lateral radiographs. There were no statistically significant variations among the reviewers. Twenty-four percent of the cases had a classification one grade worse on the lateral radiograph compared to the AP view. The lateral pillar classification provides a reproducible radiographic technique for Perthes disease characterization independent of pediatric orthopaedic experience.


[Inhibition of the growth of bacterial populations by suspensions obtained from Pseudomonas aeruginosa pyocinogenic strains].
Suspensions obtained from five Pseudomonas aeruginosa pyocinogenic strains showed inhibitory and variable activity against bacterial strains belonging to the Nocardiaceae, Micrococcaceae, Neisseriaceae, Streptococcaceae, Vibrionaceae, Enterobacteriaceae, and Pseudomonadaceae families. Under special conditions, the same pyocinogenic P. aeruginosa strain can be affected by it own suspensions. These pyocinlike particles could be considered as a regulatory factor acting on the rate and size of the population growth.


Repeated infusions of TNF-alpha cause attenuation of the thermal response and influence LPS fever in guinea pigs.
In conscious, freely moving guinea pigs, tumor necrosis factor (TNF)-alpha and TNF-beta, infused into the aortic arch within a period of 45 min at a dosage of 5 micrograms/kg, induced different thermal responses. TNF-alpha evoked a biphasic elevation of abdominal temperature, both phases together lasting longer than 6 h. In response to infusions of TNF-beta, the first phase, lasting approximately 120 min, was the same as was observed in response to TNF-alpha, whereas the longer second phase of temperature increase was missing. When the infusion of TNF-alpha was repeated four times at intervals of 3 days, the second phase of the increase in abdominal temperature (120-360 min after start of infusion) tended to decrease in response to the third and was significantly attenuated in response to the fourth infusion of TNF-alpha. A control group of guinea pigs received four infusions of solvent (0.9% sterile pyrogen-free saline). Another 3 days after the fourth infusion of TNF-alpha or solvent, all animals were injected with 20 micrograms/kg bacterial lipopolysaccharide (LPS from Escherichia coli; intramuscular injection). In those guinea pigs having developed a reduced responsiveness to TNF-alpha, the first phase of LPS-induced fever was significantly suppressed, whereas the second phase tended to be enhanced, compared with animals having received four infusions of solvent. In conclusion, guinea pigs develop a reduced responsiveness to TNF-alpha after its repeated administration. In the state of lower reactivity to exogenous TNF-alpha, a reduced response of the first phase of LPS-induced fever (during which endogenous TNF-alpha is released) can be observed. This indicates that endogenous TNF-alpha may contribute to LPS-induced fever only in the initial phase of the febrile response of guinea pigs.


Transition from Continuous to Discontinuous Shear Thickening: An Excluded-Volume Effect.
In this Letter, we present a new mechanism under the action of which a shear thickening suspension transitions from a continuous to a discontinuous regime. This transition occurs by adding high concentrations of large spheres to a continuous shear thickening suspension. We show that the solid volume fraction of the interstitial shear thickening matrix is locally enhanced due to the presence of large particles and the excluded-volume shells surrounding the large particles, thus leading to a continuous to discontinuous shear thickening transition at the local scale.


Functional characterization of promoter region polymorphisms of human CYP2C19 gene.
CYP2C19 is an enzyme involved in the metabolism of several clinically important drugs. The variations in the CYP2C19 promoter region may alter the transcription of the gene by altering the interaction between the trans and cis-acting elements. In the present study, CYP2C19 promoter region with different variant alleles were cloned into a pGL-3 basic luciferase reporter vector and transfected into HepG2 cell lines. Subsequently, dual luciferase activity was measured to evaluate the activity of the promoter region. Gel shift assays with predicted binding sites for CCAAT displacement protein, activating transcription factor-2 and glucocorticoid receptor were performed. Results from this study indicate that few variations present in the putative cis-acting elements of the CYP2C19 promoter region such as -1442T>C, -779A>C and -98T>C -1498T>G and -828del>T alter the transcription of the gene. Specific binding with nuclear proteins was also observed in gel shift assays. This may account for the interindividual variations in gene expression and genotype dependant differences in gene transcription. The results also suggest the role of activating transcription factor-2 and CCAAT displacement repressor protein on CYP2C19 gene transcription.


A lab-on-a-chip for free-flow electrophoretic preconcentration of viruses and gel electrophoretic DNA extraction.
Nucleic acid amplification techniques such as real-time PCR are essential instruments for the identification and quantification of viruses. They are fast, very sensitive and highly specific, but often require elaborate and labor intensive sample preparation to achieve successful amplification of the target sequence. In this work we demonstrate the complete microfluidic preparation of amplifiable virus DNA from dilute specimens. Our approach combines free-flow electrophoretic preconcentration of viral particles with thermal lysis and gel-electrophoretic nucleic acid extraction on a single device. The on-chip preconcentration achieves a capture efficiency of >99% for dilute suspensions of bacteriophage PhiX174. Following preconcentration, phages are thermally lysed and released DNA is recovered after 40 s of on-chip gel-electrophoresis with a recovery rate of ∼73%. Furthermore we demonstrate a detection limit of ∼1 PFU ml-1 (∼0.02 DNA copies per μl) for the detection of bacteriophage PhiX174 by PCR. To simplify operation of the device, we describe the development of a custom-made chip holder as well as a compact peristaltic pump and power supply, which enable user-friendly operation with low risk of cross-contamination and high potential for automation in the field of point-of-care diagnostics.


Prone position is essential for detection of pulmonary vein pseudostenosis by enhanced multidetector computed tomography in patients who undergo pulmonary vein isolation.
Pulmonary vein (PV) stenosis is a major complication of PV isolation (PVI) by catheter ablation, so in the present study the optimal position for detecting PV stenosis on enhanced multidetector computed tomography (MDCT) image acquisition was determined. The 64-slice enhanced MDCT was carried out before and after PVI in 116 consecutive patients with atrial fibrillation while they were in the prone position, as well as while supine. The supine position MDCT image showed >50% diameter stenosis of the PV in 11 (9%) patients before PVI (% diameter stenosis: mean 55+/-4%, range 51-65%). Greater than 50% diameter stenosis was seen in the left inferior PV in all 11 patients. The prone position attenuated the PV stenosis findings in the MDCT images in all 11 patients (mean 9+/-6%, range 2-18%). Stenosis visualized on images acquired in the supine position was, therefore, concluded to be pseudostenosis caused by descending aorta compression. At 3 months after PVI, no significant changes in PV diameter were observed in these 11 patients. The present study demonstrated that the prone position is essential for eliminating PV pseudostenosis observed on supine-position enhanced MDCT images. The results also indicate that preexisting PV organic stenosis is rare.


Evolution of the terminal complement genes: ancient and modern.
The data on the structure and relationships of the TCC genes are reviewed and a model is presented for the processes of gene duplication by which the modern genes might have evolved. Data on variations of the overall gene numbers and relationships in modern species are also reviewed, together with the polymorphisms found in man. The apparent contradictions of lack of allelic association between markers and lack of direct evidence for recombination in the C6/C7 gene region is also discussed.


Laparoscopic redo Nissen fundoplication.
Nine patients underwent redo laparoscopic Nissen fundoplication because of failed primary laparoscopic antireflux procedure. Symptoms prior to reoperation included heartburn (n = 5), dysphagia (n = 2), dysphagia and heartburn (n = 1), and early satiety and epigastric pain (n = 1). Endoscopic and radiologic findings prior to reoperation included esophagitis (n = 6), reflux (n = 6), stenosis (n = 2), and hiatal hernia (n = 1). Findings at reoperation included fundoplication positioned on the stomach (n = 5); a disrupted cruroplasty (n = 1); gastric volvulus (n = 1); and an excessively tight wrap (n = 1) or cruroplasty (n = 1). Reconstruction of the fundoplication was performed according to accepted principles for this procedure. All patients were discharged within 2 days after the redo procedure. Follow-up time is 4-14 months. Preoperative symptoms were relieved in all patients and all antireflux medication have been discontinued. Routine postoperative esophagram and endoscopy demonstrated intact repair and without gastroesophageal reflux or stenosis. Reoperative laparoscopic Nissen fundoplication is feasible and effective.


Rapid Response to Drive COVID-19 Research in a Learning Health Care System: Rationale and Design of the Houston Methodist COVID-19 Surveillance and Outcomes Registry (CURATOR).
The COVID-19 pandemic has exacerbated the challenges of meaningful health care digitization. The need for rapid yet validated decision-making requires robust data infrastructure. Organizations with a focus on learning health care (LHC) systems tend to adapt better to rapidly evolving data needs. Few studies have demonstrated a successful implementation of data digitization principles in an LHC context across health care systems during the COVID-19 pandemic. We share our experience and provide a framework for assembling and organizing multidisciplinary resources, structuring and regulating research needs, and developing a single source of truth (SSoT) for COVID-19 research by applying fundamental principles of health care digitization, in the context of LHC systems across a complex health care organization. Houston Methodist (HM) comprises eight tertiary care hospitals and an expansive primary care network across Greater Houston, Texas. During the early phase of the pandemic, institutional leadership envisioned the need to streamline COVID-19 research and established the retrospective research task force (RRTF). We describe an account of the structure, functioning, and productivity of the RRTF. We further elucidate the technical and structural details of a comprehensive data repository-the HM COVID-19 Surveillance and Outcomes Registry (CURATOR). We particularly highlight how CURATOR conforms to standard health care digitization principles in the LHC context. The HM COVID-19 RRTF comprises expertise in epidemiology, health systems, clinical domains, data sciences, information technology, and research regulation. The RRTF initially convened in March 2020 to prioritize and streamline COVID-19 observational research; to date, it has reviewed over 60 protocols and made recommendations to the institutional review board (IRB). The RRTF also established the charter for CURATOR, which in itself was IRB-approved in April 2020. CURATOR is a relational structured query language database that is directly populated with data from electronic health records, via largely automated extract, transform, and load procedures. The CURATOR design enables longitudinal tracking of COVID-19 cases and controls before and after COVID-19 testing. CURATOR has been set up following the SSoT principle and is harmonized across other COVID-19 data sources. CURATOR eliminates data silos by leveraging unique and disparate big data sources for COVID-19 research and provides a platform to capitalize on institutional investment in cloud computing. It currently hosts deeply phenotyped sociodemographic, clinical, and outcomes data of approximately 200,000 individuals tested for COVID-19. It supports more than 30 IRB-approved protocols across several clinical domains and has generated numerous publications from its core and associated data sources. A data-driven decision-making strategy is paramount to the success of health care organizations. Investment in cross-disciplinary expertise, health care technology, and leadership commitment are key ingredients to foster an LHC system. Such systems can mitigate the effects of ongoing and future health care catastrophes by providing timely and validated decision support.


Use of Ethyl Formate Fumigation to Control Adult Bean Thrips in Navel Oranges.
Shipments of California Navel oranges (Citrus sinensis) (Osbeck)) that are found to be infested with adult bean thrips (Caliothrips fasciatus (Pergande) (Thysanoptera: Thripidae)) upon arrival in Australia either undergo mandatory fumigation with methyl bromide (MeBr) to kill the thrips or are refused entry. Ethyl formate (EtF) mixed with carbon dioxide (CO₂) is an effective fumigant for control of various arthropods including but not limited to, thrips, aphids, Pacific spider mites, California red scale, and omnivorous leaf rollers. Dose-mortality curves at 5°C, 10°C, and 15°C were developed for control of adult bean thrips using EtF plus CO₂, with 5°C being more effective. In further testing, the efficacy of EtF plus CO₂ against adult bean thrips in Navel oranges and the impact on fruit quality after fumigation followed by 5 wk of storage at 5°C and shelf life at 20°C was determined. Fruit fumigated with 31 g/m3 EtF plus CO₂ at 5°C for 1 h showed no difference in quality compared with untreated control fruit. Ethyl formate plus CO₂ fumigation efficacy was confirmed in a 27.32 m3 sea freight container with eight pallets of packed Navel oranges (load factor 28.69%) and 10,000-15,000 adult bean thrips in each of three replications. Complete control of adult bean thrips was achieved with no negative effects on fruit quality.


Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.
Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.


Expression of erythropoietin receptor splice variants in human cancer.
Erythropoietin (EPO) regulates mammalian erythropoiesis by binding to its transmembrane receptor EPOR. Recent studies demonstrated functional EPOR expression in human cancer cells. Recombinant human EPO was reported to stimulate the proliferation of monolayer cultures of breast and renal carcinoma cells. Furthermore, administration of EPO-EPOR antagonists delayed the growth of uterine, ovarian, and mammary carcinoma cells in experimental animal models. In this study, we show EPOR transcript and protein expression in breast, colon, lung, ovary, and prostate cancer cells. Using reverse transcription-polymerase chain reaction, we isolated and characterized several novel cDNAs for EPOR splice variants expressed in cancer cells. Deduced amino acid sequences of the cDNAs revealed splice variants encoding soluble EPOR or membrane-bound EPOR peptides with intra-cytoplasmic, carboxy-terminal truncations. These findings indicate the expression of multiple EPOR isoforms in human cancer cells that may modulate the cellular effects of recombinant human EPO or EPO-EPOR antagonists.


Doping in sport: a review of medical practitioners' knowledge, attitudes and beliefs.
Central to the work of many medical practitioners is the provision of pharmaceutical support for patients. Patients can include athletes who are subject to anti-doping rules and regulations which prohibit the use of certain substances in and out of competition. This paper examines the evidence on medical practitioners' knowledge, attitudes and beliefs towards doping in sport. A systematic search strategy was followed. Research questions and relevance criteria were developed a priori. Potentially relevant studies were located through electronic and hand searches limited to English language articles published between 1990 and 2010. Articles were assessed for relevance by two independent assessors and the results of selected studies were abstracted and synthesised. Outcomes of interest were knowledge, attitudes and beliefs in relation to doping in sport. Six studies met the inclusion criteria and were examined in detail. Samples reflected a range of medical practitioners drawn from the UK, France (2), Greece, Italy and Ireland. The investigations varied with respect to outcome focus and quality of evidence presented. Whilst the extant empirical research posits a negative attitude towards illegal performance enhancement combined with a positive inclination towards doping prevention, it also exposes a limited knowledge of anti-doping rules and regulations. Insufficient education, leading to a lack of awareness and understanding, could render this professional group at risk of doping offences considering Article 2.8 of the World Anti-Doping Agency Code (WADC). Moreover, in light of the incongruence between professional medical codes and WADC Article 2.8, medical professionals may face doping dilemmas and therefore further discourse is required. At present, the current evidence-base makes it difficult to plan developmentally appropriate education to span the exposure spectrum. Addressing this situation appears warranted.


The role of stress waves and cavitation in stone comminution in shock wave lithotripsy.
Using an experimental system that mimics stone fragmentation in the renal pelvis, we have investigated the role of stress waves and cavitation in stone comminution in shock-wave lithotripsy (SWL). Spherical plaster-of-Paris stone phantoms (D = 10 mm) were exposed to 25, 50, 100, 200, 300 and 500 shocks at the beam focus of a Dornier HM-3 lithotripter operated at 20 kV and a pulse repetition rate of 1 Hz. The stone phantoms were immersed either in degassed water or in castor oil to delineate the contribution of stress waves and cavitation to stone comminution. It was found that, while in degassed water there is a progressive disintegration of the stone phantoms into small pieces, the fragments produced in castor oil are fairly sizable. From 25 to 500 shocks, clinically passable fragments (< 2 mm) produced in degassed water increases from 3% to 66%, whereas, in castor oil, the corresponding values are from 2% to 11%. Similar observations were confirmed using kidney stones with a primary composition of calcium oxalate monohydrate. After 200 shocks, 89% of the fragments of the kidney stones treated in degassed water became passable, but only 22% of the fragments of the kidney stones treated in castor oil were less than 2 mm in size. This apparent size limitation of the stone fragments produced primarily by stress waves (in castor oil) is likely caused by the destructive superposition of the stress waves reverberating inside the fragments, when their sizes are less than half of the compressive wavelength in the stone material. On the other hand, if a stone is only exposed to cavitation bubbles induced in SWL, the resultant fragmentation is much less effective than that produced by the combination of stress waves and cavitation. It is concluded that, although stress wave-induced fracture is important for the initial disintegration of kidney stones, cavitation is necessary to produce fine passable fragments, which are most critical for the success of clinical SWL. Stress waves and cavitation work synergistically, rather than independently, to produce effective and successful disintegration of renal calculi in SWL


Fluorescence imaging with one-nanometer accuracy (FIONA).
Fluorescence imaging with one-nanometer accuracy (FIONA) is a simple but useful technique for localizing single fluorophores with nanometer precision in the x-y plane. Here a summary of the FIONA technique is reported and examples of research that have been performed using FIONA are briefly described. First, how to set up the required equipment for FIONA experiments, i.e., a total internal reflection fluorescence microscopy (TIRFM), with details on aligning the optics, is described. Then how to carry out a simple FIONA experiment on localizing immobilized Cy3-DNA single molecules using appropriate protocols, followed by the use of FIONA to measure the 36 nm step size of a single truncated myosin Va motor labeled with a quantum dot, is illustrated. Lastly, recent effort to extend the application of FIONA to thick samples is reported. It is shown that, using a water immersion objective and quantum dots soaked deep in sol-gels and rabbit eye corneas (>200 µm), localization precision of 2-3 nm can be achieved.


EGFR methylation and outcome of patients with advanced colorectal cancer treated with cetuximab.
Targeted therapy of metastatic colorectal cancer (mCRC) with monoclonal antibody anti-epidermal growth factor receptor (EGFR) agents, such as cetuximab (CTX) or panitumumab, is the treatment strategy of choice in patients characterised by a wild-type (wt) RAS gene status. However, despite selection based on RAS status, a high proportion of patients do not respond to therapy. EGFR methylation has been reported to have a role in predicting the response to anti-EGFR agents. The present study aimed to evaluate the role of EGFR methylation in association with the clinical outcome of patients with mCRC treated with CTX. In total, 64 patients with mCRC were assessed in the present study. Genomic DNA was extracted from tumoral tissue and EGFR methylation and mutation of the KRAS, BRAF and PIK3CA genes were analysed by pyrosequencing. EGFR expression was assessed by immunohistochemistry. The various alterations were analysed by assessing the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) rates. In total, 42 cases (66%) exhibited >10% EGFR methylation and there was no correlation with EGFR expression. Mean EGFR methylation of 41 and 9% was observed in KRAS-mutated and -wt patients, respectively (P=0.05). Conversely, a high EGFR methylation was observed in BRAF-wt patients with compared with patients possessing the mutated gene (18 vs. 3%, respectively; P=0.07). EGFR methylation was significantly correlated with the OS rate [hazard ratio, 0.98; 95% confidence interval (CI), 0.96-1.00; P=0.019], but not PFS rate. In patients with a methylation rate <10 and >10%, the median OS rate was 7.5 months (95% CI, 4.4-9.4 months) and 12.0 months (95% CI, 8.7-13.9 months), respectively (P=0.034). In conclusion, the present study revealed a correlation between EGFR methylation and improved OS rate in patients treated with CTX-based chemotherapy. The presence of EGFR methylation is inversely correlated with BRAF and PIK3CA mutations, indicating that the prognostic value of gene methylation may be worth verifying in further studies.


Safety Measures for Maintaining Low Endophthalmitis Rate after Intravitreal Anti-Vascular Endothelial Growth Factor Injection before and during the COVID-19 Pandemic.
During the COVID-19 pandemic, intravitreal injections are performed with patients wearing masks. The risk of endophthalmitis after intravitreal injection is reported to increase due to an influx of exhaled air containing oral bacteria from the upper part of the mask onto the ocular surface. We retrospectively investigated the incidence of endophthalmitis when intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections were performed using the same infection control measures before and during the pandemic. Vitreoretinal specialists performed intravitreal injections of anti-VEGF agents in the outpatient room of a university hospital. Infection control measures before and during the pandemic included covering the patient's eye with adhesive face drape and irrigating the ocular surface with 0.25% povidone-iodine before draping, and immediately before and after injection. Before the COVID-19 pandemic (February 2016 to December 2019), one case of endophthalmitis occurred among 31,173 injections performed (0.0032%; 95% confidence interval (CI), 0.000008-0.017872%). During the COVID-19 pandemic (January 2020 to August 2021), one case of endophthalmitis occurred among 14,725 injections performed (0.0068%; 95% CI, 0.000017-0.037832%). There was no significant difference between the two periods (Fisher's exact test: p = 0.5387). Even during the COVID-19 pandemic, very low incidence of endophthalmitis after intravitreal injection can be maintained by implementing basic infection prophylactic measures, including face draping and 0.25% povidone-iodine irrigation, established before COVID-19 pandemic.


Profile of Rio de Janeiro's violent lethality perpetrators, Brazil (2015).
This study presents the profile of the perpetrators of deaths caused by intentional aggressions in Rio de Janeiro, Brazil, in 2015, as per data from the State Civil Police (PCERJ) investigations. This is a quantitative, descriptive, and cross-sectional study. The information encompasses "premeditated murder", "larceny", "bodily injury followed by death" and "homicide caused by resisting police intervention". The study analyzes the profile of the authors of each category, except homicides committed by police intervention. The crimes committed by police intervention were excluded from the total number of the 1,562 identified deaths. Only about 20% of the perpetrators of the 1,255 crimes investigated were identified. The data recognized show the relevance of drug traffickers and militiamen illegal activities in the deaths and interpersonal violence in domestic and community spaces and neighborhoods. A remarkable similarity is observed between the profile of violent lethality perpetrators and victims in the studied urban contexts: men, young people, and young adults aged 19-39 years, blacks, with low schooling, high levels of unemployment, and informal occupations.


Optimization of isothermal amplification method for Mycobacteriumtuberculosisdetection and visualization method for fieldwork
Tuberculosis is still one of the most contagious diseases around the world. Key factors of tuberculosis control are rapid diagnostic, efficient treatment, and prevention of contamination by surveillance and monitoring. However, culture is the gold standard method for laboratory diagnosis of tuberculosis; the results are several weeks to obtain. In order to prevent contamination of tuberculosis, diagnosis must be made in short time and treatment should be started as soon as possible. The aim of this study is to optimize the loop-mediated isothermal amplification (LAMP) method, which provides a much faster and more sensitive result than the polymerase chain reaction (PCR) method and allows the replication of target nucleic acid sequences under isothermal conditions without the need for laboratory infrastructure. Sputum samples were homogenized with 5% trypsin solution in CaCl2 to obtain DNA.DNA was purified using QIAGEN QIAamp DNA mini kit. LAMP primers were design using Primer explorer V5 program according to IS6110 gene of Mycobacterium tuberculosis. NEB Bst 3.0 DNA polymerase kit was used for LAMP reactions. Besides, LAMP reactions were compared with TaqMan based RT-PCR method using NEB's Taq polymerase kit. Finally, for visualization of LAMP products, lateral flow dipsticks that produced by Milenia Biotec, colorimetric 2X LAMP master mix that produced by NEB and 2% w/v agarose gel electrophoresis methods were used. Optimum amplification temperature for LAMP was found to be 71.4 °C. The detection limit of the method was 102 CFU/mL and sensitivity was determined 100% compared to five different Mycobacterium species. The current study indicated that the LAMP-LFD and colorimetric LAMP protocol optimized with sputum samples can be reliable used as a rapid, sensitive and specific assay in the diagnosis of tuberculosis in the field.


A group-specific prior distribution for effect-size heterogeneity in meta-analysis.
While both methodological and applied work on Bayesian meta-analysis have flourished, Bayesian modeling of differences between groups of studies remains scarce in meta-analyses in psychology, education, and the social sciences. On rare occasions when Bayesian approaches have been used, non-informative prior distributions have been chosen. However, more informative prior distributions have recently garnered popularity. We propose a group-specific weakly informative prior distribution for the between-studies standard-deviation parameter in meta-analysis. The proposed prior distribution incorporates a frequentist estimate of the between-studies standard deviation as the noncentrality parameter in a folded noncentral t distribution. This prior distribution is then separately modeled for each subgroup of studies, as determined by a categorical factor. Use of the new prior distribution is shown in two extensive examples based on a published meta-analysis on psychological interventions aimed at increasing optimism. We compare the folded noncentral t prior distribution to several non-informative prior distributions. We conclude with discussion, limitations, and avenues for further development of Bayesian meta-analysis in psychology and the social sciences.


Acute Headache in the Emergency Setting.
Acute headache is a common symptom and is reported by approximately 2%-4% of patients who present to the emergency department. Many abnormalities manifest with headache as the first symptom, and it is crucial to obtain a patient's complete clinical history for correct diagnosis. Headache onset, duration, and severity; risk factors such as hypertension, immunosuppression, or malignancy; and the presence of focal neurologic deficits or systemic symptoms may aid the radiologist in deciding whether imaging is appropriate and which modality to choose. Imaging findings are more likely to be abnormal in patients with a "thunderclap" headache than in those with headaches of lesser severity. The causes of headache in the emergency setting are various. They may manifest at imaging as subarachnoid hemorrhage (ruptured aneurysm, reversible vasoconstriction syndrome, or pituitary apoplexy), parenchymal hemorrhage (hypertension, ruptured arteriovenous malformation, cerebral amyloid angiopathy, dural arteriovenous fistula, or sinus thrombosis), or parenchymal edema (posterior reversible encephalopathy syndrome, reversible cerebral vasoconstriction syndrome, sinus thrombosis, or encephalitis). Alterations in intracranial pressure that are related to idiopathic intracranial hypertension or spontaneous intracranial hypotension and prior lumbar puncture or epidural injection may manifest with specific imaging findings. With accumulating knowledge of disease pathophysiology, radiologists have started to play a more central role in making the correct diagnosis. This article reviews multiple causes of acute headache and their characteristic appearances at multimodality imaging and familiarizes the reader with current concepts in imaging.Online supplemental material is available for this article.©RSNA, 2019.


Coronary collateral function in patients without occlusive coronary artery disease.
Little is known of the functional capacity of coronary collaterals in humans without occlusive coronary artery disease. We, therefore, measured peripheral coronary pressure (PCP) and retrograde flow (RF) from coronary arteries at aortic valve replacement in seven patients without occlusive coronary artery disease. Using a T-connection interposed in left (LCA) and right (RCA) coronary perfusion lines, data were obtained during brief proximal occlusion of each line. PCP was expressed as a fraction of perfusion pressure (PP), and collateral resistance (CR) was calculated as PP/RF. Median values were as follows: (a table was included). In contrast, previous studies of well-collateralized distal segments of diseased coronary arteries revealed mean RF 15.7, CR 5.1 and PCP/PP 0.50. Under the conditions of study, all vessels interconnecting the non-diseased RCA and LCA delivered flow and pressure less readily than collaterals to a single distal segment of a diseased coronary artery. Thus, collaterals in patients without diseased coronary arteries have an extremely limited capacity to transmit either flow or pressure. The absolute values of RF were small relative to the muscle mass perfused by each coronary artery, suggesting that perfusion of only one coronary artery in man during operation may not provide substantial perfusion for large portions of myocardium. Comparison of performance of collaterals supplying atherosclerotic and nonatherosclerotic coronary arteries indicates that proximal occlusion may be an important factor stimulating enhancement of collateral function. Moreover, the nitroglycerin-induced improvement in collateral function seen in patients with chronic occlusive coronary disease was not demonstrable in patients without coronary occlusion. Thus, coronary collaterals may acquire nitroglycerin responsiveness as a result of changes induced by chronic coronary occlusion.


GEP, a local growth factor, is critical for odontogenesis and amelogenesis.
Granulin epithelin precursor (GEP) is a new growth factor that functions in brain development, chondrogenesis, tissue regeneration, tumorigenesis, and inflammation. The goal of this study was to study whether GEP was critical for odontogenesis and amelogenesis both in vivo and in vitro. The in situ hybridization and immunohistochemistry data showed that GEP was expressed in both odontoblast and ameloblast cells postnatally. Knockdown of GEP by crossing U6-ploxPneo-GEP and Sox2-Cre transgenic mice led to a reduction of dentin thickness, an increase in predentin thickness, and a reduction in mineral content in enamel. The in vitro application of recombinant GEP up-regulated molecular markers important for odontogenesis (DMP1, DSPP, and ALP) and amelogenesis (ameloblastin, amelogenin and enamelin). In conclusion, both the in vivo and the in vivo data support an important role of GEP in tooth formation during postnatal development.


Immunotherapy for Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.


Regulation of early endosomes across eukaryotes: Evolution and functional homology of Vps9 proteins.
Endocytosis is a crucial process in eukaryotic cells. The GTPases Rab 5, 21 and 22 that mediate endocytosis are ancient eukaryotic features and all available evidence suggests retained conserved function. In animals and fungi, these GTPases are regulated in part by proteins possessing Vps9 domains. However, the diversity, evolution and functions of Vps9 proteins beyond animals or fungi are poorly explored. Here we report a comprehensive analysis of the Vps9 family of GTPase regulators, combining molecular evolutionary data with functional characterization in the non-opisthokont model organism Trypanosoma brucei. At least 3 subfamilies, Alsin, Varp and Rabex5 + GAPVD1, are found across eukaryotes, suggesting that all are ancient features of regulation of endocytic Rab protein function. There are examples of lineage-specific Vps9 subfamily member expansions and novel domain combinations, suggesting diversity in precise regulatory mechanisms between individual lineages. Characterization of the Rabex5 + GAPVD1 and Alsin orthologues in T. brucei demonstrates that both proteins are involved in endocytosis, and that simultaneous knockdown prevents membrane recruitment of Rab5 and Rab21, indicating conservation of function. These data demonstrate that, for the Vps9-domain family at least, modulation of Rab function is mediated by evolutionarily conserved protein-protein interactions.


[Arrest of the painful syndrome by moradol and nubain in patients with ischemic heart disease].
Moradol was used for analgesia in 154 patients with unstable angina pectoris and small- and large-focal myocardial infarction and noubain in 69 patients aged 46 to 83. Moradol was found to be an effective analgesic for patients with acute myocardial infarction, exerting a hyperdynamic effect on the circulation, which was easily eliminated if the drug was combined with droperidol or relanium. Noubain is also effective in myocardial infarction, but exerts no hyperdynamic effect on the circulation.


Strain-Dependent Modifier Genes Determine Survival in Zfp423 Mice.
Zfp423 encodes a transcriptional regulatory protein that interacts with canonical signaling and lineage pathways. Mutations in mouse Zfp423 or its human ortholog ZNF423 are associated with a range of developmental abnormalities reminiscent of ciliopathies, including cerebellar vermis hypoplasia and other midline brain defects. Null mice have reduced viability in most strain backgrounds. Here we show complete lethality on a C57BL/6J background, dominant rescue in backcrosses to any of 13 partner strains, with strain-dependent survival frequencies, and evidence for a BALB/c-derived survival modifier locus on chromosome 5. Survival data indicate both perinatal and postnatal periods of lethality. Anatomical data from a hypomorphic gene trap allele observed on both C57BL/6J and BALB/c congenic backgrounds shows an aggregate effect of background on sensitivity to Zfp423 loss rather than a binary effect on viability.


Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands.
Potassium channels are essential for maintaining a normal ionic balance across cell membranes. Central to this function is the ability of such channels to support transmembrane ion conduction at nearly diffusion-limited rates while discriminating for K+ over Na+ by more than a thousand-fold. This selectivity arises because the transfer of the K+ ion into the channel pore is energetically favoured, a feature commonly attributed to a structurally precise fit between the K+ ion and carbonyl groups lining the rigid and narrow pore. But proteins are relatively flexible structures that undergo rapid thermal atomic fluctuations larger than the small difference in ionic radius between K+ and Na+. Here we present molecular dynamics simulations for the potassium channel KcsA, which show that the carbonyl groups coordinating the ion in the narrow pore are indeed very dynamic ('liquid-like') and that their intrinsic electrostatic properties control ion selectivity. This finding highlights the importance of the classical concept of field strength. Selectivity for K+ is seen to emerge as a robust feature of a flexible fluctuating pore lined by carbonyl groups.


Effectiveness of a Mobile-Based Influenza-Like Illness Surveillance System (FluMob) Among Health Care Workers: Longitudinal Study.
Existing studies have suggested that internet-based participatory surveillance systems are a valid sentinel for influenza-like illness (ILI) surveillance. However, there is limited scientific knowledge on the effectiveness of mobile-based ILI surveillance systems. Previous studies also adopted a passive surveillance approach and have not fully investigated the effectiveness of the systems and their determinants. The aim of this study was to assess the efficiency of a mobile-based surveillance system of ILI, termed FluMob, among health care workers using a targeted surveillance approach. Specifically, this study evaluated the effectiveness of the system for ILI surveillance pertaining to its participation engagement and surveillance power. In addition, we aimed to identify the factors that can moderate the effectiveness of the system. The FluMob system was launched in two large hospitals in Singapore from April 2016 to March 2018. A total of 690 clinical and nonclinical hospital staff participated in the study for 18 months and were prompted via app notifications to submit a survey listing 18 acute respiratory symptoms (eg, fever, cough, sore throat) on a weekly basis. There was a period of study disruption due to maintenance of the system and the end of the participation incentive between May and July of 2017. On average, the individual submission rate was 41.4% (SD 24.3%), with a rate of 51.8% (SD 26.4%) before the study disruption and of 21.5% (SD 30.6%) after the disruption. Multivariable regression analysis showed that the adjusted individual submission rates were higher for participants who were older (<30 years, 31.4% vs 31-40 years, 40.2% [P<.001]; 41-50 years, 46.0% [P<.001]; >50 years, 39.9% [P=.01]), ethnic Chinese (Chinese, 44.4% vs non-Chinese, 34.7%; P<.001), and vaccinated against flu in the past year (vaccinated, 44.6% vs nonvaccinated, 34.4%; P<.001). In addition, the weekly ILI incidence was 1.07% on average. The Pearson correlation coefficient between ILI incidence estimated by FluMob and that reported by Singapore Ministry of Health was 0.04 (P=.75) with all data and was 0.38 (P=.006) including only data collected before the study disruption. Health care workers with higher risks of ILI and influenza such as women, non-Chinese, allied health staff, those who had children in their households, not vaccinated against influenza, and reported allergy demonstrated higher surveillance correlations. Mobile-based ILI surveillance systems among health care workers can be effective. However, proper operation of the mobile system without major disruptions is vital for the engagement of participants and the persistence of surveillance power. Moreover, the effectiveness of the mobile surveillance system can be moderated by participants' characteristics, which highlights the importance of targeted disease surveillance that can reduce the cost of recruitment and engagement.


Recent Insights Into Molecular Mechanisms of Propofol-Induced Developmental Neurotoxicity: Implications for the Protective Strategies.
Mounting evidence has demonstrated that general anesthetics could induce developmental neurotoxicity, including acute widespread neuronal cell death, followed by long-term memory and learning abnormalities. Propofol is a commonly used intravenous anesthetic agent for the induction and maintenance of anesthesia and procedural and critical care sedation in children. Compared with other anesthetic drugs, little information is available on its potential contributions to neurotoxicity. Growing evidence from multiple experimental models showed a similar neurotoxic effect of propofol as observed in other anesthetic drugs, raising serious concerns regarding pediatric propofol anesthesia. The aim of this review is to summarize the current findings of propofol-induced developmental neurotoxicity. We first present the evidence of neurotoxicity from animal models, animal cell culture, and human stem cell-derived neuron culture studies. We then discuss the mechanism of propofol-induced developmental neurotoxicity, such as increased cell death in neurons and oligodendrocytes, dysregulation of neurogenesis, abnormal dendritic development, and decreases in neurotrophic factor expression. Recent findings of complex mechanisms of propofol action, including alterations in microRNAs and mitochondrial fission, are discussed as well. An understanding of the toxic effect of propofol and the underlying mechanisms may help to develop effective novel protective or therapeutic strategies for avoiding the neurotoxicity in the developing human brain.


Polychlorinated biphenyl-77 induces adipocyte differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis.
Obesity, an inflammatory condition linked to cardiovascular disease, is associated with expansion of adipose tissue. Highly prevalent coplanar polychlorinated biphenyls (PCBs) such as 3,3',4,4'-tetrachlorobiphenyl (PCB-77) accumulate in adipose tissue because of their lipophilicity and increase with obesity. However, the effects of PCBs on adipocytes, obesity, and obesity-associated cardiovascular disease are unknown. In this study we examined in vitro and in vivo effects of PCB-77 on adipocyte differentiation, proinflammatory adipokines, adipocyte morphology, body weight, serum lipids, and atherosclerosis. PCB-77 or 2,2',4,4,5,5'-hexachlorobiphenyl (PCB-153) was incubated with 3T3-L1 adipocytes either during differentiation or in mature adipocytes. Concentration-dependent effects of PCB-77 were contrasted with those of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For in vivo studies, we treated C57BL/6 wild-type (WT) or aryl hydrocarbon receptor (AhR)(-/-) mice with vehicle or PCB-77 (49 mg/kg, by intraperitoneal injection) and examined body weight gain. In separate studies, we injected ApoE(-/-) mice with vehicle or PCB-77 over a 6-week period and examined body weight, adipocyte size, serum lipids, and atherosclerosis. Low concentrations of PCB-77 or TCDD increased adipocyte differentiation, glycerol-3-phosphate dehydrogenase activity, and expression of peroxisome proliferator-activated receptor gamma, whereas higher concentrations inhibited adipocyte differentiation. Effects of PCB-77 were abolished by the AhR antagonist alpha-naphthoflavone. PCB-77 promoted the expression and release of various proinflammatory cytokines from 3T3-L1 adipocytes. Administration of PCB-77 increased body weight gain in WT but not AhR(-/-) mice. ApoE(-/-) mice injected with PCB-77 exhibited greater body weight, adipocyte hypertrophy, serum dyslipidemia, and augmented atherosclerosis. Our findings suggest that PCB-77 may contribute to the development of obesity and obesity-associated atherosclerosis.


A Novel Missense Mutation in Human Receptor Roundabout-1 (ROBO1) Gene Associated with Pituitary Stalk Interruption Syndrome
Pituitary stalk interruption syndrome (PSIS) is characterized by the association of an absent or thin pituitary stalk, an absent or hypoplastic anterior pituitary lobe and an ectopic posterior pituitary (EPP) lobe. The causes of this anatomical defect include both genetic and environmental factors. Molecular genetic defects have been indentified in a small number of patients with PSIS. A 4-year-old boy presented with hypoglycemia and hyponatremia associated with growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone deficiencies. The patient had right sided strabismus. magnetic resonance imaging images showed pituitary hypoplasia, EPP and absent pituitary stalk. A novel Receptor Roundabout-1 (ROBO1) missense mutation (c.1690C>T, p.Pro564Ser) that may contribute to the disorder was found in this patient and his mother, who also exhibited pituitary abnormalities.


Direct identification of bacteria from BacT/ALERT anaerobic positive blood cultures by MALDI-TOF MS: MALDI Sepsityper kit versus an in-house saponin method for bacterial extraction.
In cases of bacteraemia, a rapid species identification of the causal agent directly from positive blood culture broths could assist clinicians in the timely targeting of empirical antimicrobial therapy. For this purpose, we evaluated the direct identification of micro-organisms from BacT/ALERT (bioMérieux) anaerobic positive blood cultures without charcoal using the Microflex matrix-assisted laser desorption/ionization (MALDI) time of flight MS (Bruker), after bacterial extraction by using two different methods: the MALDI Sepsityper kit (Bruker) and an in-house saponin lysis method. Bruker's recommended criteria for identification were expanded in this study, with acceptance of the species identification when the first three results with the best matches with the MALDI Biotyper database were identical, whatever the scores were. In total, 107 monobacterial cultures and six polymicrobial cultures from 77 different patients were included in this study. Among monomicrobial cultures, we identified up to the species level 67 and 66 % of bacteria with the MALDI Sepsityper kit and the saponin method, respectively. There was no significant difference between the two extraction methods. The direct species identification was particularly inconclusive for Gram-positive bacteria, as only 58 and 52 % of them were identified to the species level with the MALDI Sepsityper kit and the saponin method, respectively. Results for Gram-negative bacilli were better, with 82.5 and 90 % of correct identification to the species level with the MALDI Sepsityper kit and the saponin method, respectively. No misidentifications were given by the direct procedures when compared with identifications provided by the conventional method. Concerning the six polymicrobial blood cultures, whatever the extraction method used, a correct direct identification was only provided for one of the isolated bacteria on solid medium in all cases. The analysis of the time-to-result demonstrated a reduction in the turnaround time for identification ranging from 1 h 06 min to 24 h 44 min, when performing the blood culture direct identification in comparison with the conventional method, whatever the extraction method.


Problems of Translating Oil Contracts of Multinational Companies from English into Arabic.
This study investigated challenges that Saudi undergraduate learners face in translating oil contracts from English into Arabic. The study used a quantitative approach of data collection. The sample of this study consisted of 18 Saudi undergraduate learners of transaction departments at some Saudi universities. To achieve the objectives of this study, a test was designed and administered. Additionally, the relevant theoretical framework of legal translation and features of oil contracts were analysed to pinpoint the problematic areas and the gaps. The results of the study indicated that undergraduate learners provided unacceptable translation based on lexical and textual features. On the other hand, they provided poor translation based on syntactic features. The study suggests some practical solutions to overcome the difficulties of legal texts for translators.


Goodbye to the term 'ankylosing spondylitis', hello 'axial spondyloarthritis': time to embrace the ASAS-defined nomenclature.
Ankylosing spondylitis (AS) is the historic term used for decades for the HLA-B27-associated inflammatory disease affecting mainly the sacroiliac joints (SIJ) and spine. Classification criteria for AS have radiographic sacroiliitis as a dominant characteristic. However, with the availability of MRI of SIJ, it could be demonstrated that the disease starts long before definite SIJ changes become visible on radiographs. The Assessment of SpondyloArthritis international Society, representing a worldwide group of experts reached consensus on changes in the nomenclature pertaining to axial spondyloarthritis (axSpA), such as the terminology of diagnosis and of assessment of disease activity tools. These are important changes in the field, as experts in axSpA are now in agreement that the term axSpA is the overall term for the disease. A further differentiation, of which radiographic versus non-radiographic is only one aspect, may be relevant for research purposes. Another important decision was that the terms AS and radiographic axSpA (r-axSpA) can be used interchangeably, but that the preferred term is r-axSpA. Based on the decision that axSpA is the correct terminology, a proposal was made to officially change the meaning of the ASDAS acronym to 'Axial Spondyloarthritis Disease Activity Score'. In addition, for simplification it was proposed that the term ASDAS (instead of ASDAS-CRP) should be preferred and applied to the ASDAS calculated with C reactive protein (CRP). It is hoped that these changes will be used consequently for education, in textbooks, manuscripts and presentations.


Synchronization of local neural networks in the somatosensory cortex: A comparison of stationary and moving stimuli.
Spontaneous and stimulus-induced responses were recorded from neighboring groups of neurons by an array of electrodes in the primary (SI) somatosensory cortex of intact, halothane-anesthetized cats. Cross-correlation analysis was used to characterize the coordination of spontaneous activity and the responses to peripheral stimulation with moving or stationary air jets. Although synchronization was detected in only 10% (88 of 880) of the pairs of single neurons that were recorded, cross-correlation analysis of multiunit responses revealed significant levels of synchronization in 64% of the 123 recorded electrode pairs. Compared with spontaneous activity, both stationary and moving air jets caused substantial increases in the rate, proportion, and temporal precision of synchronized activity in local regions of SI cortex. Among populations of neurons that were synchronized by both types of air-jet stimulation, the mean rate of synchronized activity was significantly higher during moving air-jet stimulation than during stationary air-jet stimulation. Moving air jets also produced significantly higher correlation coefficients than stationary air jets in the raw cross-correlograms (CCGs) but not in the shift-corrected CCGs. The incidence and rate of stimulus-induced synchronization varied with the distance separating the recording sites. For sites separated by </=300 microm, 80% of the multiunit responses displayed significant levels of synchronization during both types of air-jet stimulation. For sites separated by >/=500 microm, only 37% of the multiunit responses were synchronized by discrete stimulation with a single air jet. Measurements of the multiunit CCG peak half-widths showed that the correlated activity produced by moving air jets had slightly less temporal variability than that produced by stationary air jets. These results indicate that moving stimuli produce greater levels of synchronization than stationary stimuli among local groups of SI neurons and suggest that neuronal synchronization may supplement the changes in firing rate which code intensity and other attributes of a cutaneous stimulus.


Insights into the pathophysiology and pathogenesis of Gilles de la Tourette syndrome.
The role of D1 and D2 dopaminergic receptors in the occurrence of dyskinesia, particularly that of tics, is discussed. Observation of neuroleptic-induced oral movements in rats strongly suggests that stimulation of D1 receptors triggers or increases dyskinesia. Such distinction between the action of D1 and D2 dopamine agonists is not yet possible in humans. Experiments on the resting finger tremor in man or women enable to suspect and interaction between D1 and D2 receptors. Prenatal neuroleptic exposure during vulnerable periods of pregnancy decreases the density of dopaminergic D2 receptors in rat.


Diabetes mellitus--advances and challenges in human β-cell proliferation.
The treatment of diabetes mellitus represents one of the greatest medical challenges of our era. Diabetes results from a deficiency or functional impairment of insulin-producing β cells, alone or in combination with insulin resistance. It logically follows that the replacement or regeneration of β cells should reverse the progression of diabetes and, indeed, this seems to be the case in humans and rodents. This concept has prompted attempts in many laboratories to create new human β cells using stem-cell strategies to transdifferentiate or reprogramme non-β cells into β cells or to discover small molecules or other compounds that can induce proliferation of human β cells. This latter approach has shown promise, but has also proven particularly challenging to implement. In this Review, we discuss the physiology of normal human β-cell replication, the molecular mechanisms that regulate the cell cycle in human β cells, the upstream intracellular signalling pathways that connect them to cell surface receptors on β cells, the epigenetic mechanisms that control human β-cell proliferation and unbiased approaches for discovering novel molecules that can drive human β-cell proliferation. Finally, we discuss the potential and challenges of implementing strategies that replace or regenerate β cells.


Drug treatment of neuropathic pain.
Neuropathic pain results from damage to or dysfunction in the nervous system. The term usually refers to pain caused by a primary abnormality in the peripheral nervous system, while pain caused by damage to the central nervous system tends to be called central pain. Once established, neuropathic pain frequently runs a chronic course and can be severe and difficult to treat. Most doctors (but especially GPs, neurologists, neurosurgeons, oncologists and pain clinic specialists) will encounter patients with neuropathic pain. Management, ideally in a multidisciplinary pain-relief clinic, often involves the combined use of a range of pharmacological and non-drug approaches, the latter including transcutaneous electrical nerve stimulation, psychological treatments, and specialist procedures to stimulate, block or destroy discrete areas of the nervous system. Here, we review just the drug treatments for neuropathic pain.


Experiences of Assistive Products and Home Care among Older Clients with and without Dementia in Sweden.
The purpose was to compare selection, use and outcomes of assistive products among older home care clients with and without dementia in Sweden, and to explore the relations between the use of assistive products and perceptions of home care, loneliness and safety. Self-reported data from 89,811 home care clients aged 65 years or more, of whom 8.9% had dementia, were analysed using regression models. Excluding spectacles, 88.2% of them used assistive products. Respondents without dementia were more likely to use at least one assistive product but less likely to use assistive products for remembering. Respondents with dementia participated less in the selection of assistive products, used less assistive products, and benefited less from them. Users of assistive products were more likely to be anxious and bothered by loneliness, to feel unsafe at home with home care, to experience that their opinions and wishes regarding assistance were disregarded by home care personnel, and to be treated worse by home care personnel. The findings raise concerns about whether the needs for assistive products among home care clients with dementia are adequately provided for. They also indicate a need to strengthen a person-centred approach to providing home care to users of assistive products.


In vivo X-Nuclear MRS Imaging Methods for Quantitative Assessment of Neuroenergetic Biomarkers in Studying Brain Function and Aging.
Brain relies on glucose and oxygen metabolisms to generate biochemical energy in the form of adenosine triphosphate (ATP) for supporting electrophysiological activities and neural signaling under resting or working state. Aging is associated with declined mitochondrial functionality and decreased cerebral energy metabolism, and thus, is a major risk factor in developing neurodegenerative diseases including Alzheimer's disease (AD). However, there is an unmet need in the development of novel neuroimaging tools and sensitive biomarkers for detecting abnormal energy metabolism and impaired mitochondrial function, especially in an early stage of the neurodegenerative diseases. Recent advancements in developing multimodal high-field in vivo X-nuclear (e.g., 2H, 17O and 31P) MRS imaging techniques have shown promise for quantitative and noninvasive measurement of fundamental cerebral metabolic rates of glucose and oxygen consumption, ATP production as well as nicotinamide adenine dinucleotide (NAD) redox state in preclinical animal and human brains. These metabolic neuroimaging measurements could provide new insights and quantitative bioenergetic markers associated with aging processing and neurodegeneration and can therefore be employed to monitor disease progression and/or determine effectiveness of therapeutic intervention.


Hypotension in preterm infants.
Hypotension is a frequent occurrence in sick preterm neonates. It is important to appropriately recognise and treat hypotension in preterm infants due to the possible association with short and long term adverse outcomes. An extensive search for relevant articles was carried out on PubMed, Embase and Cochrane database of systematic reviews. Cross references were hand searched. The pathophysiology hypotension in preterm infants is multifactorial. Hypovolemia plays only a minor role in the absence of overt fluid losses. Cardiac dysfunction seems to be a factor in some neonates. Assessment of hypotension should be based on an overall clinical condition. Overzealous fluid administration seems to be associated with adverse outcomes and should be avoided in the absence of obvious fluid losses. Inotropes should be used if fluid boluses fail to correct hypotension. Dopamine is the most effective inotrope. Dobutamine can be used as add on therapy or as first line if cardiac dysfunction is an obvious cause. Evidence points to hypocortisolism in at least some hypotensive infants. Steroids have been used successfully in inotrope-resistant hypotension in some infants. Steroids should be used judiciously since there have been concerns about adverse neurological outcome in preterm infants who received steroids in the neonatal period.


Near-infrared indocyanine green videoangiography (ICGVA) and intraoperative computed tomography (iCT): are they complementary or competitive imaging techniques in aneurysm surgery?
In this pilot study we compared advantages and drawbacks of near-infrared indocyanine green videoangiography (ICGVA) and intraoperative computed tomography (iCT) to investigate if these are complementary or competitive methods to acquire immediate information about blood vessels and potential critical impairment of brain perfusion during vascular neurosurgery. A small subset of patients (n = 10) were prospectively enrolled in this feasibility study and received ICGVA immediately after placement of the aneurysm clips. An intraoperative cranial CT angiography (iCTA) was followed by dynamic perfusion CT scan (iCTP) using a 40-slice, sliding-gantry, CT scanner. The vascular patency of major (aneurysm bearing) arteries, visualisation of arising perforating arteries and brain perfusion after clip application were analysed with both techniques. The ICGVA was able to visualise blood flow and vascular patency of all major vessels and perforating arteries within the visual field of the microscope, but failed to display vessels located within deeper areas of the surgical field. Even small coverage with brain parenchyma impaired detection of vessels. With iCTA high image quality could be obtained in 7/10 cases of clipped aneurysms. Intraoperative CTA was not sufficiently evaluable in one PICA aneurysm and one case of a previously coiled recurrent aneurysm, due to extensive coil artefacts. Small, perforating arteries could not be detected with iCTA. Intraoperative CTP allowed the assessment of global blood flow and brain perfusion in sufficient quality in 5/10 cases, and enabled adequate intraoperative decision making. A combination of ICGVA and iCT is feasible, with very good diagnostic imaging quality associated with short acquisition time and little interference with the surgical workflow. Both techniques are complementary rather than competing analysing tools and help to assess information about local (ICGVA/iCTA) as well as regional (iCTA/iCTP) blood flow and cerebral perfusion immediately after clipping of intracranial aneurysms.


Papillon-Lefèvre Syndrome: A Rare Case Report of Two Brothers and Review of the Literature.
Papillon-Lefèvre is an autosomal recessive syndrome that starts in early periods of childhood. Characteristic features include palmar plantar hyperkeratosis, aggressive periodontal disease, and a tendency for dry and chopped skin, thin and sparse hair. Patients show signs of premature tooth loss at the age of 2 to 4 years, which is then followed by the loss of permanent dentition during adolescence. The presence of both skin and oral lesions in this syndrome differentiates this unusual genodermatosis from other pathology of palmoplantar keratoderma (PPK). The etiopathogenesis of this syndrome is somewhat obscure; however, immunologic, genetic, and possible bacterial etiologies have been proposed. The dental practitioner is often the first to diagnose the disease, as there is a significant degree of periodontal breakdown that is involved at an early age. This report presents a clinical presentation of two brothers detected with Papillon-Lefèvre syndrome (PLS). How to cite this article: Fageeh HN. Papillon-Lefèvre Syndrome: A Rare Case Report of Two Brothers and Review of the Literature. Int J Clin Pediatr Dent 2018;11(4):352-355.


Burden of prehypertension among adults in Kenya: a retrospective analysis of findings from the Healthy Heart Africa (HHA) Programme.
Hypertension is the leading risk factor for mortality globally. African countries, including Kenya, have a high and rising prevalence of hypertension. Prehypertension is associated with an increased risk of progression to overt hypertension and a higher risk of cardiovascular disease and mortality. Despite this, little is documented on the prevalence and distribution of prehypertension in sub-Saharan Africa. This study sought to estimate the overall burden of prehypertension in Kenyan adults enrolled in a large hypertension control programme, Healthy Heart Africa. The distribution and determinants of prehypertension in the sample were explored as secondary objectives. This was a post hoc analysis of cross-sectional data obtained from population-level blood pressure (BP) screening of adults aged ≥18 years in the community and ambulatory care facilities in 17/47 sub-national administrative units in Kenya. All participants with a complete record for systolic and diastolic BP were included. Descriptive analyses were performed for sociodemographic characteristics. Pearson's chi-square test was used to assess differences in categorical variables. Multivariate logistic regression analysis was performed to identify factors independently associated with prehypertension. Of 5,985,185 participant records that were included in the analysis, 34% were men (mean age: 45 [SD 2.9] years). The majority (63%) lived in rural Kenya. The prevalence of prehypertension was 54.5% and that of hypertension was 20.8%. Characteristics that were independently associated with prehypertension (adjusted odds ratio [95% CI]) included male sex (1.23 [±0.0023], p < 0.001 for all age groups > 25 years) and rural residence (1.60 [±0.023], p < 0.001). Approximately one in every two Kenyan adults has prehypertension. This calls for urgent development and roll-out of a national BP screening and control programme. It also provides a strong basis for the formulation of multisectoral national policies that will ensure implementation of evidence-based, low-cost public health interventions geared towards primary prevention of hypertension, especially in population groups that are traditionally considered at low risk, such as young adults and rural residents.


Interrelationship of mid-diastolic mitral valve motion, pulmonary venous flow, and transmitral flow.
This study offers a unifying mechanism of left ventricular filling dynamics to link the unexplained mid-diastolic motion of the mitral valve with an associated increase in transmitral flow, with the phasic character of pulmonary vein flow, and with changes in the atrioventricular pressure difference. M mode echograms of mitral valve motion and Doppler echocardiograms of mitral and pulmonary vein flow velocities were recorded in 12 healthy volunteers (heart rate = 60 +/- 9 beats/min). All echocardiograms showed an undulation in the mitral valve (L motion) at a relatively constant delay from the peak of the diastolic phase of pulmonary vein flow (K phase). In six subjects, the L motion was also associated with a distinct wave of mitral flow (L wave). Measured from the onset of the QRS complex, Q-K was 577 +/- 39 msec; Q-L was 703 +/- 42 msec, and K-L was 125 +/- 16 msec. Multiple measurements within each subject during respiratory variations in RR interval indicated exceptionally small differences in the temporal relationships (mean coefficient of variation 2%). Early rapid flow deceleration is caused by a reversal of the atrioventricular pressure gradient, and the L wave arises from the subsequent reestablishment of a positive gradient due to left atrial filling via the pulmonary veins. The mitral valve moves passively in response to the flowing blood and the associated pressure difference. This interpretation is confirmed by (1) a computational model, and (2) a retrospective analysis of data from patients with mitral stenosis and from conscious dogs instrumented to measure transmitral pressure-flow relationships.


The role of antioxidants and zinc in minimal hepatic encephalopathy: a randomized trial.
Minimal hepatic encephalopathy (MHE) has a far-reaching impact on quality and function ability in daily life and may progress to overt hepatic encephalopathy. There is a synergistic effect between systemic oxidative stress and ammonia that is implicated in the pathogenesis of hepatic encephalopathy. The aim of this study is to investigate the effectiveness of oral supplementation of antioxidants and zinc gluconate on MHE versus lactulose. Our study included 58 patients with cirrhosis diagnosed as having MHE by neuropsychometric tests, including number connection test part A (NCT-A), digit symbol test (DST) and block design tests (BDTs). Patients were randomized to receive 175 mg zinc gluconate, 50,000 IU vitamin A, 500 mg vitamin C and 100 mg vitamin E once daily plus lactulose, dose 30-60 ml/day for 3 months [group A (n = 31)] or initiated and maintained on lactulose dose 30-60 ml/day for 3 months [group B (n = 27)]. Neuropsychometric tests and laboratory investigations were repeated after 3 months of therapy. Compared with the baseline neuropsychometric tests, a significant improvement was reported in patients with MHE after 3 months of antioxidant and zinc therapy (group A) versus patients with lactulose therapy (group B) (NCT-A, p <0.001; DST, p = 0.006; BDT, p < 0.001). Antioxidant and zinc supplementation significantly decreased arterial ammonia level, alanine aminotransferase (ALT), aspartate aminotransferase (AST) (p < 0.001) and improved Child-Pugh score in MHE after 3 months of therapy (p= 0.024). Antioxidant and zinc supplementation can improve MHE in patients with liver cirrhosis.


Evaluation of a Family-Centered Preventive Intervention for Military Families: Parent and Child Longitudinal Outcomes.
This study evaluates the longitudinal outcomes of Families OverComing Under Stress (FOCUS), a family-centered preventive intervention implemented to enhance resilience and to reduce psychological health risk in military families and children who have high levels of stress related to parental wartime military service. We performed a secondary analysis of evaluation data from a large-scale service implementation of the FOCUS intervention collected between July 2008 and December 2013 at 15 military installations in the United States and Japan. We present data for 2,615 unique families (3,499 parents and 3,810 children) with completed intake and at least 1 postintervention assessment. Longitudinal regression models with family-level random effects were used to assess the patterns of change in child and parent (civilian and military) psychological health outcomes over time. Improvement in psychological health outcomes occurred in both service member and civilian parents. Relative to intake, parental anxiety and depression symptoms were significantly reduced postintervention, and these reductions were maintained at 2 subsequent follow-up assessments. In addition, we identified an improvement over time in emotional and behavioral symptoms and in prosocial behaviors for both boys and girls. We observed reductions in the prevalence of unhealthy family functioning and child anxiety symptoms, as well as parental depression, anxiety, and posttraumatic stress symptoms from intake to follow-up. Longitudinal program evaluation data show sustained trajectories of reduced psychological health risk symptoms and improved indices of resilience in children, civilian, and active duty military parents participating in a strength-based, family-centered preventive intervention.


Analysis of the dynamics of renal vascular resistance and urine flow rate in the cat following electrical stimulation of the renal nerves.
In ten sino aortic denervated, vagotomized and aneasthetized cats, renal efferent nerves were stimulated for 30 s with trains of constant current pulses at frequencies in the range 5-30 Hz. The arterial pressure, heart rate, urine flow rate (electronic drop counter) and renal blood flow (electromagnetic technique) were recorded. Subsequent computer processing gave the true means of renal artery pressure (MRAP) and renal blood flow (MRBF) and hence the renal vascular resistance (MRVR), over each cardiac cycle. Recovery of MRVR after the end of stimulation exhibited two distinct time constants. The fast component had a time constant of 2.03 +/- 0.26 s and represented 60.2 +/- 1.71% of the recovery. The time constant of the slower component was 14.1 +/- 1.9 s and represented 36.0 +/- 1.6% of the recovery. The relationship between MRVR and stimulus frequency was sigmoidal with maximum sensitivity at stimulus frequencies of 12.6 +/- 0.76 Hz. Changes in urine flow rate, in contrast, followed a hyperbolic function with maximum response sensitivity occurring at very low stimulus frequencies. Changes in urine flow rate were 50% complete at stimulus frequencies of 5 Hz. Identification of two distinct components in the relaxation phase of renal vascular resistance leads to a reasonable hypothesis that 60% of total renal vascular resistance may lie proximal to the glomerulus, whereas 36% may be accounted for by the efferent arterioles.


Loss of p16 expression is of prognostic significance in locally advanced prostate cancer: an analysis from the Radiation Therapy Oncology Group protocol 86-10.
The retinoblastoma (RB) cell cycle regulatory pathway is known to be deregulated in virtually all known human tumors. The protein product of the RB gene, pRB, and its upstream regulator, p16, are among the most commonly affected members of this pathway. We investigated the prognostic significance of both pRB and p16 expression in locally advanced prostate cancers, from patients treated on the Radiation Therapy Oncology Group (RTOG) protocol 86-10. Sixty-seven cases from RTOG 86-10 had immunohistochemically stained slides, judged interpretable for both p16 and pRB, available for analysis. Median follow-up was 8.9 years (range, 6.0 to 11.8 years) for surviving patients. Staining for each marker was then correlated with overall survival, local progression, distant metastasis, and disease-specific survival. Loss of p16 expression, as defined by expression was significantly associated with reduced overall survival (P =.039), disease-specific survival (P =.006), and higher risk of local progression (P =.0007) and distant metastasis (P =.026) in the univariate analysis. In the multivariate analysis, loss of p16 was significantly associated with reduced disease-specific survival (P =.0078) and increased risk of local failure (P =.0035) and distant metastasis (P =.026). A borderline association with reduced overall survival (P =.07) was also evident. Loss of pRB was associated with improved disease-specific survival on univariate (P =.028) and multivariate analysis (P =.043), but carried no other significant outcome associations. Loss of p16 is significantly associated with adverse clinical outcome in cases of locally advanced prostate cancer.


Medicinal cannabinoids in palliative care.
The treatment of symptoms in people with palliative diagnoses begins with meticulous clinical assessment with treatment choice(s) selected based on an understanding of the symptom aetiology and the evidence which underpins its treatment. Increasingly, the merits of palliative care have been established earlier in the disease trajectory where treatment outcomes may include increased survival and maintenance of function. There is strong public support for the availability of medicinal cannabis, particularly for people with palliative diagnoses. There are several areas where there is potential for symptom benefits through modulation of the endocannabinoid system, though clinical data to date has been inconclusive in key symptoms such as pain and nausea, and data from other settings such as chemotherapy-induced nausea and vomiting not readily extrapolated. Ideally exploration of medicinal cannabinoids should occur within a clinical trial to accelerate the evidence base to inform practice. In people with refractory symptoms, the consideration of unregistered products or off-label prescribing should be guided by the potential influences of pharmacokinetic, pharmacodynamic and drug-drug interactions, supported by an informed discussion with the patient, and regular review of net clinical benefit.


A PD control-based QRS detection algorithm for wearable ECG applications.
We present a QRS detection algorithm for wearable ECG applications using a proportional-derivative (PD) control. ECG data of arrhythmia have irregular intervals and magnitudes of QRS waves that impede correct QRS detection. To resolve the problem, PD control is applied to avoid missing a small QRS wave followed from a large QRS wave and to avoid falsely detecting noise as QRS waves when an interval between two adjacent QRS waves is large (e.g. bradycardia, pause, and arioventricular block). ECG data was obtained from 78 patients with various cardiovascular diseases and tested for the performance evaluation of the proposed algorithm. The overall sensitivity and positive predictive value were 99.28% and 99.26%, respectively. The proposed algorithm has low computational complexity, so that it can be suitable to apply mobile ECG monitoring system in real time.


Comparison of concentration, shape, and polymer composition between microplastics and mesoplastics in Japanese river waters.
While plastics are classified by size as microplastics (<5 mm), mesoplastics (5-25 mm), and macroplastics (>25 mm), research in rivers has centered on microplastics, followed by macroplastics, with limited research on mesoplastics (research gap). This study aims to clarify the concentration, shape, and polymer composition of microplastics and mesoplastics in Japanese river water. We conducted field surveys for microplastics and mesoplastics in 147 rivers and at 185 measurement stations. The novelty of this study is in the use of a large number of field data to minimize the effect of the spatial difference in the microplastics and mesoplastics on the data analysis. Microplastics and mesoplastics were found at 183 (99 %) and 136 (74 %) stations, respectively. The difference between the concentration of microplastics and mesoplastics increased significantly with the increase in the concentration of microplastics, showing that the concentration of both microplastics and mesoplastics should be monitored to prevent an underestimation of plastic pollution in rivers with the appropriate sampling. A 2-stage size classification with microplastics (<5 mm) and macroplastics (>5 mm) is not suitable because the mesoplastics may be substantially overlooked. The regression slopes between microplastics and mesoplastics concentrations significant decrease in variance with increasing data number, suggesting the necessity of the large number of samples used in this study. The predominant shapes and polymer types of microplastics and mesoplastics were found to be fragment and fiber and polyethylene and polyethylene terephthalate (PET), respectively, which were affected appreciably by many fiber clusters. The fiber and PET ratios were dominant at stations with small population densities and urban ratios and can be attributed to atmospheric deposition and the underdeveloped rate of wastewater treatment plants (WWTPs). Therefore, it is necessary to monitor the dynamics and fate of fiber clusters inside and outside the basin.


Not all instability training devices enhance muscle activation in highly resistance-trained individuals.
The objective of this study was to measure the electromyographic (EMG) activity of the soleus, bicep femoris, rectus femoris, lower abdominal, and lumbosacral erector spinae (LSES) muscles with a variety of (a) instability devices, (b) stable and unstable (Dyna Disc) exercises, and (c) a fatiguing exercise in 16 highly conditioned individuals. The device protocol had participants assume standing and squatting postures while balancing on a variety of unstable platforms (Dyna Disc, BOSU ball, wobble board, and a Swiss ball) and a stable floor. The exercise protocol had subjects performing, static front lunges, static side lunges, 1-leg hip extensions, 1-leg reaches, and calf raises on a floor or an unstable Dyna Disc. For the fatigue experiment, a wall sit position was undertaken under stable and unstable (BOSU ball) conditions. Results for the device experiment demonstrated increased activity for all muscles when standing on a Swiss ball and all muscles other than the rectus femoris when standing on a wobble board. Only lower abdominals and soleus EMG activity increased while squatting on a Swiss ball and wobble board. Devices such as the Dyna Disc and BOSU ball did not exhibit significant differences in muscle activation under any conditions, except the LSES in the standing Dyna Disc conditions. During the exercise protocol, there were no significant changes in muscle activity between stable and unstable (Dyna Disc) conditions. With the fatigue protocol, soleus EMG activity was 51% greater with a stable base. These results indicate that the use of moderately unstable training devices (i.e., Dyna Disc, BOSU ball) did not provide sufficient challenges to the neuromuscular system in highly resistance-trained individuals. Since highly trained individuals may already possess enhanced stability from the use of dynamic free weights, a greater degree of instability may be necessary.


Amnion membrane organ-on-chip: an innovative approach to study cellular interactions.
The amnion membrane that lines the human intrauterine cavity is composed of amnion epithelial cells (AECs) connected to an extracellular matrix containing amnion mesenchymal cells (AMCs) through a basement membrane. Cellular interactions and transitions are mechanisms that facilitate membrane remodeling to maintain its integrity. Dysregulation of cellular remodeling, primarily mediated by oxidative stress (OS), is often associated with preterm birth. However, the mechanisms that maintain membrane homeostasis remain unclear. To understand these mechanisms, we developed an amnion membrane organ-on-chip (AM-OOC) and tested the interactive and transition properties of primary human AECs and AMCs under normal and OS conditions. AM-OOC contained 2 chambers connected by type IV collagen-coated microchannels, allowing independent culture conditions that permitted cellular migration and interactions. Cells grown either independently or coculture were exposed to OS inducing cigarette smoke extract, antioxidant N-acetyl-l-cysteine (NAC), or both. When grown independently, AECs transitioned to AMCs and migrated, whereas AMCs migrated without transition. OS caused AECs' transition but prevented migration, whereas AMCs' migration was unhindered. Coculture of cells facilitated transition, migration, and eventual integration in the contiguous population. OS cotreatment in both chambers facilitated AECs' transition, prevented migration, and increased inflammation, a process that was prevented by NAC. AM-OOC recapitulated cellular mechanisms observed in utero and enabled experimental manipulation of cells to determine their roles during pregnancy and parturition.-Richardson, L., Jeong, S., Kim, S., Han, A., Menon, R. Amnion membrane organ-on-chip: an innovative approach to study cellular interactions.


Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer.
FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p = 4.89 × 10(-57)), high mitotic index (p = 5.25 × 10(-28)), pleomorphism (p = 6.31 × 10(-19)), ER negative (p = 9.02 × 10(-35)), PR negative (p = 9.24 × 10(-24)), triple negative phenotype (p = 6.67 × 10(-21)), PAM50.Her2 (p = 5.19 × 10(-13)), PAM50. Basal (p = 2.7 × 10(-41)), PAM50.LumB (p = 1.56 × 10(-26)), integrative molecular cluster 1 (intClust.1) (p = 7.47 × 10(-12)), intClust.5 (p = 4.05 × 10(-12)) and intClust. 10 (p = 7.59 × 10(-38)) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p = 4.4 × 10(-16)) and multivariate analysis (p = 9.19 × 10(-7)). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps < 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps < 0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps < 0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps < 0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer.


Redirecting Human Conventional and Regulatory T Cells Using Chimeric Antigen Receptors.
The adaptive immune system exhibits exquisite specificity and memory and is involved in virtually every process in the human body. Redirecting adaptive immune cells, in particular T cells, to desired targets has the potential to lead to the creation of powerful cell-based therapies for a wide range of maladies. While conventional effector T cells (Teff) would be targeted towards cells to be eliminated, such as cancer cells, immunosuppressive regulatory T cells (Treg) would be directed towards tissues to be protected, such as transplanted organs. Chimeric antigen receptors (CARs) are designer molecules comprising an extracellular recognition domain and an intracellular signaling domain that drives full T cell activation directly downstream of target binding. Here, we describe procedures to generate and evaluate human CAR CD4+ helper T cells, CD8+ cytotoxic T cells, and CD4+FOXP3+ regulatory T cells.


[Medical and psychosocial evaluation of a mentally retarded adult population].
This study is aimed at describing the psychological, psychopathological, medical and social aspects of a mentally retarded population being provided with care by AFANAS-Jerez affording the possibility of assessing this type of problem from an epidemiological standpoint. A descriptive case series study is conducted to characterize a mentally retarded (MR) population. An assessment was made of the psychological, medical and social aspects. The degree of intelligence was analyzed using the Weschler Adult Intelligence Scale. The adaptive behavior, frequency, typology and seriousness of the behavior problems were assessed by means of the Service Planning and Individual Scheduling Inventory. A psychopathological screening examination was conducted. This study is rounded out with a social and medical evaluation by means of structured interviews. The information from the different areas was encoded and was analyzed using the EPIINFO v6.0 and C.I.A. programs. The average age of the mentally retarded population studied was 32.2 (S.D. 9.2 years). Seventy-three percent (73%) males as compared to 27% females. Behavior problems were found to exist among 45.1% of the subjects. We have set up a statistical relationship between the existence/non-existence of said problems and the degree of MR, such that the greater the loss of intellectual capacity, the greater the probability of having behavior problems. One of the psychopathological symptoms worthy of special mention is the anxiety found to exist among 60.2%. The medical examination reveals the large number of problems related to with MR, we thus finding 22.48% of the subjects to have epilepsy, nearly 20% Down's Syndrome, etc. Also worthy of special mention is the low educational level of the parents and the family conflicts resulting from the child's retardation. Special mention must be made of how MR is a highly complex whole entailing a large number of related medical, psychological, psychiatric and social disorders, this being a situation brought to fore in this study, many of the disorders revealed to exist being related to the degree of MR. We are of the opinion that an epidemiological approach to the study of MR may be of use for a better comprehension of this problem.


Novel Loci Underlie Natural Variation in Vitamin E Levels in Maize Grain.
Tocopherols, tocotrienols, and plastochromanols (collectively termed tocochromanols) are lipid-soluble antioxidants synthesized by all plants. Their dietary intake, primarily from seed oils, provides vitamin E and other health benefits. Tocochromanol biosynthesis has been dissected in the dicot Arabidopsis thaliana, which has green, photosynthetic seeds, but our understanding of tocochromanol accumulation in major crops, whose seeds are nonphotosynthetic, remains limited. To understand the genetic control of tocochromanols in grain, we conducted a joint linkage and genome-wide association study in the 5000-line U.S. maize (Zea mays) nested association mapping panel. Fifty-two quantitative trait loci for individual and total tocochromanols were identified, and of the 14 resolved to individual genes, six encode novel activities affecting tocochromanols in plants. These include two chlorophyll biosynthetic enzymes that explain the majority of tocopherol variation, which was not predicted given that, like most major cereal crops, maize grain is nonphotosynthetic. This comprehensive assessment of natural variation in vitamin E levels in maize establishes the foundation for improving tocochromanol and vitamin E content in seeds of maize and other major cereal crops.