Decidual T Cells Exhibit a Highly Differentiated Phenotype and Demonstrate Potential Fetal Specificity and a Strong Transcriptional Response to IFN.
Immune tolerance during human pregnancy is maintained by a range of modifications to the local and systemic maternal immune system. Lymphoid infiltration is seen at the implantation site of the fetal-maternal interface, and decidual NK cells have been demonstrated to facilitate extravillous trophoblast invasion into maternal decidua during the first trimester, optimizing hemochorial placentation. However, although there is considerable T cell infiltration of the maternal decidua, the functional properties of this T cell response remain poorly defined. We investigated the specificity and regulation of CD4+ and CD8+ T cells obtained from human third trimester decidua and demonstrated that decidual CD4+ and CD8+ T cells exhibit a highly differentiated effector memory phenotype in comparison with peripheral blood and display increased production of IFN-γ and IL-4. Moreover, decidual T cells proliferated in response to fetal tissue, and depletion of T regulatory cells led to an increase in fetal-specific proliferation. HY-specific T cells were detectable in the decidua of women with male pregnancies and were shown to be highly differentiated. Transcriptional analysis of decidual T cells revealed a unique gene profile characterized by elevated expression of proteins associated with the response to IFN signaling. These data have considerable importance both for the study of healthy placentation and for the investigation of the potential importance of fetal-specific alloreactive immune responses within disorders of pregnancy.


Antibiofilm efficacy of photoactivated curcumin, triple and double antibiotic paste, 2% chlorhexidine and calcium hydroxide against Enterococcus fecalis in vitro.
Root canal disinfection is one of the most important factors governing success of root canal treatment, especially when regenerative strategies are used. This study evaluated the efficacy of 5 intracanal medicaments against mature biofilms of Enterococcus fecalis in vitro: Light activated curcumin, triple antibiotic paste (TAP), double antibiotic paste (DAP), chlorhexidine, calcium hydroxide. Untreated teeth with biofilms served as controls. Confocal microscopy was used to analyse the biofilm mass and percentage of live/dead bacteria within the root canal as well as dentinal tubules. Dentinal shavings obtained from the root canal walls (at 200 and 400 microns depth) were used to quantify the colony forming units/mL. The results showed that light activated curcumin and triple antibiotic paste brought about complete disruption of the biofilm structure (P < 0.05) while chlorhexidine and calcium hydroxide were not significantly different from the control (P > 0.05). Light activated curcumin brought about the highest percentage of dead cells at both depths, but this was not significantly different from triple antibiotic paste (P > 0.05). Curcumin, TAP and DAP brought about a significant reduction of CFU/mL at both depths compared to the control and other groups (P < 0.05). Light activated curcumin brought about a 7 log reduction of bacteria at both depths.


Inhibition of cell-plate formation by brefeldin A inhibited the depolymerization of microtubules in the central region of the phragmoplast.
Treatment of tobacco BY-2 cells with 20 microM brefeldin A (BFA), which causes disassembly of the Golgi apparatus (Yasuhara et al. 1995), completely inhibited the formation of the cell plate when the treatment was started before the chromosomes had begun to to condense. In cells in which cell-plate formation was inhibited by BFA, the centrifugal development of the phragmoplast was also inhibited. In such cells, the depolymerization of microtubules in the central region of the phragmoplast did not occur at least for 1 h after the formation of the phragmoplast, while the centrifugal development of the phragmoplast and cell-plate formation were completed in almost all cells not treated with BFA. The inhibition of cell-plate formation seems to inhibit the centrifugal development of the phragmoplast by inhibiting the depolymerization of microtubules in the central region of the phragmoplast, which is required for the supply of free tubulin necessary for the polymerization of microtubules at the outer margins of the phragmoplast.


Introducing the first whole genomes of nationals from the United Arab Emirates.
Whole Genome Sequencing (WGS) provides an in depth description of genome variation. In the era of large-scale population genome projects, the assembly of ethnic-specific genomes combined with mapping human reference genomes of underrepresented populations has improved the understanding of human diversity and disease associations. In this study, for the first time, whole genome sequences of two nationals of the United Arab Emirates (UAE) at >27X coverage are reported. The two Emirati individuals were predominantly of Central/South Asian ancestry. An in-house customized pipeline using BWA, Picard followed by the GATK tools to map the raw data from whole genome sequences of both individuals was used. A total of 3,994,521 variants (3,350,574 Single Nucleotide Polymorphisms (SNPs) and 643,947 indels) were identified for the first individual, the UAE S001 sample. A similar number of variants, 4,031,580 (3,373,501 SNPs and 658,079 indels), were identified for UAE S002. Variants that are associated with diabetes, hypertension, increased cholesterol levels, and obesity were also identified in these individuals. These Whole Genome Sequences has provided a starting point for constructing a UAE reference panel which will lead to improvements in the delivery of precision medicine, quality of life for affected individuals and a reduction in healthcare costs. The information compiled will likely lead to the identification of target genes that could potentially lead to the development of novel therapeutic modalities.


Eye movements in response to different cognitive activities measured by eyetracking: a prospective study on some of the neurolinguistics programming theories.
The eyes are in constant movement to optimize the interpretation of the visual scene by the brain. Eye movements are controlled by complex neural networks that interact with the rest of the brain. The direction of our eye movements could thus be influenced by our cognitive activity (imagination, internal dialogue, memory, etc.). A given cognitive activity could then cause the gaze to move in a specific direction (a brief movement that would be instinctive and unconscious). Neuro Linguistic Programming (NLP), which was developed in the 1970s by Richard Bandler and John Grinder (psychologist and linguist respectively), issued a comprehensive theory associating gaze directions with specific mental tasks. According to this theory, depending on the visual path observed, one could go back to the participant's thoughts and cognitive processes. Although NLP is widely used in many disciplines (communication, psychology, psychotherapy, marketing, etc), to date, few scientific studies have examined the validity of this theory. Using eye tracking, this study explores one of the hypotheses of this theory, which is one of the pillars of NLP on visual language. We created a protocol based on a series of questions of different types (supposed to engage different brain areas) and we recorded by eye tracking the gaze movements at the end of each question while the participants were thinking and elaborating on the answer. Our results show that 1) complex questions elicit significantly more eye movements than control questions that necessitate little reflection, 2) the movements are not random but are oriented in selected directions, according to the different question types, 3) the orientations observed are not those predicted by the NLP theory. This pilot experiment paves the way for further investigations to decipher the close links between eye movements and neural network activities in the brain.


PTM-SD: a database of structurally resolved and annotated posttranslational modifications in proteins.
Posttranslational modifications (PTMs) define covalent and chemical modifications of protein residues. They play important roles in modulating various biological functions. Current PTM databases contain important sequence annotations but do not provide informative 3D structural resource about these modifications. Posttranslational modification structural database (PTM-SD) provides access to structurally solved modified residues, which are experimentally annotated as PTMs. It combines different PTM information and annotation gathered from other databases, e.g. Protein DataBank for the protein structures and dbPTM and PTMCuration for fine sequence annotation. PTM-SD gives an accurate detection of PTMs in structural data. PTM-SD can be browsed by PDB id, UniProt accession number, organism and classic PTM annotation. Advanced queries can also be performed, i.e. detailed PTM annotations, amino acid type, secondary structure, SCOP class classification, PDB chain length and number of PTMs by chain. Statistics and analyses can be computed on a selected dataset of PTMs. Each PTM entry is detailed in a dedicated page with information on the protein sequence, local conformation with secondary structure and Protein Blocks. PTM-SD gives valuable information on observed PTMs in protein 3D structure, which is of great interest for studying sequence-structure- function relationships at the light of PTMs, and could provide insights for comparative modeling and PTM predictions protocols. Database URL: PTM-SD can be accessed at http://www.dsimb.inserm.fr/dsimb_tools/PTM-SD/.


Iterative Reconstruction May Improve Diagnosis of Gout: An Ex Vivo (Bio)Phantom Dual-Energy Computed Tomography Study.
We hypothesize that, compared with filtered back projection (FBP), iterative reconstruction (IR) increases the detected volume of uric acid, which serves as a measure of the sensitivity of the method, and therefore allows examinations with lower radiation exposure. Thus, the aim of our study was to evaluate the role of IR in dual-energy computed tomography (DECT) for gout assessment and volumetry in an ex vivo gout model using an epoxy phantom and a biophantom. We prepared specimens with different concentrations of monosodium uric acid in ultrasound gel (30%-50%) and inserted them into an epoxy-based phantom and a porcine foreleg. Computed tomography scanning was performed on a 320-row single-source DECT scanner in volume mode with an ascending order of tube currents. Image data sets were reconstructed using FBP and IR with 2 iteration levels (IR1 and IR2). Measurements in regions of interest (ROIs) and volumetric measurements were performed using either fixed parameters for the analysis software (epoxy phantom) or parameters specifically adapted for each data set (porcine phantom). Seven retrospectively identified clinical data sets were used for validation in patients. Rm-ANOVA was used for statistical analysis. No institutional review board approval was required. We found no differences in Hounsfield units between the different reconstruction algorithms (P = 0.09 and 0.05 for 80 and 135 kVp, respectively) and the calculated dual-energy gradient (P = 0.27). Filtered back projection detected less uric acid compared with IR (with fixed parameters: 6.0 ± 0.3 cm for FBP and 6.1 ± 0.2 for IR1 and IR2; with adapted thresholds: 1.2 ± 0.3 cm for FBP and 1.8 ± 0.1 and 2.0 ± 0.1 for IR1 and IR2, respectively). The differences were significant for all measurements (P = 0.0003). Also in the test cases, FBP detected significantly fewer tophi (mean volume, 1.38 ± 2.1 cm) compared with IR1 (1.86 ± 2.9) and IR2 (2.07 ± 3.1) (P = 0.04). Iterative reconstruction has the potential to improve the sensitivity of a DECT scan for gouty tophi, to decrease radiation exposure, or to combine both options.


Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation.
Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory-activated neurons to regulate memory stability. Neuronal activity triggers a late-onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity-dependent phosphorylation of p66α via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity-dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications.


Influence of cryopreservation on mitochondrial functions in equine spermatozoa.
Cryopreservation of spermatozoa is of essential importance for artificial insemination and breeding programs in horses. Besides other factors, spermatozoal motility depends on mitochondrial energy metabolism. Based on changes of single mitochondrial functions it has been suggested that mitochondrial damage during cryopreservation could be a major reason for diminished post thaw semen quality. However, it is still unclear to which extent this influences the whole bioenergetic performance of mitochondria and whether this plays a role during routine cryopreservation procedures. Therefore, it was the aim of this study to compare changes in mitochondrial bioenergetics in spermatozoa during shock freezing and routine cryopreservation. Mitochondrial integrity in spermatozoa was studied by determination of oxygen consumption, mitochondrial membrane potential, and the oxidation of externally added cytochrome c(2+). Shock freezing of spermatozoa resulted in an irreversible loss of mitochondrial functions. However, respiration difference of uncoupled minus resting state and routine respiration also decreased by 48+/-14 and 58+/-6% (p<0.05), respectively, after routine cryopreservation. This was accompanied by a decline in the mitochondrial membrane potential to 83+/-4% (p<0.05) and spermatozoal motility to 56+/-11% (p<0.05) of pre-freezing values. In contrast, the oxidation rates of externally added cytochrome c(2+) by cytochrome c oxidase slightly increased by 26+/-14% (p<0.1) suggesting a partial rupture of cellular and outer mitochondrial membranes. Our data indicate that also widely used cryopreservation protocols for equine spermatozoa need adjustment to optimize post thaw mitochondrial functions.


Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic β cell insufficiency.
Rare functional variants of ankyrin-B have been implicated in human disease, including hereditary cardiac arrhythmia and type 2 diabetes (T2D). Here, we developed murine models to evaluate the metabolic consequences of these alterations in vivo. Specifically, we generated knockin mice that express either the human ankyrin-B variant R1788W, which is present in 0.3% of North Americans of mixed European descent and is associated with T2D, or L1622I, which is present in 7.5% of African Americans. Young AnkbR1788W/R1788W mice displayed primary pancreatic β cell insufficiency that was characterized by reduced insulin secretion in response to muscarinic agonists, combined with increased peripheral glucose uptake and concomitantly increased plasma membrane localization of glucose transporter 4 (GLUT4) in skeletal muscle and adipocytes. In contrast, older AnkbR1788W/R1788W and AnkbL1622I/L1622I mice developed increased adiposity, a phenotype that was reproduced in cultured adipocytes, and insulin resistance. GLUT4 trafficking was altered in animals expressing mutant forms of ankyrin-B, and we propose that increased cell surface expression of GLUT4 in skeletal muscle and fatty tissue of AnkbR1788W/R1788W mice leads to the observed age-dependent adiposity. Together, our data suggest that ankyrin-B deficiency results in a metabolic syndrome that combines primary pancreatic β cell insufficiency with peripheral insulin resistance and is directly relevant to the nearly one million North Americans bearing the R1788W ankyrin-B variant.


[Our experience with hydro-debridement in varied skin lesions. Technical and innovating advance in pediatric surgery].
We present our experience in the use of Hydrosurgery with debridement of necrotic tissues from skin wounds in children. The Hydrosurgery system uses a high velocity stream of sterile saline solution, which can be controlled according to the state of the lesion. We have used this system in 15 patients suffering from a wide range of pathologies (burns, severe traumatic wounds, skin necrosis etc), achieving its complete resolution in shorter period of time. This method is an innovative technique in the management of patients with acute o r chronic skin lesions that require periodic procedures.


An update on pharmacological interventions for diabetic foot ulcers.
Diabetic foot ulcers are the most common lower extremity complications of diabetes. Peripheral neuropathy and peripheral vascular disease are the underlying risk factors for diabetic foot ulcers, subsequently leading to infections and requiring antimicrobial therapy for the management of the disease. Each risk factor is a target for clinical intervention, with the intent to delay or prevent disease progression to amputation. The effective therapy includes interdisciplinary care, which involves optimized pharmacological interventions in concert with other treatments such as debridement strategies and specialized wound dressings. The pharmacological therapy alone cannot lead to successful therapy, and therefore, these supplementary techniques/modalities should not be overlooked. It is therefore the aim of this report to review various pharmacological interventions, specific to the diabetic foot and wound healing, along with incorporation of advanced therapies required to achieve a multifaceted treatment of diabetic foot ulcers and provide basis for superior drugs as well as drug delivery systems.


The immune modifying effects of amino acids on gut-associated lymphoid tissue.
The intestine and the gut-associated lymphoid tissue (GALT) are essential components of whole body immune defense, protecting the body from foreign antigens and pathogens, while allowing tolerance to commensal bacteria and dietary antigens. The requirement for protein to support the immune system is well established. Less is known regarding the immune modifying properties of individual amino acids, particularly on the GALT. Both oral and parenteral feeding studies have established convincing evidence that not only the total protein intake, but the availability of specific dietary amino acids (in particular glutamine, glutamate, and arginine, and perhaps methionine, cysteine and threonine) are essential to optimizing the immune functions of the intestine and the proximal resident immune cells. These amino acids each have unique properties that include, maintaining the integrity, growth and function of the intestine, as well as normalizing inflammatory cytokine secretion and improving T-lymphocyte numbers, specific T cell functions, and the secretion of IgA by lamina propria cells. Our understanding of this area has come from studies that have supplemented single amino acids to a mixed protein diet and measuring the effect on specific immune parameters. Future studies should be designed using amino acid mixtures that target a number of specific functions of GALT in order to optimize immune function in domestic animals and humans during critical periods of development and various disease states.


An Ethical Analysis of Coverage With Evidence Development.
Sometimes a government or other payer is called on to fund a new health technology even when the evidence leaves a lot of uncertainty. One option is for the payer to provisionally fund the technology and reduce uncertainty by developing evidence. This is called coverage with evidence development (CED). Only-in-research CED, when the payer funds the technology only for patients who participate in the evidence development, raises the sharpest ethical questions. Is the patient coerced or induced into participating? If so, under what circumstances, if any, is this ethically justified? Building on work by Miller and Pearson, we argue that patients have a right to funding for a technology only when the payer can be confident that the technology provides reasonable value for money. Technologies are candidates for CED precisely because serious questions remain about value for money, and therefore patients have no right to technologies under a CED arrangement. This is why CED induces rather than coerces. The separate question of whether the inducement is ethically justified remains. We argue that CED does pose risks to patients, and the worse these risks are, the harder it is to justify the inducement. Finally, we propose conditions under which the inducement could be ethically justified and means of avoiding inducement altogether. We draw on the Australian context, and so our conclusions apply most directly to comparable contexts, where the payer is a government that provides universal coverage with a regard for cost-effectiveness that is prominent and fairly clearly defined.


Unified Parkinson's Disease Rating Scale-Motor Exam: inter-rater reliability of advanced practice nurse and neurologist assessments.
This paper is a report of a study to establish the inter-rater reliability of advanced practice nurse and neurologist neurological assessments which included ratings with the Unified Parkinson's Disease Rating Scale-Motor Exam. Around the world, advanced practice nurses are performing tasks once completed only by physicians. To promote consumer and provider confidence, it is important to establish that nurse and physician ratings using assessment tools are similar. In addition in research settings, when different raters are used, establishment of inter-rater reliability for study assessments is needed. Advanced practice nurses and neurologists independently recorded findings on neurological examinations of 46 participants in a study conducted between August 2007 and January 2008. An intraclass correlation coefficient was calculated to estimate overall agreement between the nurse and neurologist ratings. Agreement for individual items measured on a dichotomous scale was assessed by calculating Cohen's kappa. There was substantial agreement between advanced practice nurses and neurologists on the mean Unified Parkinson's Disease Rating Scale-Motor Exam ratings (intraclass correlation coefficient = 0.65) and the U.S. National Alzheimer's Coordinating Center Uniform Data Set neurological examination ratings of unremarkable findings (kappa = 0.74) and of gait disorder (kappa = 0.73). Moderate agreement (kappa = 0.53) was reached for the rating of whether all Unified Parkinson's Disease Rating Scale-Motor Exam items were normal. These findings are consistent with studies of the inter-rater agreement of the Unified Parkinson's Disease Rating Scale-Motor Exam and support the conduct of neurological assessments by advanced practice nurses.


The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review.
Opioid-induced constipation (OIC) is associated with negative impact of opioid analgesics on opioid receptors located in the gut wall. Until recently, OIC was treated symptomatically only, with different laxatives which did not target the pathophysiology of OIC. Recently, several opioid receptor antagonists have been introduced in the treatment of OIC. Methylnaltrexone (MNTX) is a peripheral mu-opioid receptor antagonist for subcutaneous administration, which does not evoke symptoms of opioid abstinence. MNTX is indicated for patients with OIC who are not amenable to therapy with oral laxatives. In clinical trials, the effectiveness of MNTX assessed as its ability to induce spontaneous bowel movement, is 50%-60% of treated patients; MNTX demonstrates significant superiority over placebo. Another product is combination of oral formulation of prolonged release oxycodone and prolonged release naloxone (PR oxycodone/PR naloxone), indicated for patients who require opioid administration for chronic pain and have already developed OIC, and for those who need opioid therapy and take the drug to prevent OIC. Naloxone administered orally displays local, antagonist effects on opioid receptors in the gut wall, negligible systemic bioavailability, and significantly reduces the oxycodone constipating effect. PR oxycodone/PR naloxone has similar analgesic efficacy, but causes less constipation and less laxative consumption in comparison with patients treated with oxycodone alone. Both products are expensive, therefore their administration should be carefully considered. On the other hand, uncontrolled OIC and the necessity to perform rectal invasive procedures (enema, manual evacuation) lead not only to increased health care costs, but most importantly, cause severe patient suffering.


The Italian National External quality assessment program in molecular genetic testing: results of the VII round (2010-2011).
Since 2001 the Istituto Superiore di Sanità established a quality assurance programme for molecular genetic testing that covers four pathologies: Cystic Fibrosis (CF), Beta Thalassemia (BT), Fragile X Syndrome (FX), and Familial Adenomatous Polyposis Coli (APC). Since 2009 this activity is an institutional activity and participation is open to both public and private laboratories. Seven rounds have been performed until now and the eighth is in progress. Laboratories receive 4 DNA samples with mock clinical indications. They analyze the samples using their routine procedures. A panel of assessors review the raw data and the reports; all data are managed through a web utility. In 2010 the number of participants was 43, 17, 15, 5 for CF, BT, FX, APC schemes respectively. Genotyping results were correct in 96%, 98.5%, 100%, and 100% of CF, BT, FX, and APC samples, respectively. Interpretation was correct in 74%, 91%, 88%, and 60% of CF, BT, FX, and APC reports, respectively; however in most of them it was not complete but a referral to genetic counseling was given. Reports were satisfactory in more than 60% of samples in all schemes. This work presents the 2010 results in detail comparing our data with those from other European schemes.


[Reactions of the neurons of the anterior and posterior regions of the hypothalamus to light stimulation and stimulation of the splanchnic and sciatic nerves].
Responses of single hypothalamic neurons to splanchnic, sciatic nerves and photic stimulation were studied in anesthetized, curarized cats. It is found that units of the posterior and anterior hypothalamus are "convergence neurons" with multisensory inputs. Convergence of somatosensory and visceral (splanchnic) impulses to such neurons was complete. No neurons responding only to the splanchnic nerve stimulation were found. In the posterior hypothalamus some units responded only to stimulation of splanchnic and sciatic nerves and were unresponsive to a flash. On the contrary, in the anterior hypothalamus a part of units responded only to photic stimulation. The polysensory neurons of the posterior and anterior hypothalamus were of a nonspecific modality: they responded with a similar pattern of phasic or tonic discharge with a predominance of phasic responses. Units were more often excited than inhibited. A high responsibility (68%) of spontaneously active neurons to somato-visceral and photic stimulation was observed in the posterior, as well as in the anterior hypothalamus. The principles of functional organization of hypothalamic afferent system are discussed.


Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia.
Anticancer properties of non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated on tumors of different histogenesis. Different molecular targets for CBD were proposed, including cannabinoid receptors and some plasma membrane ion channels. Here we have shown that cell lines derived from acute lymphoblastic leukemia of T lineage (T-ALL), but not resting healthy T cells, are highly sensitive to CBD treatment. CBD effect does not depend on cannabinoid receptors or plasma membrane Ca2+-permeable channels. Instead, CBD directly targets mitochondria and alters their capacity to handle Ca2+. At lethal concentrations, CBD causes mitochondrial Ca2+ overload, stable mitochondrial transition pore formation and cell death. Our results suggest that CBD is an attractive candidate to be included into chemotherapeutic protocols for T-ALL treatment.


Pericranial flap for endoscopic anterior skull-base reconstruction: clinical outcomes and radioanatomic analysis of preoperative planning.
One of the major challenges of cranial base surgery is reconstruction of the dural defect and prevention of postoperative cerebrospinal fluid (CSF) fistula. The introduction of endoscopic techniques and an endonasal approach to the ventral skull base has created new challenges for reconstruction. We have developed an endoscopic pericranial flap (PCF) for skull base reconstruction and hereby present the initial cohort of patients who had endonasal reconstruction with a PCF after endoscopic skull base resection. We also demonstrate a method to radiographically incorporate anticipated skull base defects for preoperative planning of PCF length. Dural defects after endonasal skull base resection of invasive tumors were reconstructed with an onlay PCF (n = 10). We performed radiological studies to assist preoperative planning for where to make incisions while harvesting a PCF for anterior skull base, sellar, and clival defects. Each of the 10 patients had excellent healing of their skull base and had no evidence of any postoperative cerebrospinal fluid leaks. Eight patients had radiation therapy without flap complications. Radiographic studies demonstrate that the adequate PCF length, covering defects of the anterior skull base, sellar, and clival defects are 11.31 to 12.44 cm, 14.31 to 15.57 cm, and 18.5 to 20.42 cm, respectively. The PCF provides an option for endonasal reconstruction of cranial base defects and can be harvested endoscopically. Pre-operative radiographic evaluation may guide surgical planning. There is minimal donor site morbidity, and the flap provides enough surface area to cover the entire ventral skull base.


Epitaxial growth of CeO2(111) film on Ru(0001): scanning tunneling microscopy (STM) and x-ray photoemission spectroscopy (XPS) study.
We formed an epitaxial film of CeO2(111) by sublimating Ce atoms on Ru(0001) surface kept at elevated temperature in an oxygen ambient. X-ray photoemission spectroscopy measurement revealed a decrease of Ce(4+)/Ce(3+) ratio in a small temperature window of the growth temperature between 1070 and 1096 K, which corresponds to the reduction of the CeO2(111). Scanning tunneling microscope image showed that a film with a wide terrace and a sharp step edge was obtained when the film was grown at the temperatures close to the reduction temperature, and the terrace width observed on the sample grown at 1060 K was more than twice of that grown at 1040 K. On the surface grown above the reduction temperature, the surface with a wide terrace and a sharp step was confirmed, but small dots were also seen in the terrace part, which are considerably Ce atoms adsorbed at the oxygen vacancies on the reduced surface. This experiment demonstrated that it is required to use the substrate temperature close to the reduction temperature to obtain CeO2(111) with wide terrace width and sharp step edges.


Dynamics of amino acid side chains in membrane proteins by high field solid state deuterium nuclear magnetic resonance spectroscopy. Phenylalanine, tyrosine, and tryptophan.
We have obtained the first deuterium NMR spectra of individual types of aromatic amino acids in a defined membrane protein, bacteriorhodopsin, in the photosynthetic purple membrane of Halobacterium halobium R1. Isotopic labeling and high field (8.5 Tesla) operation permitted relatively rapid data acquisition at a variety of temperatures. At the temperature of growth (37 degrees C), we find that all 7 tryptophan residues are rigid on the time scale of the NMR experiment (approximately 10(-5) s), except for likely librational motions of approximately 10 degrees amplitude. By contrast, nearly all (9 +/- 2) of the 11 tyrosines and (13 +/- 2) 13 phenylalanines undergo rapid (greater than 10(5) s-1) 2-fold rotational flips about C gamma-C zeta, causing formation of line shapes dominated by effectively axially asymmetric (asymmetry parameter eta = 0.66) deuteron electric field gradient tensors. On cooling the phenylalanine- and tyrosine-labeled samples to approximately -30 degrees C, all such motions are frozen out, i.e. occur at rates less than 10(4) s-1, and axially symmetric (eta approximately 0.05) line shapes are observed. At T greater than 91 degrees C, phenylalanine-, tyrosine-, and tryptophan-labeled membrane spectra undergo dramatic narrowing to an isotropic line of approximately 4-9 kHz width. This transition is a reflection of the loss of tertiary structure in the membrane protein with resultant fast unrestricted motion of these aromatic side chains, and is only partly reversible. These results, in conjunction with those obtained using [gamma-2H6]valine-labeled bacteriorhodopsin (Kinsey, R. A., Kintanar, A., Tsai, M-D., Smith, R. L., Janes, N., and Oldfield, E. (1981) J. Biol. Chem., 256, 4146-4149) indicate the rather rigid nature of amino acid side chains in the H. halobium purple membrane, the principal fast lage amplitude motions being methyl group rotation and discontinuous benzene ring "flipping."


Associations of neighborhood social environment attributes and physical activity among 9-11 year old children from 12 countries.
We investigated whether associations of neighborhood social environment attributes and physical activity differed among 12 countries and levels of economic development using World Bank classification (low/lower-middle-, upper-middle- and high- income countries) among 9-11 year old children (N=6161) from the International Study of Childhood Obesity, Lifestyle, and the Environment (ISCOLE). Collective efficacy and perceived crime were obtained via parental/guardian report. Moderate-to-vigorous physical activity (MVPA) was assessed with waist-worn Actigraph accelerometers. Neighborhood environment by country interactions were tested using multi-level statistical models, adjusted for covariates. Effect estimates were reported by country and pooled estimates calculated across World Bank classifications for economic development using meta-analyses and forest plots. Associations between social environment attributes and MVPA varied among countries and levels of economic development. Associations were more consistent and in the hypothesized directions among countries with higher levels economic development, but less so among countries with lower levels of economic development.


Selective Laser Trabeculoplasty: A Clinical Review.
Selective laser trabeculoplasty (SLT) is a safe and effective treatment modality for lowering the intraocular pressure in patients with glaucoma. It achieves its results by selective absorption of energy in the trabecular pigmented cells, sparing adjacent cells and tissues from thermal damage, with minimal morphological tissue alteration following treatment. On the basis of the peer-reviewed medical literature, SLT is efficacious in lowering IOP, as initial treatment or when medical therapy is insufficient in all types of open-angle glaucoma in all races. SLT achieves intraocular pressure reduction similar to that of argon laser trabeculoplasty but without the tissue destruction and side effects. Observed side effects following SLT were almost uniformly transient and minor. We review highlights of recently published studies on the mechanisms and clinical outcome of SLT in order to address frequently raised issues pertinent to SLT in the clinical practice. Selective laser trabeculoplasty is a safe and effective treatment modality for lowering the intraocular pressure in patients with glaucoma. How to cite this article: Alon S. Selective Laser Trabeculoplasty: A Clinical Review. J Current Glau Prac 2013; 7(2):58-65.


Factors contributing to parental 'vaccine hesitancy' for childhood immunisations.
Childhood immunisations have contributed to saving millions of lives worldwide. However, a growing number of parents are declining immunisations, while other parents are choosing to delay them or opting for selective immunisations. These behaviours contribute to the reduction of herd immunity and to the possible resurgence of certain diseases. The aim of this extended literature review was to investigate factors that contribute to 'vaccine hesitancy' for childhood immunisation among parents. Seven qualitative studies were included in the review and examined using thematic analysis. The main themes identified were vaccine safety, effectiveness of vaccines and healthcare factors, which suggest that vaccine hesitancy is more complex than parents simply agreeing or disagreeing for their child to be immunised. A range of factors contribute to vaccine hesitancy and patients' decisions are highly influenced by their perceived need to research information about immunisation online. Healthcare professionals involved in childhood immunisations need to be aware of these factors and behaviours that attribute to vaccine hesitancy to enhance their professional practice.


Correcting for missing and irregular data in home-range estimation.
Home-range estimation is an important application of animal tracking data that is frequently complicated by autocorrelation, sampling irregularity, and small effective sample sizes. We introduce a novel, optimal weighting method that accounts for temporal sampling bias in autocorrelated tracking data. This method corrects for irregular and missing data, such that oversampled times are downweighted and undersampled times are upweighted to minimize error in the home-range estimate. We also introduce computationally efficient algorithms that make this method feasible with large data sets. Generally speaking, there are three situations where weight optimization improves the accuracy of home-range estimates: with marine data, where the sampling schedule is highly irregular, with duty cycled data, where the sampling schedule changes during the observation period, and when a small number of home-range crossings are observed, making the beginning and end times more independent and informative than the intermediate times. Using both simulated data and empirical examples including reef manta ray, Mongolian gazelle, and African buffalo, optimal weighting is shown to reduce the error and increase the spatial resolution of home-range estimates. With a conveniently packaged and computationally efficient software implementation, this method broadens the array of data sets with which accurate space-use assessments can be made.


Treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: preliminary report of 7 cases.
Stem cells are characterized by self renewal and multipotent differentiation.We report the effects of intracavernosal transplant of human umbilical cord blood stem cells on diabetic erectile dysfunction. Seven type 2 diabetics who had failed to achieve an erection for at least 6 months despite medications, and who are currently awaiting penile prostheses, participated. All laboratory results were normal, except for impotence and diabetes mellitus. A total of 1.5 x 10(7) human umbilical cord blood stem cells were infused into the corpus cavernosum. No immunosuppressive measures were taken in any of the patients. International index of erectile function-5, SEP, GAQ, erection diary, blood glucose diary, and medication dosage were followed for 9 months. The mean age was 69.5 years (range, 57-87 years). Morning erections were regained in 3 participants within 1 month, and for all except 1 by the third month, and maintained for more than 6 months. Rigidity increased as the result of stem cell therapy alone, but was insufficient for penetration. With the addition of PDE5 inhibitor before coitus, 2 achieved penetration and experienced orgasm, and maintained for more than 6 months; however, 1 participant could not achieved penetration at ninth month. All but 1 reported increased desire. During follow-up, 2 returned for prosthesis, 4 returned to a nonerectile condition at 9 months, and 1 maintained erection sufficient for coitus with medication until the 11th month. Blood glucose levels decreased by 2 weeks, and medication dosages were reduced in all but 1 subject for 4 to 7 months. Glycosylated hemoglobin levels improved after treatment for up to 3 to 4 months. Human umbilical cord blood stem cell therapy has positive effects on erectile dysfunction and diabetes mellitus. Stem cells and unknown humoral factors of human umbilical cord blood stem cells mediate mechanism may contribute to these positive effects.


Topiramate for essential tremor.
Essential tremor (ET) is one of the most common movement disorders. The management is primarily based on pharmacological agents and in clinical practice propranolol and primidone are considered the first-line therapy. However, these treatments can be ineffective in 25% to 55% of people and are frequently associated with serious adverse events (AEs). For these reasons, it is worthwhile evaluating other treatments for ET. Topiramate has been suggested as a potentially useful agent for the treatment of ET but there is uncertainty about its efficacy and safety. To assess the efficacy and safety of topiramate in the treatment of ET. We carried out a systematic search without language restrictions to identify all relevant trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to January 2017), Embase (January 1988 to January 2017), National Institute for Health and Care Excellence (1999 to January 2017), ClinicalTrials.gov (1997 to January 2017) and World Health Organization International Clinical Trials Registry Platform (ICTRP; 2004 to January 2017). We searched BIOSIS Citation Index (2000 to January 2017) for conference proceedings. We handsearched grey literature and the reference lists of identified studies and reviews. We included all randomised controlled trials (RCTs) of topiramate versus placebo/open control or any other treatments. We included studies in which the diagnosis of ET was made according to accepted and validated diagnostic criteria. We excluded studies conducted in people presenting with secondary forms of tremor or reporting only neurophysiological parameters to assess outcomes. Two review authors independently collected and extracted data using a data collection form. We assessed the risk of bias and the quality of evidence. We used a fixed-effect meta-analysis for data synthesis. This review included three trials comparing topiramate to placebo (309 participants). They were all at high overall risk of bias. The quality of evidence ranged from very low to low. Compared to placebo, participants treated with topiramate showed a significant improvement in functional disability and an increased risk of withdrawal (risk ratio (RR) 1.78, 95% confidence interval (CI) 1.23 to 2.60). There were more AEs for topiramate-treated participants, particularly paraesthesia, weight loss, appetite decrease and memory difficulty. This systematic review highlighted the presence of limited data and very low to low quality evidence to support the apparent efficacy and the occurrence of treatment-limiting AEs in people with ET treated with topiramate. Further research to assess topiramate efficacy and safety on ET is needed.


LncRNA SOX2OT is Upregulated in Gestational Diabetes Mellitus (GDM) and Correlated with Multiple Adverse Events.
LncRNA SOX2OT plays protective roles in high glucose-induced injuries, suggesting its potential involvement in diabetes. Therefore, we analyzed the role of SOX2OT in gestational diabetes mellitus (GDM). A total of 216 pregnant women with a gestational age of about 2 months were enrolled in this study. The 216 pregnant women were monitored until delivery to record the occurrence of GDM. Adverse events, including miscarriage, premature delivery, intrauterine distress, intrauterine death, intrauterine infection, fetal malformation, macrosomia, and hypertension, were recorded. Two hundred sixteen pregnant women were divided into high and low SOX2OT level groups (n=108), with the median plasma SOX2OT level on the day of admission as the cutoff value. It was observed that the incidence of GDM was higher in the high SOX2OT level group (40/108) than in the low SOX2OT level group (12/108). Moreover, the SOX2OT expression level was higher in GDM patients than in non-GDM participants, and ROC curve analysis showed that plasma SOX2OT levels on the day of admission could separate potential GDM patients from the rest participants. Importantly, higher incidences of miscarriage, premature delivery, intrauterine distress, intrauterine death, intrauterine infection, fetal malformation, macrosomia, and hypertension were observed in the high SOX2OT group compared to the low SOX2OT group. SOX2OT is highly expressed in GDM and is closely correlated with multiple adverse events.


The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats.
Chronic consumption of morphine induces physical dependency, anxiety, and neurodegeneration. In this study, morphine on its own has been used for the management of morphine-induced dependency, oxidative stress, and apoptosis. Forty-eight male rats were randomly divided into six groups. Rats in groups 1-5 were made morphine dependent by an increasing manner of morphine for 7 days (15-45 mg/kg). For the next 14 days, morphine was administered using the following regimen: (i) once daily 45 mg/kg (positive controls), (ii) the same dose at additional intervals (6 h longer than the previous intervals each time), (iii) 45 mg/kg of morphine at irregular intervals like of 12, 24, 36 h, (iv) decreasing dose once daily (every time 2.5 mg/kg less than the former dosage). Group 5 received 45 mg/kg of morphine and 10 mg/kg of SOD mimetic agent (M40401) injection per day. Group 6 (negative control) received saline solution only. On day 22, all animals received naloxone (3 mg/kg) and their Total Withdrawal Index (TWI) and blood cortisol levels were measured. After drug treatment, hippocampus cells were isolated, and oxidative, antioxidative, and apoptotic factors were evaluated. Various regimens of morphine reduced TWI, cortisol levels, Bax activity, caspase-3, caspase-9, TNF-α, and IL-1β and lipid peroxidation. In all treatment groups, GSH level, superoxide dismutase, glutathione peroxidase, and Bcl-2 activity were significantly increased. Furthermore, SOD mimetic agent c diminished morphine effect on SOD activity. Thus, varying the dosage regimen of morphine can reduce the severity of morphine-induced dependency and neurodegeneration.


Ergonomic factors influencing handwriting performance.
Handwriting is one of the first things children are taught at school and need to perform in an efficient manner throughout life. Various studies have indicated that handwriting skills are related to many different variables including ergonomic factors. The purpose of this study was to investigate the differences between children with good and poor handwriting on ergonomic factors that underlie handwriting (e.g. body and paper positioning, pencil-grip and pressure) and to examine the relationship between the handwriting legibility and speed and these ergonomic factors. The study included 209 students in Grades 2 and 3 in Israel. The students were identified as good (N=116) and as poor handwriters (N=103) by their teachers. The Hebrew Handwriting Evaluation (HHE) was used to collect data on handwriting quality and speed as well as on ergonomic factors. A Chi square procedure was used to compare the differences between the handwriting groups. Discriminant analysis determined the percent of correct discrimination of subjects with poor or good handwriting based on the ergonomic factors. Finally, Spearman correlation coefficients were employed between the ergonomic variables and speed and quality of handwriting. The results indicated that children with poor handwriting had inferior pencil, paper and body positioning, stabilization of paper and consistency of pressure, compared to children with good handwriting. The implications of the results in general, and specifically for clinical practice are discussed. Finally, further research related to this topic is suggested.


Modified three-step iterative algorithm for phase-shifting interferometry in the presence of vibration.
To suppress the sensitivity of phase-shifting interferometry to mechanical vibration, a modified three-step iteration algorithm (MTIA) is proposed. The wavefront phase, x- and y-directional phase shifts are calculated in three individual steps in an iteration cycle. MTIA solves the tilt factors of phase shift through orthogonal decomposition and linear regression, avoiding the nonlinear optimization. The advantage of MTIA lies in its ability of calculating and compensating tilt-shifting error and fringe contrast variation caused by vibration. The simulations show that MTIA could provide more accurate results than an algorithm without contrast compensation. The superiority of MTIA is demonstrated experimentally. The experiment results show that MTIA could suppress the effect of vibration on surface measurement, which is of amplitude larger than the wavelength and of frequency over a large range. MTIA manifests good insensitivity to exposure time increase as well.


Skeletal muscle metabolism during high-intensity sprint exercise is unaffected by dichloroacetate or acetate infusion.
This study investigated whether increased provision of oxidative substrate would reduce the reliance on nonoxidative ATP production and/or increase power output during maximal sprint exercise. The provision of oxidative substrate was increased at the onset of exercise by the infusion of acetate (AC; increased resting acetylcarnitine) or dichloroacetate [DCA; increased acetylcarnitine and greater activation of pyruvate dehydrogeanse (PDH-a)]. Subjects performed 10 s of maximal cycling on an isokinetic ergometer on three occasions after either DCA, AC, or saline (Con) infusion. Resting PDH-a with DCA was increased significantly over AC and Con trials (3.58 +/- 0.4 vs. 0.52 +/- 0.1 and 0.74 +/- 0.1 mmol. kg wet muscle(-1). min(-1)). DCA and AC significantly increased resting acetyl-CoA (35.2 +/- 4.4 and 22.7 +/- 2.9 vs. 10.2 +/- 1.3 micromol/kg dry muscle) and acetylcarnitine (12.9 +/- 1.4 and 11.0 +/- 1.0 vs. 3.3 +/- 0.6 mmol/kg dry muscle) over Con. Resting contents of phosphocreatine, lactate, ATP, and glycolytic intermediates were not different among trials. Average power output and total work done were not different among the three 10-s sprint trials. Postexercise, PDH-a in AC and Con trials had increased significantly but was still significantly lower than in DCA trial. Acetyl-CoA did not increase in any trial, whereas acetylcarnitine increased significantly only in DCA. Exercise caused identical decreases in ATP and phosphocreatine and identical increases in lactate, pyruvate, and glycolytic intermediates in all trials. These data suggest that there is an inability to utilize extra oxidative substrate (from either stored acetylcarnitine or increased PDH-a) during exercise at this intensity, possibly because of O(2) and/or metabolic limitations.


Comparative Analysis of Cuticular Wax in Various Grape Cultivars During Berry Development and After Storage.
Cuticular wax covering the surface of fleshy fruit is closely related to fruit glossiness, development, and post-harvest storage quality. However, the information about formation characteristics and molecular mechanisms of cuticular wax in grape berry is limited. In this study, crystal morphology, chemical composition, and gene expression of cuticular wax in grape berry were comprehensively investigated. Morphological analysis revealed high density of irregular lamellar crystal structures, which were correlated with the glaucous appearances of grape berry. Compositional analysis showed that the dominant wax compounds were triterpenoids, while the most diverse were alkanes. The amounts of triterpenoids declined sharply after véraison, while those of other compounds maintained nearly constant throughout the berry development. The amounts of each wax compounds varied among different cultivars and showed no correlation with berry skin colors. Moreover, the expression profiles of related genes were in accordance with the accumulation of wax compounds. Further investigation revealed the contribution of cuticular wax to the water preservation capacity during storage. These findings not only facilitate a better understanding of the characteristics of cuticular wax, but also shed light on the molecular basis of wax biosynthesis in grape.


Acute respiratory distress syndrome: the Berlin Definition.
The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.


Quantitative assessment of hepatic fibrosis in an animal model with magnetic resonance elastography.
Chronic liver disease is a world-wide problem that causes progressive hepatic fibrosis as a hallmark of progressive injury. At present, the gold standard for diagnosing hepatic fibrosis is liver biopsy, which is an invasive method with many limitations, including questionable accuracy and risks of complications. MR elastography (MRE), a phase-contrast MRI technique for quantitatively assessing the mechanical properties of soft tissues, is a potential noninvasive diagnostic method to assess hepatic fibrosis. In this work, MRE was evaluated as a quantitative method to assess the in vivo mechanical properties of the liver tissues in a knockout animal model of liver fibrosis. This work demonstrates that the shear stiffness of liver tissue increases systematically with the extent of hepatic fibrosis, as measured by histology. A linear correlation between liver stiffness and fibrosis extent was well-defined in this animal model. An additional finding of the study was that fat infiltration, commonly present in chronic liver disease, does not significantly correlate with liver stiffness at each fibrosis stage and thus does not appear to interfere with the ability of MRE to assess fibrosis extent. In conclusion, MRE has the potential not only for assessing liver stiffness, but also for monitoring potential therapies for hepatic fibrosis.


Cell surface nucleolin as a target for anti-cancer therapies.
A large number of mostly recent reports show enhanced expression of the multi-functional protein nucleolin (NCL) on the surface of activated lymphocytes, angiogenic endothelial and many different types of cancer cells. Translocation of NCL at the external side of the plasma membrane occurs via a secretory pathway independent of the endoplasmic reticulum-Golgi complex, requires intracellular intact actin cytoskeleton, and seems to be mediated by a variety of factors. Cell surface NCL serves as a binding partner of several molecules implicated in cell differentiation, adhesion, and leukocyte trafficking, inflammation, angiogenesis and tumor development, mediating their biological activities and in some cases, leading to their internalization. Accumulating evidence validates cell surface NCL as a strategic target for treatment of cancer, while its property of tumor-specific uptake of targeted ligands seems to be useful for the development of non-invasive imaging tools for the diagnosis of cancer and for the targeted release of chemotherapeutic drugs. The observation that cell surface NCL exists in complexes with several other proteins implicated in tumorigenesis and angiogenesis suggests that targeting cell surface NCL might trigger multi-inhibitory effects, depending on the cell type. This review summarizes papers and patents related to the redistribution and the biological functions of cell surface NCL, with emphasis on the potential importance and advantages of developing efficient anti-cell surface NCL strategies.


Neuroimaging, behavioral, and psychological sequelae of repetitive combined blast/impact mild traumatic brain injury in Iraq and Afghanistan war veterans.
Abstract Whether persisting cognitive complaints and postconcussive symptoms (PCS) reported by Iraq and Afghanistan war veterans with blast- and/or combined blast/impact-related mild traumatic brain injuries (mTBIs) are associated with enduring structural and/or functional brain abnormalities versus comorbid depression or posttraumatic stress disorder (PTSD) remains unclear. We sought to characterize relationships among these variables in a convenience sample of Iraq and Afghanistan-deployed veterans with (n=34) and without (n=18) a history of one or more combined blast/impact-related mTBIs. Participants underwent magnetic resonance imaging of fractional anisotropy (FA) and macromolecular proton fraction (MPF) to assess brain white matter (WM) integrity; [(18)F]-fluorodeoxyglucose positron emission tomography imaging of cerebral glucose metabolism (CMRglu); structured clinical assessments of blast exposure, psychiatric diagnoses, and PTSD symptoms; neurologic evaluations; and self-report scales of PCS, combat exposure, depression, sleep quality, and alcohol use. Veterans with versus without blast/impact-mTBIs exhibited reduced FA in the corpus callosum; reduced MPF values in subgyral, longitudinal, and cortical/subcortical WM tracts and gray matter (GM)/WM border regions (with a possible threshold effect beginning at 20 blast-mTBIs); reduced CMRglu in parietal, somatosensory, and visual cortices; and higher scores on measures of PCS, PTSD, combat exposure, depression, sleep disturbance, and alcohol use. Neuroimaging metrics did not differ between participants with versus without PTSD. Iraq and Afghanistan veterans with one or more blast-related mTBIs exhibit abnormalities of brain WM structural integrity and macromolecular organization and CMRglu that are not related to comorbid PTSD. These findings are congruent with recent neuropathological evidence of chronic brain injury in this cohort of veterans.


The association between diet quality, dietary patterns and depression in adults: a systematic review.
Recent evidence suggests that diet modifies key biological factors associated with the development of depression; however, associations between diet quality and depression are not fully understood. We performed a systematic review to evaluate existing evidence regarding the association between diet quality and depression. A computer-aided literature search was conducted using Medline, CINAHL, and PsycINFO, January 1965 to October 2011, and a best-evidence analysis performed. Twenty-five studies from nine countries met eligibility criteria. Our best-evidence analyses found limited evidence to support an association between traditional diets (Mediterranean or Norwegian diets) and depression. We also observed a conflicting level of evidence for associations between (i) a traditional Japanese diet and depression, (ii) a "healthy" diet and depression, (iii) a Western diet and depression, and (iv) individuals with depression and the likelihood of eating a less healthy diet. To our knowledge, this is the first review to synthesize and critically analyze evidence regarding diet quality, dietary patterns and depression. Further studies are urgently required to elucidate whether a true causal association exists.


Optical absorption enhancement in 3D nanofibers coated on polymer substrate for photovoltaic devices.
Recent research in the field of photovoltaics has shown that polymer solar cells have great potential to provide low-cost, lightweight and flexible electronic devices to harvest solar energy. In this paper, we propose a new method for the generation of three-dimensional nanofibers coated on polymer substrate induced by femtosecond laser pulses. In this new method, a thin layer of polymer is irradiated by megahertz femtosecond laser pulses under ambient conditions, and a thin fibrous layer is generated on top of the polymer substrate. This method is single step; no additional materials are added, and the layers of the three-dimensional (3D) polymer nanofibrous structures are grown on top of the substrate after laser irradiation. Light spectroscopy results show significant enhancement of light absorption in the generated 3D nanofibrous layers of polymer. Finally, we suggest how to maximize the light trapping and optical absorption of the generated nanofiber cells by optimizing the laser parameters.


Three-Dimensional Motion Capture of a Smile in Repaired Unilateral Cleft Lip: What's Our Vector, Victor?
Following surgical repair, patients with unilateral cleft lip (UCL) exhibit dynamic asymmetry during facial expressions compared to healthy individuals. Previous studies using Euclidean distances to describe this asymmetry fail to take the direction of the movement into account. The aim of this study is to compare differences in participants with UCL and controls using analysis of motion vectors during facial expressions. In this cross-sectional study, twenty-six pediatric participants were recruited: 13 participants with repaired left UCL and 13 participants with no craniofacial diagnosis. Participants were recorded performing a maximal smile by a 4D stereophotogrammetric system. Phases of the smile were divided into closed lip and open lip smiles. Ten regions of interest were analyzed: subnasal area, upper lip, lower lip, oral commissure, and ala on both sides. The motion vectors were calculated and vector magnitude and direction for each region was compared. Between cleft and control groups, the differences in vector direction were greater than the magnitude differences. Significant differences in vector direction were identified at both oral commissures in the closed lip smile; and at the oral commissure, subnasal, upper lip, and lower lip regions during open lip smile. Vector analysis demonstrated significant movement asymmetry during facial animation in participants following UCL repair, not previously identified when analyzing magnitude of skin displacement.


Salmonella typhimurium mutants defective in flagellar filament regrowth and sequence similarity of FliI to F0F1, vacuolar, and archaebacterial ATPase subunits.
Many flagellar proteins are exported by a flagellum-specific export pathway. In an initial attempt to characterize the apparatus responsible for the process, we designed a simple assay to screen for mutants with export defects. Temperature-sensitive flagellar mutants of Salmonella typhimurium were grown at the permissive temperature (30 degrees C), shifted to the restrictive temperature (42 degrees C), and inspected in a light microscope. With the exception of switch mutants, they were fully motile. Next, cells grown at the permissive temperature had their flagellar filaments removed by shearing before the cells were shifted to the restrictive temperature. Most mutants were able to regrow filaments. However, flhA, fliH, fliI, and fliN mutants showed no or greatly reduced regrowth, suggesting that the corresponding gene products are involved in the process of flagellum-specific export. We describe here the sequences of fliH, fliI, and the adjacent gene, fliJ; they encode proteins with deduced molecular masses of 25,782, 49,208, and 17,302 Da, respectively. The deduced sequence of FliI shows significant similarity to the catalytic beta subunit of the bacterial F0F1 ATPase and to the catalytic subunits of vacuolar and archaebacterial ATPases; except for limited similarity in the motifs that constitute the nucleotide-binding or catalytic site, it appears unrelated to the E1E2 class of ATPases, to other proteins that mediate protein export, or to a variety of other ATP-utilizing enzymes. We hypothesize that FliI is either the catalytic subunit of a protein translocase for flagellum-specific export or a proton translocase involved in local circuits at the flagellum.


Prediction of Permanent Shunt Dependency in Patients with Intraventricular Hemorrhage: Outcomes of Early External Ventricular Drainage Weaning Protocol.
Hydrocephalus remains a common sequela of intraventricular hemorrhage (IVH) despite adequate drainage of the hematoma, including endoscopic surgery, intraventricular fibrinolysis, and external ventricular drainage (EVD). Moreover, the appropriate timing for conversion from EVD to ventriculoperitoneal shunt (VPS) is uncertain. This study aimed to evaluate the predictors of shunt dependency in patients with IVH based on the early EVD weaning protocol in our institution. We retrospectively reviewed medical records of patients who were diagnosed with primary IVH and secondary IVH from spontaneous intracerebral hemorrhage during the period 2018-2021. Predictors associated with shunt dependency were identified using a logistic regression model. The cutoff point of each variable was selected by receiver operating characteristic curve analysis. Furthermore, shunt complications were reported as a safety measure of our early EVD weaning protocol. The analysis included 106 patients. After IVH treatment, 15 (14%) patients required ventriculoperitoneal shunt, whereas 91 (86%) patients were shunt-free. The diameter of posttreatment temporal horn and the degree of IVH reduction were the significant predictors of shunt dependency. Moreover, patients with IVH reduction of >45% and temporal horn diameter of <9 mm had a lower probability of shunt dependency. Shunt failure was found in 2 (13.3%) patients. This study showed that a large temporal horn diameter and a lower degree of IVH removal were predictors of shunt dependency in patients with IVH. In addition, early conversion from EVD to ventriculoperitoneal shunt is safe and feasible.


[Use of antihypoxants in the acute period of myocardial infarction].
A total of 620 patients with acute myocardial infarction were followed up in order to assess the efficacy of antihypoxants as a component of intensive care. 385 of these patients, divided into groups of 20-40 subjects, were administered one of 12 antihypoxants or sessions of hyperbaric oxygenation during the acute period of the disease, the rest were treated traditionally. Analysis of clinical, laboratory, and prognostic values showed the highest protective effect of amtizol, lithium hydroxybutyrate, piracetam, and ubiquinone. Cytochrome C, riboxine, mildronate, and olifen were somewhat less active, and solcoseryl, bemitil, trimethasidine, and aspisol were the least effective. The protective potentialities of standard sessions of hyperbaric oxygenation were virtually null. The author proposes a parameter D, reflecting the difference between actual and predicted mortality, and the rating (score) system for assessing the routine laboratory diagnostic tests to be used together with the known criteria for evaluation of the protective effects of antihypoxants in patients with acute myocardial infarction.


Transplantation resistance of drug-treated hybrid or allogeneic mice against murine lymphomas. I. Immunopharmacology studies.
Sequential treatment of mice with non-lethal doses of 5(3,3'-dimethyl-l-triazeno)-imidazole-4-carboxamide (DTIC) and cyclophosphamide (Cy) was found to produce long-term inhibition of endogenous cell proliferation in the spleen and profound impairment of classical allograft responses, similar to that detectable in lethally irradiated mice. Studies were carried out with drug-treated (i.e. treated with DTIC + Cy) conventional or nude mice inoculated with lymphoma cells homozygous for the H-2b or H-2d haplotype. Transplantation resistance in various tumour-host combinations was studied in terms of survival times after tumor challenge or lymphoma cell proliferation in spleen and liver, measured by the uptake of DNA precursor 125I-labelled 5-iodo-2'-deoxyuridine ([125I]dUrd). The results of in vivo transplantation immunity tests or in vitro tests of generation of cytotoxic lymphocytes confirmed that classical T-dependent allograft responses were abrogated by drug treatment of H-2-incompatible hosts. However, localized resistance against lymphoma graft, mainly at spleen level, was found in drug-treated hybrid mice, or conventional and "nude" allogeneic recipients, as judged by [123I]dUrd uptake inhibition. Resistance presumably regulated, at least in part by the Hh (hemopoietic histocompatibility) system, was abrogated by pretreatment with carrageenan, an antimacrophage agent. In addition, treatment with DTIC + Cy did not abrogate NK activity of mice when the in vitro cytotoxicity test was conducted 5 h after Cy administration, i.e. at the time used for tumor challenge in vivo. It was concluded that selected immunological functions (i.e., antilymphoma natural resistance insensitive to DTIC + Cy, called drug-resistant inhibition of tumors, DRIT) possibly of non-T origin, similar to those detectable in lethally-irradiated mice, can be retained by hosts subjected to high doses of certain anti-tumor agents.


Efficacy and safety of periprostatic nerve block combined with perineal subcutaneous anaesthesia and intrarectal lidocaine gel in transrectal ultrasound guided transperineal prostate biopsy: A Prospective Randomised Controlled Trial.
To determine the efficacy and safety of a periprostatic nerve block combined with perineum subcutaneous anaesthesia and intrarectal lidocaine gel for transrectal ultrasound-guided transperineal prostate biopsy (TPBx) through a prospective randomised controlled trial. In total, 216 patients from May 2018 to November 2018 were randomly assigned to the experimental group and the control group at a ratio of 1:1. The experimental group received a periprostatic nerve block combined with subcutaneous perineal anaesthesia and intrarectal lidocaine gel. The control group received total intravenous anaesthesia. A visual analogue scale (VAS) score (0-10) was used to evaluate pain at different stages. The operative time, duration of hospitalisation, intraoperative vital signs, perioperative complications and clinicopathological features were recorded. The overall detection rate of prostate cancer was 40.74%, and the median Gleason score was 8 for all patients diagnosed with prostate cancer. No significant differences in terms of detection rates, Gleason scores and ISUP/WHO Grade Groups were found between the two groups (P > 0.05). The experimental group had no pain or just met the criteria for mild pain during the biopsy, which was significantly alleviated after the biopsy, and had a shorter operation time compared with that of the control group (P < 0.05). Compared with the control group, the experimental group had more stable haemodynamics and respiratory status and fewer surgical complications (P < 0.05). In multiple aspects, a periprostatic nerve block combined with subcutaneous perineal anaesthesia and intrarectal lidocaine gel is a safer and more efficient approach to local anaesthesia for TPBx that can almost replace total intravenous anaesthesia and is worthwhile applying in the clinical setting.


An unusual presentation of choriocarcinoma co-existing with pregnancy, successful delivery, and treatment: A case report and literature review.
Choricarcinoma co-existing with pregnancy is rare often misdiagnosed with great potential for hemorrhagic complications and death. We present a case of a 34-year-old woman diagnosed with choriocarcinoma in her 3rd pregnancy with vaginal and pulmonary metastasis. Her first episode of vaginal bleeding was in the third trimester which was misdiagnosed. She had spontaneous vaginal delivery at 34 weeks of a healthy neonate. She was refered to gyneoncology unit of our hospital 5 weeks into puerperium from a nearby State hospital due to continouos vaginal bleeding and a growth from the postero-lateral wall of the lower third of the vagina. She had five courses of EMA-CO regimen. Her beta-human chorionic gonadotropin (hCG) has fallen from pretreatment value of 168,266 mIU/ml to <5 mIU/ml by the 5th course and the metastaic lesion regressed. She however developed WHO Stage III Oral Mucositis (with Oroesophageal Candidiasis) due to the side effects of chemotherapy which was co-managed successfully with the oral medicine specialist. She was subequently discharged home with follow-up visits. The quantitative beta-hCG has remained undetectable during her follow-up visits. Choriocarcinoma co-existing with pregnancy is rare, diagnosis often missed and confused with antepartum hemorrhage. Early and correct diagnosis can be life saving. High index of suspicion is needed to make the diagnosis. The role of chemotherapy and close follow-up with quantitative beta-hCG assays are key to survival.


Dry polyacrylamide batch method for determining the binding of various compounds by plasma proteins.
A new modification of the gel diffusion method has been developed using dry polyacrylamide gel. The theoretical background is explained and the mathematical formulas are presented. The properties of the gel are studied, concerning the absorbing capacities and changes in ion equilibria. As a model compound the freely diffusible calcium is assayed and the result obtained (52.4 +/- 2.9%) agrees well with the results from previous methods by other authors. The accuracy of the method is discussed and the theoretical explanation to the sensitivity in determinations is calculated.


Insulin resistance in liver cirrhosis: decreased insulin binding to circulating monocytes.
Hyperinsulinemia and insulin resistance have been reported in patients with liver cirrhosis. Since insulin receptor decrease has been demonstrated in some conditions of insulin resistance, we have studied insulin binding to circulating monocytes in eleven patients with alcoholic liver cirrhosis. Specific insulin binding at tracer concentration was lower in cirrhotics than in control subjects (p < 0.005). Insulin binding to monocytes was correlated with basal plasma insulin level in cirrhotics (r = -0.76; p < 0.01). The inhibiting effect of native insulin on 125I-insulin binding was similar in cirrhotics and controls suggesting that concentration rather than affinity of the binding sites is affected in cirrhosis of the liver. These findings suggest that decrease in insulin receptor concentration exists in liver cirrhosis, probably as a consequence of chronic hyperinsulinemia.


Grazing Cow Behavior's Association with Mild and Moderate Lameness.
Accelerometer-based mobility scoring has focused on cow behaviors such as lying and walking. Accuracy levels as high as 91% have been previously reported. However, there has been limited replication of results. Here, measures previously identified as indicative of mobility, such as lying bouts and walking time, were examined. On a research farm and a commercial farm, 63 grazing cows' behavior was monitored in four trials (16, 16, 16, and 15 cows) using leg-worn accelerometers. Seventeen good mobility (score 0), 23 imperfect mobility (score 1), and 22 mildly impaired mobility (score 2) cows were monitored. Only modest associations with activity, standing, and lying events were found. Thus, behavior monitoring appears to be insufficient to discern mildly and moderately impaired mobility of grazing cows.


[Automatisation in microfluorometry (author's transl)].
The combination of microphotometer systems with different types of computers allows various possibilities of automatisation in fluorescence photometry. This paper presents several examples of automated fluorometry as testing of preparation and staining, determination of fluorescence intensity with instantanous background correction, controlling a scanning system for detection of immunofluorescence on microplates, rapid microspectroscopy of fluorescence emission, quantification of fading phenomena, help for chromosome analysis and also facilities of data correction and statistical data evaluation.


Increased proliferative activity caused by loss of p21(WAF1/CIP1) expression and its clinical significance in patients with early-stage gastric carcinoma.
Recurrences of gastric carcinoma are likely to take on a variety forms, even after patients undergo curative resection for early-stage gastric carcinoma. It is important to identify the biologic markers that predict tumor progression and survival in these patients. Proliferating cell nuclear antigen (PCNA) acts as a processivity factor for DNA polymerase delta, which is involved directly in DNA synthesis, and the PCNA level is correlated with the proliferative state of cells. p21(WAF1/CIP1) interacts with PCNA to inhibit DNA synthesis and plays a central role in regulating the cell cycle. The authors investigated patients with early-stage gastric carcinoma to determine the clinical significance of proliferative activity and p21 expression. Tissue specimens from 133 Japanese patients with early-stage gastric carcinoma that invaded the submucosal layer were immunostained with a monoclonal antibody against PCNA and p21(WAF1/CIP1), and the correlations between the PCNA labeling index and p21(WAF1/CIP1) expression as well as clinicopathologic factors were investigated. The PCNA labeling index varied from 9.9% to 81.4%, (mean, 31.2%). The incidence of p21 positive expression was 87 of 133 patients (65.4%). The patients with a high labeling index had a significantly higher rate of lymph node metastasis (P < 0.01) and loss of p21(WAF1/CIP1) expression (P < 0.05) compared with the patients with a low labeling index. The 5-year survival rate for patients in the high labeling index group (87.0%) was significantly lower compared with the 5-year survival rate for the patients in the low labeling index group (98.6%; P < 0.05). Loss of p21(WAF1/CIP1) expression contributes to the amplification of proliferative activity in patients with early-stage gastric carcinoma. Estimation of the proliferative activity of early-stage gastric carcinoma provides information on lymph node metastasis and prognosis. Even after patients undergo curative resection, those with early-stage gastric carcinoma should be followed closely.


Deterioration of modern concrete structures and asphalt pavements by respiratory action and trace quantities of organic matter.
In concrete structures (concrete), damage from cracks, deterioration, amorphization, and delamination occur in some structures, causing disaggregation (concrete changed to very fine particles) and hollowing out of the concrete. In concrete pavements, damage from large amounts of pop-out of aggregate occurs from the surface of the concrete pavement 4-5 hours after spraying of snow melting agent on the surface of the pavement. The damage from disaggregation, blistering, cracks, and peeling-off of a surface course have also been observed in asphalt runways and highways. The damage from disaggregation, cracks and pop-out of aggregate in asphalt pavements and concrete structures have long been seen as strange and unexpected and have defied explanation. As a result of examinations in various experiments, it was concluded that all of the unexplained kinds of damage of both asphalt pavements and concrete structures were caused by Trace Quantities of Organic Matter (TQOM), Air Entrained (AE) water reducing agent in air and/or cement, and surfactant in snow melting agent. The emission sources of TQOM and these organic substances were also identified by chemical analysis for these unexpected and unexplained phenomena. The TQOM includes phthalate compounds (phthalates in the following), amine compounds, phosphate compounds, snow melting agent and Sodium Polyoxyethylene Nonyl phenyl Ether Sulfate (SPNES). SPNES is a surfactant in windshield washer fluid for automobiles. We found that the water content and content of organic matter in damaged asphalt pavements and concrete structures are also important indicators for the damage. Further, a new evaluation method for amorphization was proposed in this study and it appears suitable for evaluating the safety of concrete structures along roads which were exposed to TQOM in severely air-polluted environments.


[The pathomorphology of acute drug-induced tubulointerstitial nephritis].
The author submits results of pathomorphologic study of 31 nephrobiopsies presenting with an acute drug-induced tubulointerstitial nephritis (ATIN). Antibiotics and non-steroidal antiinflammatory drug preparations appeared to be associated with the greatest drug-induced ATIN morbidity. The main ATIN pathomorphologic presentation includes focal inflammatory infiltration of the stroma and tubular walls, interstitial edema, dystrophy of the tubular epithelium and focal tubular necrosis. There have been identified the following four types of drug-induced ATIN depending upon the inflammatory infiltrate constitution: lymph-macrophagal, eosinophilic, plasmocytic, and granulomatous ATIN. Pathomorphologic changes are shown to be related to the time of performing a biopsy as well as to the particular features of the organism's reactivity rather than to the medicine administered.


Immune mediators in vitreous fluids from patients with vitreoretinal B-cell lymphoma.
Various immune mediators are hypothesized to have important roles in the pathogenesis of vitreoretinal B-cell lymphoma, although the exact mechanisms remain unclear. We determined the immune mediator profile in the vitreous of eyes with vitreoretinal B-cell lymphoma. We studied 28 eyes (23 patients) with vitreoretinal B-cell lymphoma, and 27 eyes (27 patients) undergoing vitrectomy for macular hole and epiretinal membrane served as controls. Undiluted vitreous samples were collected, and cytometric bead array and ELISA were used to determine the vitreous concentrations of 38 immune mediators, including 14 interleukins (IL); interferon (IFN)-γ; oncostatin M (OSM); IFN-γ-inducible protein (IP)-10; monocyte chemoattractant protein (MCP)-1; macrophage inflammatory protein (MIP)-1α; MIP-1β, regulated on activation, normal T-cell expressed and secreted (RANTES); monokine induced by IFN-γ (Mig); stromal cell-derived factor (SDF)-1α; B-cell-attracting chemokine (BCA)-1; basic fibroblast growth factor (bFGF); Fas ligand; granzyme A; and granzyme B. Vitreous levels of BCA-1, bFGF, Fas ligand, granzyme A, granzyme B, IFN-γ, IL-6, IL-8, IL-10, IP-10, MCP-1, Mig, MIP-1α, MIP-1β, OSM, RANTES, and SDF-1α were significantly higher in vitreoretinal B-cell lymphoma patients than in controls. A moderate-to-strong positive correlation was observed between granzyme A and BCA-1, IFN-γ, or MIP-1β; between IFN-γ and Mig or SDF-1α; between IL-6 and IL-8, IL-10, IP-10, or MCP-1; between IL-8 and MCP-1, Mig, or MIP-1β; between IL-10 and MCP-1 or MIP-1α; between Mig and IP-10 or Mig; and between MIP-1α and MIP-1β. Our study suggested that elevated vitreous levels of various immune mediators inducing growth, migration, and apoptosis of B-cell lymphoma are involved possibly in the pathophysiology of vitreoretinal B-cell lymphoma.


Random-start GnRH antagonist for emergency fertility preservation: a self-controlled trial.
The aim of this study is to evaluate the feasibility and safety of random-start controlled ovarian hyperstimulation (COH) for emergency fertility preservation, regardless of the phase of the menstrual cycle. A self-controlled pilot clinical trial (NCT01385332) was performed in an acute-care teaching hospital and in two private reproductive centers in Barcelona, Spain. Eleven egg donors participated in the study. Two random-start gonadotropin-releasing hormone (GnRH) antagonist protocols were assessed in which ganirelix was initiated on either day 10 (protocol B) or on day 20 (protocol C) of the menstrual cycle and was continued until estradiol levels were below 60 pg/dL. These protocols were compared with a standard protocol (protocol A). The main outcome of interest was the number of metaphase 2 oocytes retrieved. Results from this study show that the number of mature oocytes retrieved was comparable across the different protocols (14.3±4.6 in the standard protocol versus 13.0±9.1 and 13.2±5.2 in protocols B and C, respectively; values expressed as mean ± standard deviation). The mean number of days needed for a GnRH antagonist to lower estradiol levels, as well as the ongoing pregnancy rates, were also similar when protocols B (stimulation in follicular phase) and C (stimulation on luteal phase) were compared with protocol A (standard stimulation). GnRH antagonists can be effectively used for random-start controlled ovarian hyperstimulation with an ovarian response similar to that of standard protocols, and the antagonists appear suitable for emergency fertility preservation in cancer patients.


Transcription regulation by feast/famine regulatory proteins, FFRPs, in archaea and eubacteria.
Feast/famine regulatory proteins (FFRPs) comprise a single group of transcription factors systematically distributed throughout archaea and eubacteria. In the eubacterial domain in Escherichia coli, autotrophic pathways are activated and heterotrophic pathways are repressed by an FFRP, the leucine-responsive regulatory protein (Lrp), in some cases in interaction with other transcription factors. By sensing the concentration of leucine, Lrp changes its association state between hexadecamers and octamers to adapt the autotrophic or heterotrophic mode. The lrp gene is regulated so that the concentration of Lrp decreases in the presence of rich nutrition. In the archaeal domain a large part of the metabolism of Pyrococcus OT3 is regulated by another FFRP, FL11. In the presence of rich nutrition, the metabolism is released from repression by FL11; transcription of fl11 is terminated by FL11 forming octamers in interaction with lysine. When the nutrient is depleted, the metabolism is arrested by a high concentration of FL11; FL11 disassembles to dimers in the absence of lysine, and repression of transcription of fl11 is relaxed. Common characteristics of the master regulations by FL11 and Lrp hint at the prototype regulation once achieved in the common ancestor of all extant organisms. Mechanisms of discrimination by FFRPs between DNA sequences and also between co-regulatory molecules, mostly amino acids, and variations of transcription regulations observed with archaea and eubacteria are reviewed.


Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function.
Pathologic blood clotting is a leading cause of morbidity and mortality in the developed world, underlying deep vein thrombosis, myocardial infarction, and stroke. Genetic predisposition to thrombosis is still poorly understood, and we hypothesize that there are many additional risk alleles and modifying factors remaining to be discovered. Mammalian models have contributed to our understanding of thrombosis, but are low throughput and costly. We have turned to the zebrafish, a tool for high-throughput genetic analysis. Using zinc finger nucleases, we show that disruption of the zebrafish antithrombin III (at3) locus results in spontaneous venous thrombosis in larvae. Although homozygous mutants survive into early adulthood, they eventually succumb to massive intracardiac thrombosis. Characterization of null fish revealed disseminated intravascular coagulation in larvae secondary to unopposed thrombin activity and fibrinogen consumption, which could be rescued by both human and zebrafish at3 complementary DNAs. Mutation of the human AT3-reactive center loop abolished the ability to rescue, but the heparin-binding site was dispensable. These results demonstrate overall conservation of AT3 function in zebrafish, but reveal developmental variances in the ability to tolerate excessive clot formation. The accessibility of early zebrafish development will provide unique methods for dissection of the underlying mechanisms of thrombosis.


Effect of various Er:YAG laser conditioning energies on dentin surface: micromorphological investigation and dentin-resin shear bond strength test.
The aim of this study is to assess the influence of various Er:YAG laser energies on dentin surface micromorphology and dentine-resin shear bond strength (SBS). Eighty dentin specimens were prepared and divided randomly into ten groups: control group (CG), phosphoric acid-etched group (AG), four laser-conditioned groups treated with various pulse energies of 40, 60, 80, and 100 mJ (L40, L60, L80, L100), and four laser-conditioned acid-etched groups (LA40, LA60, LA80, LA100). Two specimens from each group underwent scanning electron microscopy examination, while the remaining six were subjected to the dentin-resin SBS test. Statistical analyses included Welch's analysis of variance (ANOVA), followed by post hoc Tamhane's T2 multiple comparisons test, Pearson's correlation, and Fisher's exact test. Pulse energies of 60, 80, and 100 mJ fully exposed the dentin tubule orifices, although 100 mJ lead to microcracks. Laser-conditioned surfaces exhibited smaller tubule diameters compared to acid-etched surfaces, and tubule diameters positively correlated with dentin-resin SBS. Laser-conditioned groups showed lower SBS values, while laser-conditioned acid-etched groups demonstrated higher SBS values. No significant relationship was observed between dentin surface roughness and SBS. The range of laser energies used for dentin conditioning had limited effects on SBS or failure modes. Laser conditioning with energies ranging from 40 to 100 mJ effectively removes the smear layer from the dentin surface. However, to enhance dentin-resin bond strength, further acid etching of the laser-conditioned surface is necessary.


Vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children.
Nutritional rickets is a disease which affects children, especially in low- and middle-income countries. It causes problems such as skeletal deformities and impaired growth. The most common cause of nutritional rickets is vitamin D deficiency. Vitamin D administered with or without calcium is commonly regarded as the mainstay of treatment. In some sunny countries, however, where children are believed to have adequate vitamin D production from exposure to ultraviolet light, but who are deficient in calcium due to low dietary intake, calcium alone has also been used in the treatment of nutritional rickets. Therefore, it is important to compare the effects of vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children living in different settings. To assess the effects of vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children. We searched CENTRAL, MEDLINE, LILACS, WHO ICTRP Search Portal and ClinicalTrials.gov. The date of the last search of all databases was 25 July 2019. We applied no language restrictions. We included randomised controlled trials (RCT) involving children aged 0 to 18 years with nutritional rickets which compared treatment with vitamin D, calcium or a combination of vitamin D and calcium. Two review authors independently screened the title and abstracts of all studies, extracted data and assessed the risk of bias of included studies. We resolved any disagreements by consensus or recourse to a third review author. We conducted meta-analyses for the outcomes reported by study authors. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI) and, for continuous outcomes, we calculated mean differences (MD) with 95% CIs. We assessed the certainty of the evidence of the included studies using GRADE. We identified 4562 studies; of these, we included four RCTs with 286 participants. The studies compared two or more of the following: vitamin D, calcium or vitamin D plus calcium. The number of participants randomised to receive vitamin D was 64, calcium was 102 and vitamin D plus calcium was 120. Two studies were conducted in India and two were conducted in Nigeria. None of the included studies had a low risk of bias in all domains. Three studies had a high risk of bias in at least one domain. The age of the participants ranged between six months and 14 years. The duration of follow-up ranged between 12 weeks and 24 weeks. Two studies compared vitamin D to calcium. There is low-certainty evidence that, at 24 weeks' follow-up, calcium alone improved the healing of rickets compared to vitamin D alone (RR 3.26, 95% CI 1.59 to 6.69; P = 0.001; 1 study, 71 participants). Comparing vitamin D to calcium showed no firm evidence of an advantage or disadvantage in reducing morbidity (fractures) (RR 0.27, 95% CI 0.03 to 2.32; P = 0.23; 1 study, 71 participants; very low-certainty evidence). Adverse events were not reported. Two studies compared vitamin D plus calcium to vitamin D at 12 or 24 weeks. Vitamin D plus calcium improved healing of rickets compared to vitamin D alone at 24 weeks' follow-up (RR 3.06, 95% CI 1.49 to 6.29; P = 0.002; 1 study, 75 participants; low-certainty evidence). There is no conclusive evidence in favour of either intervention for reducing morbidity (fractures) (RR 0.24, 95% CI 0.03 to 2.08; P = 0.20; 1 study, 71 participants; very low-certainty evidence) or adverse events (RR 4.76, 95% CI 0.24 to 93.19; P = 0.30; 1 study, 39 participants; very low-certainty evidence). All four included studies compared vitamin D plus calcium to calcium at different follow-up times. There is no conclusive evidence on whether vitamin D plus calcium in comparison to calcium alone improved healing of rickets at 24 weeks' follow-up (RR 1.17, 95% CI 0.72 to 1.90; P = 0.53; 2 studies, 140 participants; very low-certainty evidence). Evidence is also inconclusive for morbidity (fractures) (RR 0.89, 95% CI 0.06 to 13.76; P = 0.94; 1 study, 72 participants; very low-certainty evidence) and adverse events (RR 4.29, 0.22 to 83.57; P = 0.34; 1 study, 37 participants; very low-certainty evidence). Most of the evidence in the review is low or very low certainty due to risk of bias, imprecision or both. None of the included studies assessed all-cause mortality, health-related quality of life or socioeconomic effects. One study assessed growth pattern but this was not measured at the time-point stipulated in the protocol of our review (one or more years after commencement of therapy). This review provides low-certainty evidence that vitamin D plus calcium or calcium alone improve healing in children with nutritional rickets compared to vitamin D alone. We are unable to make conclusions on the effects of the interventions on adverse events or morbidity (fractures).