Final report on the safety assessment of methoxyisopropanol and methoxyisopropyl acetate as used in cosmetics.
Methoxyisopropanol and Methoxyisopropyl Acetate, commonly known as propylene glycol monomethyl ether (PGME) and propylene glycol monomethyl ether acetate (PGMEA), respectively, have fragrance, solvent, and viscosity-decreasing functions in cosmetics, although only Methoxyisopropanol is in current use at concentrations ranging from 4% to 35%. Methoxyisopropanol is easily absorbed into the bloodstream upon inhalation or ingestion. The acetate ester is readily metabolized to Methoxyisopropanol in the body, which is excreted unchanged in the expired breath or in the urine as free or conjugated Methoxyisopropanol, or as the primary metabolite propylene glycol. In acute oral toxicity studies, the LD(50) values of Methoxyisopropanol were 4.6 to 9.2 g/kg in rats, with similar low acute toxicity in other animal species. Inhalation exposures of rats, mice, and rabbits to 3000 ppm Methoxyisopropanol for 6 h per day for 9 days to 13 weeks produced increased relative liver weights, signs of central nervous system (CNS) depression, and in some cases, elevated serum alkaline phosphatase, alanine aminotransferase, or hepatocellular hypertrophy, but the kidneys were unaffected. The no observed adverse effect level (NOAEL) for 13-week inhalation exposures to Methoxyisopropanol was 1000 ppm in rats and rabbits. In a 90-day dermal exposure study using rabbits, 10 ml/kg undiluted Methoxyisopropanol produced narcosis and increased kidney weights and the NOAEL was 7.0 ml/kg. Chronic (2-year) daily inhalation exposures of rats and mice to 3000 ppm Methoxyisopropanol produced signs of liver toxicity (rats and mice) and some evidence of renal toxicity in rats. The only observation at 1000 ppm was dark foci of the liver in male rats. For female rats and male and female mice, the NOAEL of this chronic inhalation study was 1000 ppm Methoxyisopropanol. Methoxyisopropanol and Methoxyisopropyl Acetate were found to be nonirritating to slightly irritating and non-sensitizing in rabbit and guinea pig skin. Repeated applications of undiluted Methoxyisopropanol to the eyes of rabbits produced transient slight to moderate irritation. Pregnant rats exposed to 200 or 600 ppm Methoxyisopropanol by inhalation on gestation days 6 to 17 had no effects on maternal health or normal fetal development. Adult male rats exposed to these concentrations had no effects on the reproductive organs. Pregnant rats and rabbits exposed to 500 to 3000 ppm Methoxyisopropanol by inhalation during gestation had no significant embryotoxic or fetotoxic effects, althougth CNS depression and reduced body weight gain were observed in the 3000 ppm group. In a two-generation inhalation study using rats, continuous inhalation of 3000 ppm Methoxyisopropanol produced CNS depression, prolonged estrous cycles, reduced fertility indices, reduced pup weights and pup survival, and delayed sexual development, with a NOAEL for reproductive and developmental effects of 1000 ppm. In a continuous breeding protocol using mice, 2.0% Methoxyisopropanol in drinking water produced reduced growth, reduced relative epididymis weight, reduced relative prostate weight, and increased liver weight (females only) in offspring, with a NOAEL at a 1% concentration. Exposure of mice or rats to 300 ppm to 3000 ppm Methoxyisopropanol by inhalation produced no signs of carcinogenicity. Methoxyisopropanol was negative for mutagenicity or genetic toxicity in the bacterial reverse mutation assay (<or= 5000 microg/plate), the unscheduled DNA synthesis (UDS) assay (<or= 0.1 M), V79 Chinese hamster lung assay (>100 mM), and in the Siberian hamster embryo assay (concentrations not reported). In other assays, 100 mM Methoxyisopropanol increased sister chromatid exchanges in V79 cells. In human inhalation exposure studies of 1 to 7 h duration, 50 to 75 ppm Methoxyisopropanol vapor had an objectionable odor; 150 ppm was slightly irritating to the eyes and throat; 250 ppm produced eye irritation, lacrimation, blinking, rhinorrhea, and headache; 300 ppm was mildly irritating to the eyes, nose, and throat; 750 ppm was extremely irritating; and 2050 ppm produced extreme discomfort with severe lacrimation, blepharospasm, and painful breathing. None of the concentrations tested impaired motor coordination or performance on neurological tests. The irritating effects subsided within 15 min to 24 h of removal from the inhalation chamber. The National Institute of Occupational Safety and Health (NIOSH) recommended an 8-h time-weighted average for occupational exposure of 100 ppm. A margin of safety of 500 was determined, based on a calculated exposure from the normal use of nail polish remover products (100% absorption) and the NOAEL for reproductive toxicity. The absorption of Methoxyisopropanol through the nail is likely to be low, suggesting this margin of safety is conservative. Because Methoxyisopropanol is volatile, exposure by inhalation is possible, but the odor becomes objectionable at 50 to 75 ppm in air. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that Methoxyisopropanol and Methoxyisopropyl Acetate are safe for use in nail care products in the practices of use and concentration as described in this safety assessment.


Multicomponent and multimodal lipsmacking in crested macaques (Macaca nigra).
Primates' communicative signals are often dynamic and composed of multiple components, sometimes belonging to different sensory modalities. Such multicomponent signals are of crucial importance in the study of communication: the addition of extra features to a signal has the potential to modulate or change the meaning and message of the specific signal. Traditionally, however, components of compound signals are studied in isolation from each other, or communicative displays are studied as static and invariant wholes. Both approaches may not allow us to assess the full function of the signals. In crested macaques (Macaca nigra), the lipsmack (a display mainly used in affiliative interactions) can be produced alone or combined with other visual and acoustic communicative features. We investigated whether the composition of the lipsmack influenced the outcome of social interaction while controlling for relationship quality. Our results show that lipsmacks composed of both visual and vocal components (i.e. multimodal signals) increased the probability of affiliative contact, and therefore have enhanced signal value. The total number of visual components involved in the display had no effect but some visual components seemed more influential than others. By analyzing lipsmacking behavior as a composite, dynamic display, we were able to reveal a level of complexity that is not apparent when looking at each component separately. The results highlight the importance of a more integrative, multimodal approach to the study of primate communication.


Alterations in L-glutamate binding in Alzheimer's and Huntington's diseases.
Brain sections from patients who had died with senile dementia of the Alzheimer's type (SDAT), Huntington's disease (HD), or no neurologic disease were studied by autoradiography to measure sodium-independent L-[3H]glutamate binding. In brain sections from SDAT patients, glutamate binding was normal in the caudate, putamen, and claustrum but was lower than normal in the cortex. The decreased cortical binding represented a reduction in numbers of binding sites, not a change in binding affinity, and appeared to be the result of a specific decrease in numbers of the low-affinity quisqualate binding site. No significant changes in cortical binding of other ligands were observed. In brains from Huntington's disease patients, glutamate binding was lower in the caudate and putamen than in the same regions of brains from control and SDAT patients but was normal in the cortex. It is possible that development of positron-emitting probes for glutamate receptors may permit diagnosis of SDAT in vivo by means of positron emission tomographic scanning.


Validation of Bohr dead space measured by volumetric capnography.
Bohr's dead space (VD(Bohr)) is commonly calculated using end-tidal CO(2) instead of the true alveolar partial pressure of CO(2) (PACO(2)). The aim of this work was to validate VD(Bohr) using PACO(2) derived from volumetric capnography (VC) against VD(Bohr) with PACO(2) values obtained from the standard alveolar air formula. Expired gases of seven lung-lavaged pigs were analyzed at different lung conditions using main-stream VC and multiple inert gas elimination technique (MIGET). PACO(2) was determined by VC as the midpoint of the slope of phase III of the capnogram, while mean expired partial pressure of CO(2) (PeCO(2)) was calculated as the mean expired fraction of CO(2) times the barometric minus the water vapor pressure. MIGET estimated expired CO(2) output (VCO(2)) and PeCO(2) by its V/Q algorithms. Then, PACO(2) was obtained applying the alveolar air formula (PACO(2) = VCO(2)/alveolar ventilation). We found close linear correlations between the two methods for calculating both PACO(2) (r = 0.99) and VD(Bohr) (r = 0.96), respectively (both p < 0.0001). Mean PACO(2) from VC was very similar to the one obtained by MIGET with a mean bias of -0.10 mmHg and limits of agreement between -2.18 and 1.98 mmHg. Mean VD(Bohr) from VC was close to the value obtained by MIGET with a mean bias of 0.010 ml and limits of agreement between -0.044 and 0.064 ml. VD(Bohr) can be calculated with accuracy using volumetric capnography.


The hepatorenal syndrome in liver transplant recipients.
The hepatorenal syndrome (HRS) is a well-known complication of liver failure, and medical treatment is usually not successful unless liver function can be improved. The authors review their experience with 130 adults undergoing orthotopic liver transplantation (OLT) over a 20-month period to determine the incidence of HRS and its effects on patient outcome, need for hemodialysis (HD), and the degree of recovery of renal function. The clinical diagnosis of HRS preoperatively was made by using criteria to exclude prerenal azotemia, acute tubular necrosis, and primary renal diseases. Nineteen patients were identified as having the HRS for a preoperative incidence of 15.1 per cent. Overall, 41 of the 126 patients reviewed required postoperative HD, and the mortality in this group was 54 per cent. Fifty-eight per cent of the HRS patients were dialyzed postoperatively vs 28 per cent of non-HRS patients. The mean posttransplant creatinine improved over time in the HRS patients while it worsened slightly in the non-HRS group. At 12 weeks posttransplant, there was a significant difference in the mean creatinine levels (1.8 +/- 0.3 mg/dl vs 1.2 +/- 0.04 mg/dl, P = .001). However, at 24 weeks the small difference was not statistically significant between the two groups (1.6 +/- 0.15 mg/dl vs 1.3 +/- 0.06 mg/dl, P = NS). The current survival of the hepatorenal group is comparable to the nonhepatorenal patients at a follow-up of 6 to 25 months: 68 per cent vs 78 per cent, P = NS. The authors conclude that liver transplantation reverses the HRS, and that hepatorenal patients can undergo liver transplantation with outcomes comparable to nonhepatorenal patients.


The Gene Ontology resource: enriching a GOld mine.
The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles annotated. As the project matures, we continue our efforts to review older annotations in light of newer findings, and, to maintain consistency with other ontologies. As a result, 20 000 annotations derived from experimental data were reviewed, corresponding to 2.5% of experimental GO annotations. The website (http://geneontology.org) was redesigned for quick access to documentation, downloads and tools. To maintain an accurate resource and support traceability and reproducibility, we have made available a historical archive covering the past 15 years of GO data with a consistent format and file structure for both the ontology and annotations.


Superoxide dismutase and catalase in Photobacterium damselae subsp. piscicida and their roles in resistance to reactive oxygen species.
Photobacterium damselae subsp. piscicida (formerly Pasteurella piscicida) is the causative agent of pasteurellosis or pseudotuberculosis in warm water marine fish. Enzymes which neutralize reactive oxygen species, produced during aerobic metabolism or during respiratory burst in fish macrophages, are important virulence factors in many pathogens. This study characterizes a periplasmic superoxide dismutase (SOD) and a cytoplasmic catalase in P. damselae. Purification and partial amino-terminal sequencing confirmed the SOD to be iron-cofactored, with a high degree of homology to other bacterial FeSODs. The SOD was common to all strains analysed in terms of type, location and activity, whilst the catalase varied in activity between strains. The catalase was constitutively expressed, but the SOD appeared to be repressed under low oxygen conditions. In spite of the presence of a periplasmic SOD, P. damselae was susceptible to killing by exogenous superoxide anion generated in a cell-free system. Addition of exogenous SOD to this system did not abolish the bactericidal effect; however, addition of catalase was protective. These results suggest that lack of periplasmic catalase may be implicated in susceptiblity to killing by reactive oxygen species.


[Correlation and interconversion between erythrocyte cholinesterase values obtained by the Michel and the EQM techniques].
Several techniques are available to measure red cell cholinesterase; therefore, evaluations with several methods provide a measure of concordance. An equation was formulated to transform native data of reference values to reference units of cholinesterase activity as measured by Michel and EQM tests. The experimental design was descriptive, transversal and prospective. The group sampled was a representative adult working population, aged 18-75, without previous exposure to cholinesterase inhibitors pesticides. The individuals were affiliated to the Social Security System and resided in Valle de Aburrá and Cercano Oriente Antioqueño (Antioquia Province, northwestern Colombia). Of 827 individuals, quantitative erythrocytes (Michel y EQM) tests exhibited "r" coefficients between 0.67 and R2 coefficient of 44%.,This indicated that one test explained the results in other test in 44% of the cases. The corelation was higher in Aburrá than in Oriente. The linear model for the 827 individuals was as follows: EQM U/g oxy-hemoglobin = 9.575 U/ g oxy-hemoglobin + 29.791 (Michel delta pH/hour). Michel delta pH/hr = 0.3312 delta pH/hour + 0.0149 (EQM U/g oxy-hemoglobin), where EQM was expressed in U/g oxy-hemoglobin and Michel pH change/hr. Inter-sections (coefficient a) and inclines (coefficient b) were significant in this model. In the adjusted equations, after exclusion of 12 extreme data (1.5% of 827), the r coefficient increased from 0.67 to 0.72 The adjusted equations were as follows: EQM U/g oxy-hemoglobin = 8.1884 U/g oxy-hemoglobin + 31.3920 (Michel delta pH/hour); Michel delta pH/hr = 0.2925 delta pH/hr + 0.0161 (EQM U/g oxy-hemoglobin). This system of linear equations permitted the transformation of Michel (delta PH/ hr) units to EQM (U/g oxy-hemoglobin) units and vice versa. This will facilitate data comparisons by clinicians and epidemiologists who are using these methods of cholinesterase measurement.


MRA of intracranial aneurysms.
Most intracranial aneurysms are located in the circle of Willis. They occur in 5-6% of the general population. Patients with intracranial aneurysm either present catastrophically with rupture of the aneurysm have aneurysms that are incidentally discovered. Prognosis is drastically different in each case, with a greater than 50% incidence of death if there is a rupture of the aneurysm. On the other hand, the surgical or endovascular mortality following treatment of an unruptured aneurysm is minimal, with good patient neurological outcome. In the appropriate clinical setting, it is important to find a screening study that can detect a cerebral aneurysm so that definitive cerebral angiography can be performed. The combination of magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) can detect an aneurysm in 60-85% of cases. This screening test adds a few minutes of scanning time to the average MR examination. Magnetic resonance angiography techniques continue to improve with better gradients, enhanced sequences to detect flow and reduce flow-related artifacts, shorter echo times with possible use of echo-planar (short scanning time) techniques, and improved imaging matrix, and they may, in conjunction with computed tomographic angiography (CTA), become a reliable non-invasive technique for detection of intracranial aneurysm.


Development of a Delirium Risk Predication Model among ICU Patients in Oman.
Delirium is a common disorder among patients admitted to intensive care units. Identification of the predicators of delirium is very important to improve the patient's quality of life. This study was conducted in a prospective observational design to build a predictive model for delirium among ICU patients in Oman. A sample of 153 adult ICU patients from two main hospitals participated in the study. The Intensive Care Delirium Screening Checklist (ICDSC) was used to assess the participants for delirium twice daily. The results showed that the incidence of delirium was 26.1%. Multiple logistic regression analysis showed that sepsis (odds ratio (OR) = 9.77; 95% confidence interval (CI) = 1.91-49.92; P < 0.006), metabolic acidosis (odds ratio (OR) = 3.45; 95% confidence interval [CI] = 1.18-10.09; P=0.024), nasogastric tube use (odds ratio (OR) 9.74; 95% confidence interval (CI) = 3.48-27.30; P ≤ 0.001), and APACHEII score (OR = 1.22; 95% CI = 1.09-1.37; P ≤ 0.001) were predictors of delirium among ICU patients in Oman (R 2=0.519, adjusted R 2=0.519, P ≤ 0.001). To prevent delirium in Omani hospitals, it is necessary to work on correcting those predictors and identifying other factors that had effects on delirium development. Designing of a prediction model may help on early delirium detection and implementation of preventative measures.


BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.
Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (pmeta < 10-10 ), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (pmeta = 2.1 x 10-10 ) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10-5 ) and p300 (p = 1.55 x 10-3 ) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (pmeta = 1.3 x 10-15 ), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.


Evolution of two Rh blood group-related genes of the amphioxus species Branchiostoma floridae.
We determined cDNAs of two genes that belong to the Rhesus (Rh) blood group gene family in an amphioxus species (Branchiostoma floridae) and designated them Rh-related-1 (RhR-1) and Rh-related-2 (RhR-2). RhR-1 and RhR-2 consisted of 10 and 11 exons, respectively. 3' UTR sequences of RhR-1 were shorter (220-272 bp) than those of RhR-2 (1,505-1,650 bp). CDS lengths were 1,344 and 1,476 bp for RhR-1 and RhR-2, respectively, and the average nucleotide difference between their CDS regions was 0.33. The corresponding regions of Rh genes from exons 2 to 7 were relatively conserved among the chordate species examined in this study. Length difference numbers were in multiples of three, which implies that codon frames were conserved among them, and the same exon/intron boundary phases were observed in those regions. This region was used for the phylogenetic analyses. RhR-1 and RhR-2 formed a cluster on the phylogenetic tree of the Rh gene family. Gene duplication time of RhR-1 and RhR-2 was estimated to be ca. 500 million years ago. It is likely that the four Rh family genes in vertebrates emerged by gene duplications in the common ancestor of vertebrates, and functional differentiation has occurred after the first gene duplication.


Evaluation of cardiac arrhythmias by exercise testing.
Exercise testing is an important noninvasive method for the exposure of arrhythmias. It provides complementary information to that obtained from ambulatory monitoring or electrophysiologic testing. By producing a number of important physiologic changes, especially activation of the sympathetic nervous system and an increase in circulating catecholamines, exercise testing provides a more complete assessment. On continuous monitoring, exercise-induced ventricular premature beats may be found in up to 34% of healthy subjects, in 60 to 70% of those with heart disease and in all patients who have experienced sustained ventricular tachycardia. Couplets or nonsustained ventricular tachycardia can be found during exercise in 0 to 6% of healthy subjects, in 15 to 31% of patients with heart disease and in 75% of those with sustained ventricular tachycardia. Even in patients with heart disease, there is only a small risk of inducing sustained ventricular tachycardia or ventricular fibrillation during exercise. The prognostic relevance of exercise-induced ventricular arrhythmias in patients with coronary artery disease or cardiomyopathy has not been clearly established. There appears to be an increased risk, however, in patients with ventricular premature beats as well as ST-segment depression or in patients with repetitive forms of ventricular arrhythmias during exercise which cannot be medically controlled. In healthy subjects, exercise-induced ventricular premature beats are of no prognostic relevance. In particular, for patients in whom arrhythmias are induced by exercise, exercise testing should be used to assess the effectiveness of antiarrhythmic drug treatment. Importantly, serious cardiac toxicity, often not observed at rest or during routine activities, may become apparent during exercise testing. It should be a standard part of arrhythmia assessment and management.


Frequency of the G6PD nt 1311 C/T polymorphism in English and Iranian populations: relevance to studies of X chromosome inactivation.
X chromosome inactivation is widely studied using DNA sequence polymorphisms and DNA methylation as a surrogate measure of inactivation, but the correlation of methylation with inactivation is not perfect. Thus, it may be better to study sequence polymorphisms expressed in the mRNA. A recent paper reported use of a silent C/T polymorphism at nt 1311 of the G6PD cDNA, and this polymorphism was reported to have a frequency of 40% in all ethnic groups. We have screened 218 English and 50 Iranian subjects by PCR and restriction digestion; 53/218 (24%) British and 22/50 (44%) Iranian subjects were heterozygous. Thus, X inactivation studies using this polymorphism may be useful in some populations, including Iran, but much less so in the UK.


Chronic vs. acute interactions between supraoptic oxytocin neurons and astrocytes during lactation: role of glial fibrillary acidic protein plasticity.
In this article, we review studies of astrocytic-neuronal interactions and their effects on the activity of oxytocin (OXT) neurons within the magnocellular hypothalamo-neurohypophysial system. Previous work over several decades has shown that withdrawal of astrocyte processes increases OXT neuron excitability in the hypothalamic supraoptic nucleus (SON) during lactation. However, chronically disabling astrocyte withdrawal does not significantly affect the functioning of OXT neurons during suckling. Nevertheless, acute changes in a cytoskeletal element of astrocytes, glial fibrillary acidic protein (GFAP), occur in concert with changes in OXT neuronal activity during suckling. Here, we compare these changes in GFAP and related proteins with chronic changes that persist throughout lactation. During lactation, a decrease in GFAP levels accompanies retraction of astrocyte processes surrounding OXT neurons in the SON, resulting from high extracellular levels of OXT. During the initial stage of suckling, acute increases in OXT levels further strengthen this GFAP reduction and facilitate the retraction of astrocyte processes. This change, in turn, facilitates burst discharges of OXT neurons and leads to a transient increase in excitatory neurochemicals. This transient neurochemical surge acts to reverse GFAP expression and results in postburst inhibition of OXT neurons. The acute changes in astrocyte GFAP levels seen during suckling likely recur periodically, accompanied by rhythmic changes in glutamate metabolism, water transport, gliotransmitter release, and spatial relationships between astrocytes and OXT neurons. In the neurohypophysis, astrocyte retraction and reversal with accompanying GFAP plasticity also likely occur during lactation and suckling, which facilitates OXT release coordinated with its action in the SON. These studies of the dynamic interactions that occur between astrocytes and OXT neurons mediated by GFAP extend our understanding of astrocyte functions within the central nervous system.


The HEART Pathway randomized trial: identifying emergency department patients with acute chest pain for early discharge.
The HEART Pathway is a decision aid designed to identify emergency department patients with acute chest pain for early discharge. No randomized trials have compared the HEART Pathway with usual care. Adult emergency department patients with symptoms related to acute coronary syndrome without ST-elevation on ECG (n=282) were randomized to the HEART Pathway or usual care. In the HEART Pathway arm, emergency department providers used the HEART score, a validated decision aid, and troponin measures at 0 and 3 hours to identify patients for early discharge. Usual care was based on American College of Cardiology/American Heart Association guidelines. The primary outcome, objective cardiac testing (stress testing or angiography), and secondary outcomes, index length of stay, early discharge, and major adverse cardiac events (death, myocardial infarction, or coronary revascularization), were assessed at 30 days by phone interview and record review. Participants had a mean age of 53 years, 16% had previous myocardial infarction, and 6% (95% confidence interval, 3.6%-9.5%) had major adverse cardiac events within 30 days of randomization. Compared with usual care, use of the HEART Pathway decreased objective cardiac testing at 30 days by 12.1% (68.8% versus 56.7%; P=0.048) and length of stay by 12 hours (9.9 versus 21.9 hours; P=0.013) and increased early discharges by 21.3% (39.7% versus 18.4%; P<0.001). No patients identified for early discharge had major adverse cardiac events within 30 days. The HEART Pathway reduces objective cardiac testing during 30 days, shortens length of stay, and increases early discharges. These important efficiency gains occurred without any patients identified for early discharge suffering MACE at 30 days. URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01665521.


Anion Tuned Structural Modulation and Nonlinear Optical Effects of Metal-Ion Directed 310 -Helix Networks.
Metals play an important role in the structure and functions of various proteins. The combination of metal ions and peptides have been emerging as an attractive field to create advanced structures and biomaterials. Here, we are reporting the anion-influenced, silver ion coordinated diverse networks of designed short tripeptide 310 -helices with terminal pyridyl groups. The short peptides adopted classical right-handed, left-handed and 310 EL -helical conformations in the presence of different silver salts. The peptides have displayed conformational flexibility to accommodate different sizes and interactions of anions to yield a variety of metal-coordinated networks. The complexes of metal ions and peptides have shown different porous networks, right- and left-handed helical polymers, transformation of helix into superhelix and 2 : 2 metal-peptide macrocycles. Further, the metal-peptide crystals with inherent dipoles of helical peptides gave striking second harmonic generation response. The optical energy upconversion from NIR to red and green light is demonstrated. Overall, we have shown the utilization of short 310 -helices for the construction of diverse metal-coordinated helical networks and notable non-linear optical effects.


Identification of head motions by central vestibular neurons receiving linear and angular input.
Most naturally occurring displacements of the head in space, due to either an external perturbation of the body or a self-generated, volitional head movement, apply both linear and angular forces to the head. The vestibular system detects linear and angular accelerations of the head separately, but the succeeding control of gaze and posture often relies upon the combined processing of linear and angular motion information. Thus, the output of a secondary neuron may reflect the linear, the angular, or both components of the head motion. Although the vestibular system is typically studied in terms of separate responses to linear and angular acceleration of the head, many secondary and higher-order neurons in the vestibular system do, in fact, receive information from both sets of motion sensors. The present paper develops methods to analyze responses of neurons that receive both types of information, and focuses on responses to sinusoidal motions composed of a linear and an angular component. We show that each neuron has a preferred motion, but a single neuron cannot code for a single motion. However, a pair of neurons can code for a motion by the relative phases of firing-rate modulation. In this way, information about motion is enhanced by neurons combining information about linear and angular motion.


The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells.
The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, a N,N'-diphenyl urea with an IC(50) of 0.88 mumol/L on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP-AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels derived from the TT cell xenografts were inhibited shortly after treatment, when tumor volume was still unchanged, indicating that the effects of RET kinase inhibition on calcitonin secretion were temporally dissociated from its tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription. These data point to a previously unknown physiologic role of RET signaling on calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. Antagonists of RET kinase activity in patients with MTC may result in effects on plasma calcitonin that are either disproportionate or dissociated from the effects on tumor burden, because RET kinase mediates a physiologic pathway controlling calcitonin secretion. The role of traditional tumor biomarkers may need to be reassessed as targeted therapies designed against oncoproteins with key roles in pathogenesis are implemented.


Altered microRNA expression in bovine skeletal muscle with age.
Age-dependent decline in skeletal muscle function leads to several inherited and acquired muscular disorders in elderly individuals. The levels of microRNAs (miRNAs) could be altered during muscle maintenance and repair. We therefore performed a comprehensive investigation for miRNAs from five different periods of bovine skeletal muscle development using next-generation small RNA sequencing. In total, 511 miRNAs, including one putatively novel miRNA, were identified. Thirty-six miRNAs were differentially expressed between prenatal and postnatal stages of muscle development including several myomiRs (miR-1, miR-206 and let-7 families). Compared with miRNA expression between different muscle tissues, 14 miRNAs were up-regulated and 22 miRNAs were down-regulated in the muscle of postnatal stage. In addition, a novel miRNA was predicted and submitted to the miRBase database as bta-mir-10020. A dual luciferase reporter assay was used to demonstrate that bta-mir-10020 directly targeted the 3'-UTR of the bovine ANGPT1 gene. The overexpression of bta-mir-10020 significantly decreased the DsRed fluorescence in the wild-type expression cassette compared to the mutant type. Using three computational approaches - miranda, pita and rnahybrid - these differentially expressed miRNAs were also predicted to target 3609 bovine genes. Disease and biological function analyses and the KEGG pathway analysis revealed that these targets were statistically enriched in functionality for muscle growth and disease. Our miRNA expression analysis findings from different states of muscle development and aging significantly expand the repertoire of bovine miRNAs now shown to be expressed in muscle and could contribute to further studies on growth and developmental disorders in this tissue type.


Spontaneous contractile pattern of isolated circular and longitudinal muscle layers from the ampullae of normal and damaged fallopian tubes.
Ampullary biopsies were obtained from twenty-three normal fertile women and from eleven women with hydrosalpinges. The contractile activity of 4-mm muscle strips was studied isometrically in organ bath. Both normal circular and longitudinal muscle strips contracted with similar frequency, duration and amplitude. Circular and longitudinal muscle strips from hydrosalpinges contracted with a lower frequency and a longer duration and the amplitude of contractions was higher than normal. The difference in frequency and duration was statistically significant. The possible explanations for these differences in rhythmicity between normal and diseased fallopian tubes are presented and the prognostic relevance discussed.


Phospholipase D1 and D2 Synergistically Regulate Thrombus Formation.
Previously, we reported that phospholipase D1 (PLD1) and PLD2 inhibition by selective PLD1 and PLD2 inhibitors could prevent platelet aggregation in humans, but not in mice. Moreover, only the PLD1 inhibitor, but not PLD2 inhibitor, could effectively prevent thrombus formation in mice, indicating that PLD might play different roles in platelet function in humans and mice. Although PLD1 and PLD2 were reported to be implicated in thrombotic events, the role of PLD in mice remains not completely clear. Here, we investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient middle cerebral artery occlusion-induced brain injury in mice. The data revealed that inhibition of PLD1, but not of PLD2, could partially prevent pulmonary thrombosis-induced death. Moreover, concurrent PLD1 and PLD2 inhibition could considerably increase survival rate. Likewise, inhibition of PLD1, but not PLD2, partially improved ischemic stroke and concurrent inhibition of PLD1, and PLD2 exhibited a relatively better protection against ischemic stroke, as evidenced by the infarct size, brain edema, modified neurological severity score, rotarod test, and the open field test. In conclusion, PLD1 might play a more important role than PLD2, and both PLD1 and PLD2 could act synergistically or have partially redundant functions in regulating thrombosis-relevant events.


Male reproductive health research needs and research agenda: Asian and Chinese perspective.
Research that addresses male reproductive health should assist in the development of reproductive health programmes and policy; identify and test new leads in male contraceptive technology; establish effective male involvement initiatives which are likely to have a positive impact on the reproductive health of men and women; guide the allocation of health care resources to ensure cost-effectiveness of interventions; generate new knowledge, develop diagnostic technology in reproductive health and offer optimal treatment/care regimens. In considering the needs and demands of male reproductive health research in Asia and the Pacific, the following six research topics are recommended as the priority research areas: male contraceptive technology; male reproductive health behaviour and male adolescent reproductive health; male reproductive aging including male menopause and other diseases; male RTIs, STDs, HIV/AIDS; prevalence, management and prevention of male infertility; environment and semen quality and other male reproductive problems. One of the major challenges now facing us is the elaboration of a comprehensive, yet realistic male reproductive health research agenda that reflect the needs and demands of Asian developing countries. To this end, to make use of an interdisciplinary approach is of strategic importance. The most creative insights and productive leads are likely to emerge from a research team that is interdisciplinary especially in the field of reproductive health.


Effects of resuscitation from hemorrhagic shock on cerebral hemodynamics in the presence of an intracranial mass.
This study compares intracranial pressure, cerebral blood flow, and cerebral oxygen transport during hemorrhagic shock and following fluid resuscitation with crystalloid or colloid solution in a canine model with an epidural mass lesion. After placement of an epidural balloon, intracranial pressure was increased to 30 mm Hg for 5 minutes and then permitted to vary without further manipulation. Hemorrhagic shock was produced by the rapid removal of blood to achieve a mean arterial pressure of 55 mm Hg for 30 minutes. Resuscitation then was performed with intravenous lactated Ringer's solution, 60 ml/kg, or with 6.0% hetastarch, 20 ml/kg. Following both solutions mean arterial pressure and cardiac output were increased and hemoglobin concentration was reduced. Intracranial pressure was significantly lower immediately after resuscitation in the hetastarch group; it then gradually increased so that the difference was much less 1 hour later. Cerebral blood flow decreased during shock and was not restored by either fluid; cerebral oxygen transport fell further with resuscitation in both groups due to hemodilutional reductions in hemoglobin. Although colloid resuscitation improved systemic hemodynamics and maintained lower intracranial pressure, it failed, as did crystalloid resuscitation, to restore cerebral oxygen transport to prehemorrhagic shock levels.


Chronic immune stimulation correlates with reduced phenylalanine turnover.
Neuropsychiatric symptoms like mood changes and depression are common in patients with chronic inflammatory disorders such as infections, autoimmune diseases or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic, but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-gamma stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is cofactor for several aromatic amino acid monooxygenases and thus is strongly involved in the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). In macrophages, interferon-gamma also triggers the high output of reactive oxygen species, which can destroy the oxidation-labile BH4. Recent data suggest that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.


Could it have been better? A patient with peripartum cardiomyopathy treated with conventional therapy.
Peripartum cardiomyopathy is a life threatening condition of unknown cause that occurs in previously healthy women. It is characterized by symptoms of heart failure due to left ventricular dysfunction that occurs in the last month of pregnancy or the first five months after delivery. We presented woman who underwent caesarean section due to preeclampsia. Two weeks after delivery first signs of heart failure appeared and only after six weeks following the onset of symptoms peripartal cardiomyopathy was recognized. A conventional treatment with diuretics, ACE inhibitor and beta blocker along with anticoagulant therapy was applied, which resulted in a complete recovery of the left ventricular function four months after. Timely detection and initiation of treatment are an important precondition for the complete or partial recovery.


Primary chondrosarcoma of the trachea with extensive extraluminal growth.
Primary chondrosarcoma of the trachea is an extremely rare non-epithelial neoplasm with only few cases published in the literature. We present a rare case of tracheal chondrosarcoma with extensive extraluminal growth. We operated a patient with obstructive tumour of the upper third of the trachea via partial sternotomy. Before surgery, a Hanarostent was put into the trachea to treat a life-threatening stenosis. Postoperative period was uneventful. We discuss the incidence, clinical presentation and treatment options in patients with rare tracheal tumours. In some cases, a multidisciplinary approach (endoscopic intervention followed by surgical resection) is an effective treatment tool.


Inversion duplication of the short arm of chromosome 8: clinical data on seven patients and review of the literature.
We report on clinical and cytogenetic data on 5 children and 2 adults with a de novo inverted duplication of the short arm of chromosome 8, and we give a review of 26 patients from the literature. The clinical picture in young children is characterized by minor facial anomalies, hypotonia, and severe developmental delay. In older patients the facial traits are less characteristic, spastic paraplegia develops, and severe orthopedic problems are frequent. Psychomotor retardation is always severe-to-profound. Duplication of 8p21-p22 results in a clinically recognizable multiple congenital anomalies/mental retardation (MCA/MR) syndrome. It is shown that in all patients examined, the duplication was accompanied by a deletion of the most terminal part of 8p.


Validation of a simple RP-HPLC method developed for the quantification of meta-cresol in parathyroid hormones formulation.
To develop and validate a rapid and sensitive reverse phase high performance liquid chromatography (RP-HPLC) method with UV detection for quantification of meta-cresol (m-cresol) in pharmaceutical preparation of parathyroid hormone (1-34) (PTH). Chromatography was performed on a Jupiter RP C-18 (4.6 mm ID × 250 mm L, porosity 300 Å, particle size 5 μm) with a guard column (reversed-phase C18 column of 4.6 mm ID × 12.5 mm L, porosity 300 Å, particle size 5 μm) using a mobile phase containing 0.1% TFA in 60% methanol with isocratic program at 1.0 mL/min flow rate. Detection was carried out at 217 nm. The method was validated as per ICH guidelines for linearity (correlation coefficient = 0.99), range, accuracy, precision, and robustness (n = 9 during accuracy parameter whereas n =15 during linearity and range parameter and n = 6 during repeatability). Robustness was confirmed by considering two factors; age effect of the mobile phase and test sample and with different columns during method development. The method was linear over the concentration range of 75-120 μg/mL. The precision of the method in terms of relative standard deviation was evaluated from intra- and inter-day replicate injections of system suitability standards of m-cresol using different equipment and different columns. Components of within- and between-batch variances were found to be below 2% (n = 30) and 3%, respectively, which constituted an acceptable level of variation. Retention time was found to be about 5.2 min and 10.9 min for m-cresol and PTH, respectively. The developed method thus has the potential of being useful for routine quality control of m-cresol.


Inferior vena cava diameter in acute decompensated heart failure as predictor of all-cause mortality.
Inferior vena cava (IVC) diameter can be used to approximate right atrial pressure in patients admitted for acute decompensated heart failure (ADHF). Recent studies linked IVC dilation to an increased risk of early re-admission and short-term mortality. Moreover, renal insufficiency (RI) is an established risk factor for mortality in ADHF and is associated with congestion. We hypothesized that the IVC diameter is a marker of all-cause mortality but its prognostic impact may be influenced by kidney function. We analyzed data of 1101 patients admitted for ADHF with available echocardiography of the IVC by chart review and death registry linkage. Patients were dichotomized according to a cut-off value of 21 mm. Cox proportional hazards model was used to identify mortality predictors. A dilated IVC was detected in 474 (43.1%) patients. Overall, 400 (36.3%) patients died within 3 years. All-cause mortality was significantly higher in patients with dilated IVC [hazard ratio 1.45 (confidence interval 1.21-1.74); p < 0.001]. However, a dilated IVC was only associated with all-cause mortality in patients with RI function [hazard ratio 1.60 (confidence interval 1.26-2.03); p < 0.001] but not in patients with a preserved kidney function [hazard ratio 1.04 (confidence interval 0.72-1.50); P = 0.84]. IVC diameter was identified as an independent predictor for all-cause mortality in a Cox proportional hazards model with a significant interaction between IVC diameter and baseline kidney function. In conclusion, IVC dilation is a marker of high mortality risk in patients admitted for ADHF. However, this observation was confined to patients with RI.


Can a Label Help me Drink in Moderation? A Review of the Evidence on Standard Drink Labelling.
Understanding the concept of a standard drink (SD) is foundational knowledge to many public health policies aimed at reducing alcohol-related harms. These policies include adhering to low-risk drinking guidelines, screening brief intervention and referral activities, and counter alcohol-impaired driving initiatives. A lack of awareness of SDs might preclude the effectiveness of these interventions. A systematic review was conducted to review the evidence about how effective alcohol labels are in communicating SD information to the consumer. A systematic review was conducted to identify peer-reviewed articles and grey literature from relevant indexes from January 1990 to January 2016. Additionally, policy makers and researchers in countries where standard drink labels (SDLs) have been implemented were consulted to help identify relevant literature. The search strategy was focused on the impact of SDLs relative to a range of outcomes, including awareness of SDs, pouring behaviors, and consumption patterns. Eleven records were eligible for inclusion. The evidence suggests that knowledge of the definition of an SD is low. However, SDLs can help individuals more accurately identify and pour an SD. SDLs need to be supported by educational initiatives to help the consumer understand the SD information provided on the beverage container. To date, there has been no comprehensive evaluation of the impact of SDLs. SDLs have the potential to increase awareness of SDs and facilitate the monitoring of personal alcohol consumption in the context of a comprehensive alcohol strategy. However, their impact on drinking behaviors requires further exploration, especially among high-risk populations.


Effect of Bioceramic Materials on Proliferation and Odontoblast Differentiation of Human Stem Cells from the Apical Papilla.
In regenerative endodontic treatment (RET), practitioners favor the placement of bioceramics as sealing materials over blood clots. It is important to understand the interaction between sealing material and cells in the root canal. The purpose of this study was to compare the effectiveness of various bioceramic materials (ProRoot MTA [Dentsply, Tulsa, OK], Biodentine [Septodont, Saint-Maur-des-Fossés, France], and RetroMTA [BioMTA, Seoul, Korea]) as sealing materials in RET for the proliferation and differentiation of stem cells from the apical papilla (SCAPs). SCAPs were seeded at 20,000 cells/well and cultured with soluble agents of testing materials through a transwell culture plate. The proliferation of SCAPs was investigated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on days 1, 3, 7, and 14 of testing. Alizarin red staining and quantitative real-time polymerase chain reaction were used for SCAP differentiation at different time points (1, 7, 14, and 21 days). The odontoblast genes expressed are dentin matrix acidic phosphoprotein 1, dentin sialophosphoprotein, osteocalcin, and matrix extracellular phosphoglycoprotein, which were used in this study. The SCAPs were cultured in odonto/osteogenic induction medium and also contacted soluble agents from the testing materials. All 3 tested biomaterials induced SCAP proliferation. The Biodentine, ProRootMTA, and RetroMTA groups showed significant SCAP proliferation on days 7 and 14 compared with the control. In regard to odontoblastic differentiation, only Biodentine showed positive alizarin red staining. The highest expressions of dentin matrix acidic phosphoprotein 1, dentin sialophosphoprotein, and matrix extracellular phosphoglycoprotein were found on day 21 in the Biodentine group. The expression of osteocalcin was found to be significant on day 7. Biodentine, ProRootMTA, and RetroMTA can induce SCAP proliferation. Biodentine induced significant SCAP differentiation among the 3 materials.


A new glycoprotein SPG-8700 isolated from sweet potato with potential anti-cancer activity against colon cancer.
A new small molecule glycoprotein SPG-8700 with potential anti-colorectal cancer activity was firstly separated by tracking of bioactivity from a new sweet potato variety Zhongshu-1. Matrix-assisted laser desorption ionization mass spectrometry, high-performance liquid chromatography and amino acid analyzer were applied separately to determine the molecular weight and compositions of this glycoprotein. Flow cytometry analysis and western blotting analysis were employed to explore it's mechanism of the anti-colorectal cancer. The molecular weight of glycoprotein was 8703.8D (SPG-8700). Relative sugar and protein contents in SPG-8700 were 73.4 and 26.6%, comprising more than 6 types of sugars (mannose, rhamnose, glucuronic acid, glucose, galactose and arabinose with a proportion of 1:6.9:7.3:1.5:46:21). Further results indicated that SPG-8700 promoted apoptosis in HCT-116 cells through regulating the expression of Bcl-2 and Bax and had no effect on the growth of normal cells.


Promoter analysis of RPE65, the gene encoding a 61-kDa retinal pigment epithelium-specific protein.
To identify the functional promoter region and cis-acting elements that regulate the expression of RPE65, the retinal pigment epithelium (RPE)-specific gene responsible for certain forms of autosomal recessive childhood-onset severe retinal dystrophy. A human genomic DNA clone containing the 5'-flanking region of RPE65 was isolated and, 4.0 kb proximal to the transcription start site, was sequenced and analyzed for the presence of transcription factor-binding sites. Promoter activity was assayed by transient transfection of luciferase reporter constructs containing nested deletions of the upstream sequence in the human RPE cell lines ARPE19 and D407, as well as in the SK-Mel-28 and HeLa cell lines. Specific DNA protein-binding sites present in the 340 bp upstream of the transcription start site were identified by DNase I footprint analysis. Sequence analysis places the polymorphic marker, D1S2803, within the RPE65 upstream region and identifies a number of sequences homologous to the gene encoding the cellular retinaldehyde-binding protein. Functional analysis indicates that basal promoter activity is conferred by the sequence from -83 to +39 and is approximately equivalent in all cell lines tested, with no other control elements detected in 3.6 kb of the upstream sequence. At least eight protected regions are identified in DNase I footprint assays, including sequences corresponding to the predicted TATA box, AP-4, and nuclear factor-1 DNA protein-binding sites. These findings localize the basal promoter activity of RPE65, identify potential cis-acting elements that act as positive regulators of gene expression, and suggest that additional regulatory elements are likely to be involved in restricting gene expression to the retinal pigment epithelium. Identification of promoter elements and genetic markers in the upstream sequence will enable the screening of patients with retinal degeneration for possible mutations that affect RPE65 expression.


Randomized clinical trial of autologous skin cell suspension combined with skin grafting for chronic wounds.
Treatment of chronic wounds using traditional surgical procedures is challenging because of the low graft take rates. This study investigated the combination approach of split-thickness autografts with harvested skin cell suspension for chronic wound treatment. This randomized clinical trial enrolled patients with chronic wounds between March 2012 and December 2013. Patients who were assigned randomly to the active treatment received a split-thickness autograft combined with harvested skin cell suspension. Control patients received the split-thickness autograft alone. The primary outcome was the rate of complete wound closure by postoperative day 28. Analysis was by intention to treat. Patients who achieved wound closure were followed up for a minimum of 6 months to evaluate the quality of healing. A total of 88 patients were included, 44 in each group. More patients achieved complete wound closure in the skin cell group than in the control group (41 versus 34 patients; P = 0·035). Complete wound closure was observed at a median of 14 (95 per cent c.i. 12·0 to 16·0) days in the skin cell group and 20 (15·7 to 24·3) days in the control group (P = 0·001). The skin cell group had significantly fewer complications (4 versus 11 patients; P = 0·047). The autografted sites displayed better physical attributes and a reduced tendency for wound recurrence in the skin cell group. Complementary split-thickness autologous skin grafting with autologous skin cells harvested using ReCell® (Avita Medical, Cambridge, UK) technology improved the healing rate of chronic wounds. UMIN000011966 (http://www.umin.ac.jp/ctr).


Acute Marjolin's Ulcer in Chronic Foot Wounds with Previous Negative Biopsy: Report of Two Cases.
Marjolin's ulcer is a rare and often overlooked diagnosis which can be encountered by a variety of specialities. Majority of the literatures describe long latency period of 11 to 75 years. The authors present two unusual cases of rapid progression to Marjolin's ulcer in patients with previously negative biopsy 8- and 10-month prior. This highlights the importance for clinicians to have a high degree of suspicion when encountered with any non-healing wound, especially one who's symptomatology and morphological features have undergone an acute change. Even with previous negative biopsy, patients should still be followed-up closely and clinicians should not hesitate to perform re-biopsy if the suspicion arises.


Histology-based homogenization analysis of soft tissue: application to prostate cancer.
It is well known that the changes in tissue microstructure associated with certain pathophysiological conditions can influence its mechanical properties. Quantitatively relating the tissue microstructure to the macroscopic mechanical properties could lead to significant improvements in clinical diagnosis, especially when the mechanical properties of the tissue are used as diagnostic indices such as in digital rectal examination and elastography. In this study, a novel method of imposing periodic boundary conditions in non-periodic finite-element meshes is presented. This method is used to develop quantitative relationships between tissue microstructure and its apparent mechanical properties for benign and malignant tissue at various length scales. Finally, the inter-patient variation in the tissue properties is also investigated. Results show significant changes in the statistical distribution of the mechanical properties at different length scales. More importantly the loss of the normal differentiation of glandular structure of cancerous tissue has been demonstrated to lead to changes in mechanical properties and anisotropy. The proposed methodology is not limited to a particular tissue or material and the example used could help better understand how changes in the tissue microstructure caused by pathological conditions influence the mechanical properties, ultimately leading to more sensitive and accurate diagnostic technologies.


Ontogenetic development of digestive functionality in golden pompano Trachinotus ovatus (Linnaeus 1758).
Ontogenetic development of the digestive system in golden pompano (Trachinotus ovatus, Linnaeus 1758) larvae was histologically and enzymatically studied from hatch to 32 day post-hatch (DPH). The development of digestive system in golden pompano can be divided into three phases: phase I starting from hatching and ending at the onset of exogenous feeding; phase II starting from first feeding (3 DPH) and finishing at the formation of gastric glands; and phase III starting from the appearance of gastric glands on 15 DPH and continuing onward. The specific activities of trypsin, amylase, and lipase increased sharply from the onset of first feeding to 5-7 DPH, followed by irregular fluctuations. Toward the end of this study, the specific activities of trypsin and amylase showed a declining trend, while the lipase activity remained at similar levels as it was at 5 DPH. The specific activity of pepsin was first detected on 15 DPH and increased with fish age. The dynamics of digestive enzymes corresponded to the structural development of the digestive system. The enzyme activities tend to be stable after the formation of the gastric glands in fish stomach on 15 DPH. The composition of digestive enzymes in larval pompano indicates that fish are able to digest protein, lipid and carbohydrate at early developmental stages. Weaning of larval pompano is recommended from 15 DPH onward. Results of the present study lead to a better understanding of the ontogeny of golden pompano during the larval stage and provide a guide to feeding and weaning of this economically important fish in hatcheries.


Postnatal gonadal steroid effects on human behavior.
Gonadal steroid hormones, active during fetal life, continue after the birth of a fetus to influence the central nervous system and affect behavior. The characteristically different circulating concentrations of male and female steroid hormones in men and women appear to be partial determinants of certain sexually dimorphic behaviors, interacting in a complex way with psychological and sociocultural factors as well as with other biological factors. This interaction is highlighted in research on testosterone and aggression in men, mood and the menstrual cycle in women, and pubertal sex role reversal in pseudohermaphrodites.


Centrifugal Gel Crushing Tips for Gel-Based Proteome Analysis.
We have developed a centrifugal gel-crushing method using a pipet tip. Polyacrylamide gel slices are extruded from the narrowing cavity of a pipet tip by centrifugation in a few minutes to crush them into pieces of appropriate size. The size of the crushed gel could be controlled by several parameters, including centrifugal force and pipet tip cavity. In shotgun proteomics, gel-based LC/MS/MS, so-called GeLC/MS/MS, involves the essential but tedious processes of prefractionation by SDS-PAGE, followed by dicing the entire gel lane into several parts, fine dicing, and in-gel digestion after the diced gel is manually transferred to a microtube. In this study, we developed an alternative way to crush the prefractionated gel slice into optionally small and irregular-shaped gels by centrifugal extrusion of the sliced gel from the narrow cavity of a pipet tip. As a result, we observed improved recovery and reproducibility of digested proteins compared to the conventional method of manual dicing. We believe that this simple and rapid method of crushing polyacrylamide gels, which allows for parallel operations and automation, is useful for GeLC/MS/MS analysis and applicable to other approaches, including top-down proteomics.


New tools in bio-NMR: indirect detection of nitrogen-14 in solids.
This paper presents an overview of recently developed methods for the indirect detection of 14N nuclei (spin l = 1) in spinning solids by nuclear magnetic resonance spectroscopy. These methods exploit the transfer of coherence from a neighboring 'spy' nucleus with spin S = 1/2, such as 13C or 1H, to single- or double-quantum transitions of 14N nuclei. The two-dimensional correlation methods presented here are closely related to the well-known heteronuclear single- and multiple-quantum correlation (HSQC and HMQC, respectively) experiments, already widely used for the investigation of molecules in liquids. Nitrogen-14 NMR spectra exhibit powder patterns characterized by second- and third-order quadrupolar couplings which can provide important information about structure and dynamics of molecules in powder samples.


S-nitrosation of protein phosphatase 1 mediates alcohol-induced ciliary dysfunction.
Alcohol use disorder (AUD) is a strong risk factor for development and mortality of pneumonia. Mucociliary clearance, a key innate defense against pneumonia, is perturbed by alcohol use. Specifically, ciliated airway cells lose the ability to increase ciliary beat frequency (CBF) to β-agonist stimulation after prolonged alcohol exposure. We previously found that alcohol activates protein phosphatase 1 (PP1) through a redox mechanism to cause ciliary dysfunction. Therefore, we hypothesized that PP1 activity is enhanced by alcohol exposure through an S-nitrosothiol-dependent mechanism resulting in desensitization of CBF stimulation. Bronchoalveolar S-nitrosothiol (SNO) content and tracheal PP1 activity was increased in wild-type (WT) mice drinking alcohol for 6-weeks compared to control mice. In contrast, alcohol drinking did not increase SNO content or PP1 activity in nitric oxide synthase 3-deficient mice. S-nitrosoglutathione induced PP1-dependent CBF desensitization in mouse tracheal rings, cultured cells and isolated cilia. In vitro expression of mutant PP1 (cysteine 155 to alanine) in primary human airway epithelial cells prevented CBF desensitization after prolonged alcohol exposure compared to cells expressing WT PP1. Thus, redox modulation in the airways by alcohol is an important ciliary regulatory mechanism. Pharmacologic strategies to reduce S-nitrosation may enhance mucociliary clearance and reduce pneumonia prevalence, mortality and morbidity with AUD.


Arthrotomography of the glenoid labrum in shoulder instability.
Instability of the shoulder is a disabling problem which may be difficult to evaluate by routine radiographs. As detachment or absence of the labrum can lead to shoulder instability, arthrotomography of the glenoid labrum is a helpful adjunct in substantiating this diagnosis and in planning the choice of surgical reconstruction. We have found excellent correlation between the arthrotomographic findings and the glenohumeral lesion found at operation. Thirty-eight arthrotomograms of the glenoid labrum were performed in thirty-seven patients who had either shoulder pain or instability, or both. The patients were divided into three groups: those with painful subluxation (Group I), those with voluntary subluxation (Group II), and those with persistent shoulder pain (Group III). Twenty-five of the twenty-eight patients in Group I had an abnormality of the labrum shown on arthrotomography. All of the Group-II and Group-III patients had a normal labrum. There were no false-positive arthrotomograms in the eighteen patients in whom a lesion of the labrum subsequently was found at operation. Three patients with a normal labrum on arthrotomography underwent surgical exploration and no abnormalities were found.


Molecular Dissection of the Homotrimeric Sliding Clamp of T4 Phage: Two Domains of a Subunit Display Asymmetric Characteristics.
Sliding clamp proteins are circular dimers or trimers that encircle DNA and serve as processivity factors during DNA replication. Their presence in all the three domains of life and in bacteriophages clearly indicates their high level of significance. T4 gp45, besides functioning as the DNA polymerase processivity factor, also moonlights as the late promoter transcription determinant. Here we report a detailed biophysical analysis of gp45. The chemical denaturation of gp45 probed by circular dichroism spectroscopy, tryptophan fluorescence anisotropy, and blue-native polyacrylamide gel electrophoresis suggests that the protein follows a three-state denaturation profile and displays an intermediate molten globule-like state. The three-state transition was found to be the result of the sequential unfolding of the two domains, the N-terminal domain (NTD) and the C-terminal domain (CTD), of gp45. The experiments involving Trp fluorescence quenching by acrylamide demonstrate that the CTD undergoes substantial changes in conformation during formation of the intermediate state. Further biophysical dissection of the individual domain reveals contrasting properties of the two domains. The NTD unfolds at low urea concentrations and is also susceptible to protease cleavage, whereas the CTD resists urea-mediated denaturation and is not amenable to protease digestion even at higher urea concentrations. These experiments allow us to conclude that the two domains of gp45 differ in their dynamics. While the CTD shows stability and rigidity, we find that the NTD is unstable and flexible. We believe that the asymmetric characteristics of the two domains and the interface they form hold significance in gp45 structure and function.


Single and mixed infections of neonatal pigs with rotaviruses and enteroviruses: clinical signs and microscopic lesions.
Neonatal colostrum-deprived pigs were inoculated with cell-culture preparations of three rotaviruses and three enteroviruses, singly or in combination. The three enteroviruses established intestinal and systemic infection but did not induce diarrhea or intestinal lesions. The three rotaviruses produced severe enteric disease characterized by profuse watery diarrhea, dehydration and death. Villi were severely stunted. All three isolates were equally virulent. Inoculation with three different rotavirus-enterovirus combinations resulted in disease less severe than that produced by the rotaviruses alone. Intestinal lesions were less extensive and fewer pigs became moribund or died.


Initial single-center experience with levosimendan infusion for perioperative management of univentricular heart with ductal-dependent systemic circulation.
The aim of this study was to evaluate the safety and the efficacy of levosimendan, a novel calcium sensitizer agent, on postoperative hemodynamic and metabolic parameters of neonates affected by single ventricle anatomy. Twenty consecutive neonates scheduled for the Norwood procedure with Blalock Taussig shunt were prospectively enrolled. All patients received an infusion of levosimendan at 0.1 μg/kg/min commencing 24 hours before surgery, and the infusion was continued for 48 hours after surgery. No side effects (intolerance to the drug, hypotension, arrhythmias) were shown. A median inotropic score (IS) of 37 was necessary to maintain a mean arterial pressure between 45 and 50 mm Hg at intensive care unit (ICU) admission: IS was significantly reduced after 72 hours (P < .05). Brain natriuretic peptide values decreased significantly from 1210 to 459 pg/mL in 72 hours (P < .05). Median SvO2 increased significantly from 38% to 59% during the evaluated period (P < .05). Cerebral near-infrared spectroscopy values were close to 40% at ICU admission with a significant stable increase to 50% after 12 hours (P < .05). Median lactate level was 13 mmol/L at ICU admission but showed a trend to a rapid and significant decrease after 12 hours (P < .05). Median urine output was surprisingly elevated, always remaining between 5.2 and 6.2 mL/kg/h throughout the postoperative period. Survival rate was 85% at 30 days (17/20 patients) and 75% (15/20) at hospital discharge. Levosimendan infusion in a cohort of neonates with univentricular anatomy was safe and potentially beneficial on postoperative hemodynamic and metabolic parameters.


Tobacco imagery on prime time UK television.
Smoking in films is a common and well documented cause of youth smoking experimentation and uptake and hence a significant health hazard. The extent of exposure of young people to tobacco imagery in television programming has to date been far less investigated. We have therefore measured the extent to which tobacco content occurs in prime time UK television, and estimated exposure of UK youth. The occurrence of tobacco, categorised as actual tobacco use, implied tobacco use, tobacco paraphernalia, other reference to tobacco, tobacco brand appearances or any of these, occurring in all prime time broadcasting on the five most popularly viewed UK television stations during 3 separate weeks in 2010 were measured by 1-minute interval coding. Youth exposure to tobacco content in the UK was estimated using media viewing figures. Actual tobacco use, predominantly cigarette smoking, occurred in 73 of 613 (12%) programmes, particularly in feature films and reality TV. Brand appearances were rare, occurring in only 18 programmes, of which 12 were news or other factual genres, and 6 were episodes of the same British soap opera. Tobacco occurred with similar frequency before as after 21:00, the UK watershed for programmes suitable for youth. The estimated number of incidences of exposure of the audience aged less than 18 years for any tobacco, actual tobacco use and tobacco branding were 59 million, 16 million and 3 million, respectively on average per week. Television programming is a source of significant exposure of youth to tobacco imagery, before and after the watershed. Tobacco branding is particularly common in Coronation Street, a soap opera popular among youth audiences. More stringent controls on tobacco in prime time television therefore have the potential to reduce the uptake of youth smoking in the UK.


Does encountering the facial nerve during surgical management of mandibular condylar process fractures increase the risk of facial nerve weakness? A systematic review and meta-regression analysis.
The purpose of this study was to identify whether the incidence of systematically identified or incidentally encountered facial nerve branches during dissection to approach condylar fractures increases risk of transient and/or permanent facial nerve weakness. A systematic review and meta-analysis were performed that included several databases with specific keywords, a reference search, and a manual search for suitable articles. The inclusion criteria were all clinical trials, with the aim of assessing the rate of facial nerve injuries when open reduction and internal fixation (ORIF) of condylar process fractures was performed using different surgical approaches. The articles had to have documented the number of encountered facial nerve branches during ORIF. The main outcome variable was transient and permanent facial nerve injury. The dependent variable was the event and/or number of encountered facial nerve branches during surgery, and how they were handled (i.e. dissected, retracted, etc.). A total of 1202 mandibular condylar fractures were enrolled in 29 studies. Rate of transient facial nerve injury (TFNI) was 11.3 % (136/1202). The number of facial nerve branches encountered intraoperatively was 543, namely buccal, marginal mandibular, zygomatic and temporal nerve branches. There was a significant correlation suggesting that there is a strong positive linear relationship between TFNI and encountered facial nerve branches (Coef = 0.1916, P = 0.001). There was no significant relationship between permanent facial nerve injury and encountered facial nerve branches (P = 0.808). TFNI was 4.3% and 18.7% for those studies expressly reporting that facial nerve branches were encountered incidentally without dissection and with dissection, respectively. For studies reporting deliberate and systematic facial nerve dissection, TFNI was 20.9%. Finally, studies that did not report any encounters of facial nerve branches, TFNI was 7.9 %. This meta-analysis demonstrated that manipulation of the facial nerve during different surgical approaches causes different incidences of facial nerve injury. The choice of surgical approach for a given fracture should take this into consideration.


Membranous or Hypermobile Stapes Footplate: A New Anatomic Site Resulting in Third Window Syndrome.
Objectives: To describe a potentially underappreciated pathology for post-traumatic persistent intractable dizziness and third window syndrome as well as the methods to diagnose and surgically manage this disorder. Study Design: Observational analytic case studies review at a tertiary care medical center. Methods: Patients suffering persistent dizziness following head trauma and demonstrating Tullio phenomena or Hennebert signs are included. All had reportedly normal otic capsules on high resolution temporal bone CT scans (CT). The gray-scale invert function was used to visualize the stapes footplate, which helped determine the diagnosis. Gray-scale inversion can be used to improve visualization of temporal bone anatomy and pathologic changes when diagnoses are in doubt. A search to check for the presence of perilymph leakage was performed in all cases. This was accomplished using intraoperative Valsalva maneuvers. Fat grafting of round and oval windows was performed. Results: Over an 11-year period between January 2009 and December 2019, 28 patients (33 ears) were treated. Follow-up with balance testing and audiograms were performed 6-8 weeks following surgery. Follow-up ranged from 6 months to 7 years. Prior to surgery all patients reported dizziness in response to loud sounds and/or barometric pressure changes. Seven out of 33 ears had demonstrable perilymph leakage into the middle ear; the rest (26 ears) appeared to have membranous or hypermobile stapes footplates. Membranous stapes footplates were better visualized using the invert function on CT. Thirteen patients had a fistula sign positive bilaterally while 15 had unilateral pathology. Twenty-four of the 28 patients (85.7%) showed both subjective and objective improvement following surgery. No patients suffered from a deterioration in hearing. Conclusions: A previously underappreciated membranous or hypermobile stapes footplate can occur following head trauma and can cause intractable dizziness typical of third window syndrome (TWS). Durable long term success can be achieved by utilizing fat graft patching of the round and oval windows. High resolution temporal bone CT scans using the gray-scale inversion (invert) function can assist in preoperative diagnosis.


The use of mobile devices for physical activity tracking in older adults' everyday life.
The tracking of one's own physical activity with mobile devices is a way of monitoring and motivating oneself to remain healthy. Older adults' general use of mobile devices for physical activity tracking has not yet been examined systematically. The study aimed to describe the use of physical activity trackers, smartwatches and smartphones, or tablets for tracking physical activity and to examine the reasons for the use of these technologies. Participants aged ≥50 years (N = 1013) living in Switzerland were interviewed in a telephone survey. To address the research questions, we calculated descriptive frequency distributions, tested for differences between groups, and performed logistic regression analyses. Descriptive and multivariate analyses showed that (a) 20.5% of participants used mobile devices for physical activity tracking; (b) men, younger individuals, those with a strong interest in new technology, and those who frequently exercised had a higher likelihood of using mobile devices for physical activity tracking; and (c) participants more often agreed with reasons for use relating to tracking physical activity and motivating oneself to remain healthy than they did with reasons relating to social factors. The study presented representative data about the actual use of mobile tracking technology in persons over 50 years of age. Today, mainly active and younger elderly (mostly men) with a high interest in technology are using tracking technologies. Results indicate a need for further studies on motivational and usability aspects regarding the use of mobile health tracking devices by older adults.


Clinical characteristics of familial and non-familial bipolar disorder.
To explore the clinical characteristics of familial and non-familial bipolar disorder. Twenty subjects with bipolar disorder, who also had a family history of bipolar disorder in a first degree relative, were matched for current age, age of first onset of bipolar disorder and gender with 20 subjects with bipolar disorder who had no family history of any psychiatric disorders in first or second degree relatives. Fourteen subjects in each group were female. The mean age at interview was 45.2 years and the mean age at first admission was 26 years. Although familial and non-familial probands had an equivalent number of illness episodes, familial probands were significantly more likely to experience mixed states as compared to non-familial probands. The latter experienced significantly more depressive episodes and had significantly higher neuroticism (N) scores on the Eysenck Personality Inventory (EPI; Eysenck H, Eysenck S. Manual of the Eysenck Personality Inventory. London: University of London Press, 1964.). If the results are replicated, they have important implications. For example, such data may aid decisions about the targeting of additional psychosocial interventions in high N score cases. Researchers will wish to investigate whether mixed states show a stronger association with early age of onset or family history of BD.


CRM1-dependent nuclear export of dengue virus type 2 NS5.
The dengue virus multidomain RNA polymerase NS5 has been observed in the nucleus in mammalian infected cell systems. We previously showed that NS5 nuclear localization is mediated by two nuclear targeting signals within the NS5 interdomain region that are recognized by distinct members of the importin superfamily of intracellular transporters. Intriguingly, we have recently found that NS5 also possesses the ability to be exported from the nucleus by the importin family member CRM1 (exportin 1) both in Vero cells transfected to express NS5, and in dengue virus type 2 infected Vero cells, based on use of the CRM1-specific inhibitor leptomycin B (LMB). LMB treatment of Vero cells resulted in increased nuclear accumulation in both systems, and interestingly in the latter, resulted in an alteration in the kinetics of virus production. Our results imply that subcellular trafficking of NS5 at particular times in the infectious cycle may be central to the kinetics of virus production; perturbing this trafficking may represent a viable approach to develop new antiviral therapeutics.


Human endothelial cell life extension by telomerase expression.
Normal human endothelial cells, like other somatic cells in culture, divide a limited number of times before entering a nondividing state called replicative senescence. Expression of the catalytic component of human telomerase, human telomerase reverse transcriptase (hTERT), extends the life span of human fibroblasts and retinal pigment epithelial cells beyond senescence without causing neoplastic transformation (Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C. P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., and Wright, W. E. (1998) Science 279, 349-352; Jiang, X., Jimenez, G., Chang, E., Frolkis, M., Kusler, B., Sage, M., Beeche, M., Bodnar, A., Wahl, G., Tlsty, T., and Chiu, C.-P. (1999) Nat. Genet. 21, 111-114). Here, we show that both human large vessel and microvascular endothelial cells also bypass replicative senescence after introduction of hTERT. For the first time, we report that hTERT expression in these life-extended vascular cells does not affect their differentiated and functional phenotype and that these cells maintain their angiogenic potential in vitro. Furthermore, hTERT(+) microvascular endothelial cells have normal karyotype, and hTERT(+) endothelial cell strains do not exhibit a transformed phenotype. Relative to parental cells at senescence, hTERT-expressing endothelial cells exhibit resistance to induction of apoptosis by a variety of different conditions. Such characteristics are highly desirable for designing vascular transplantation and gene therapy delivery systems in vivo.


A systematic review of disability awareness interventions for children and youth.
Children's lack of knowledge about disability can adversely impact their attitudes toward people with disabilities. The purpose of this study is to review the common elements of effective disability awareness interventions. A systematic review of disability awareness interventions for children and youth was conducted to assess the effective components of these interventions. Electronic searches were conducted using OVID, CENTRAL, PsychInfo, ERIC, Social Science Citation Index, GreyNET Scopus and Google Scholar. The inclusion criteria included (i) an intervention raising awareness about disability, (ii) school-age children with the average age between 5-19 years old, (iii) at least one measurable outcome focusing on knowledge about disability or attitudes towards and/or acceptance of people with a disability and (iv) published article or grey literature. Of the 1031 articles that were identified in the search, 42 met the criteria to be included in the review. We classified the disability awareness interventions into 5 broad types including (i) social contact, (ii) simulation, (iii) curriculum, (iv) multi-media curriculum and (v) multiple components. Thirty-four studies showed an improvement in attitudes towards and/or acceptance of peers with disabilities. Eight of these studies also demonstrated an improvement in knowledge of people with disabilities. Five of the interventions found no support for improving knowledge about, or acceptance of people with disabilities. Disability awareness interventions can successfully improve children's knowledge about and attitudes towards peers with a disability; they should include several different components over multiple sessions. These findings are being used to further develop disability awareness interventions to help improve the social inclusion and participation of children with disabilities within mainstream classrooms.


Whole-exome Sequencing Reveals New Potential Susceptibility Genes for Japanese Familial Pancreatic Cancer.
The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC. Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified. We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis. Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis. Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer.


N1-Src Kinase Is Required for Primary Neurogenesis in Xenopus tropicalis.
The presence of the neuronal-specific N1-Src splice variant of the C-Src tyrosine kinase is conserved through vertebrate evolution, suggesting an important role in complex nervous systems. Alternative splicing involving an N1-Src-specific microexon leads to a 5 or 6 aa insertion into the SH3 domain of Src. A prevailing model suggests that N1-Src regulates neuronal differentiation via cytoskeletal dynamics in the growth cone. Here we investigated the role of n1-src in the early development of the amphibian Xenopus tropicalis, and found that n1-src expression is regulated in embryogenesis, with highest levels detected during the phases of primary and secondary neurogenesis. In situ hybridization analysis, using locked nucleic acid oligo probes complementary to the n1-src microexon, indicates that n1-src expression is highly enriched in the open neural plate during neurula stages and in the neural tissue of adult frogs. Given the n1-src expression pattern, we investigated a possible role for n1-src in neurogenesis. Using splice site-specific antisense morpholino oligos, we inhibited n1-src splicing, while preserving c-src expression. Differentiation of neurons in the primary nervous system is reduced in n1-src-knockdown embryos, accompanied by a severely impaired touch response in later development. These data reveal an essential role for n1-src in amphibian neural development and suggest that alternative splicing of C-Src in the developing vertebrate nervous system evolved to regulate neurogenesis.SIGNIFICANCE STATEMENT The Src family of nonreceptor tyrosine kinases acts in signaling pathways that regulate cell migration, cell adhesion, and proliferation. Srcs are also enriched in the brain, where they play key roles in neuronal development and neurotransmission. Vertebrates have evolved a neuron-specific splice variant of C-Src, N1-Src, which differs from C-Src by just 5 or 6 aa. N1-Src is poorly understood and its high similarity to C-Src has made it difficult to delineate its function. Using antisense knockdown of the n1-src microexon, we have studied neuronal development in the Xenopus embryo in the absence of n1-src, while preserving c-src Loss of n1-src causes a striking absence of primary neurogenesis, implicating n1-src in the specification of neurons early in neural development.


Neurobiology of emotion perception II: Implications for major psychiatric disorders.
To date, there has been little investigation of the neurobiological basis of emotion processing abnormalities in psychiatric populations. We have previously discussed two neural systems: 1) a ventral system, including the amygdala, insula, ventral striatum, ventral anterior cingulate gyrus, and prefrontal cortex, for identification of the emotional significance of a stimulus, production of affective states, and automatic regulation of emotional responses; and 2) a dorsal system, including the hippocampus, dorsal anterior cingulate gyrus, and prefrontal cortex, for the effortful regulation of affective states and subsequent behavior. In this critical review, we have examined evidence from studies employing a variety of techniques for distinct patterns of structural and functional abnormalities in these neural systems in schizophrenia, bipolar disorder, and major depressive disorder. In each psychiatric disorder, the pattern of abnormalities may be associated with specific symptoms, including emotional flattening, anhedonia, and persecutory delusions in schizophrenia, prominent mood swings, emotional lability, and distractibility in bipolar disorder during depression and mania, and with depressed mood and anhedonia in major depressive disorder. We suggest that distinct patterns of structural and functional abnormalities in neural systems important for emotion processing are associated with specific symptoms of schizophrenia and bipolar and major depressive disorder.


Adjuvant Systemic Therapies for Resected Stages III and IV Melanoma: A Multi-Center Retrospective Clinical Study.
Adjuvant therapies have been approved for resected melanoma based on improved recurrence-free survival. We present early findings from a real-world study on adjuvant treatments for melanoma. A comprehensive chart review was conducted for patients receiving adjuvant systemic therapy for resected high-risk stages III and IV melanoma. Statistical analysis was performed to assess recurrence-free survival and subgroup differences. A total of 149 patients (median age = 58.0 years, 61.1% men, 49.7% with BRAF V600E/K genotypes) were included, with 94.6% having resected stage III melanoma. Anti-PD-1 immunotherapy was received by 86.5% of patients, while 13.4% received BRAF-targeted therapy. At a median follow-up of 22.4 months, the recurrence rate was 31.5%, with 1-year and 2-year recurrence-free survival rates of 79% and 62%, respectively. Similar recurrence rates were observed between anti-PD-1 immunotherapy and BRAF-targeted therapy. Long-term toxicity affected 27.4% of patients, with endocrinopathies and late-emergent immune-related adverse events being common. Real-world adjuvant systemic therapy aligns with clinical trial practice. Recurrence rates remain high despite treatment, and long-term toxicities, including endocrinopathies and chronic inflammatory conditions, are not uncommon.


The Neurally Controlled Animat: Biological Brains Acting with Simulated Bodies.
The brain is perhaps the most advanced and robust computation system known. We are creating a method to study how information is processed and encoded in living cultured neuronal networks by interfacing them to a computer-generated animal, the Neurally-Controlled Animat, within a virtual world. Cortical neurons from rats are dissociated and cultured on a surface containing a grid of electrodes (multi-electrode arrays, or MEAs) capable of both recording and stimulating neural activity. Distributed patterns of neural activity are used to control the behavior of the Animat in a simulated environment. The computer acts as its sensory system providing electrical feedback to the network about the Animat's movement within its environment. Changes in the Animat's behavior due to interaction with its surroundings are studied in concert with the biological processes (e.g., neural plasticity) that produced those changes, to understand how information is processed and encoded within a living neural network. Thus, we have created a hybrid real-time processing engine and control system that consists of living, electronic, and simulated components. Eventually this approach may be applied to controlling robotic devices, or lead to better real-time silicon-based information processing and control algorithms that are fault tolerant and can repair themselves.


Budget Impact Analysis of Switching to Rituximab's Biosimilar in Rheumatology and Cancer in 13 Countries Within the Middle East and North Africa.
Biosimilars of monoclonal antibodies are being rapidly developed and approved by public health regulatory authorities worldwide. These biosimilars are expected to bring significant budgetary savings to national governments and consequently increase patients' accessibility to biological therapy. Rituximab has been used extensively for the treatment of cancer and rheumatoid disorders over the past two decades. New biosimilars of Rituximab have been developed and introduced into clinical practice. We have analyzed the budgetary impact and savings outcome of introducing Rituximab's biosimilar into 13 countries within the Middle East and North Africa through the implementation of a budget impact analysis model. Our model was based on a 1-year full uptake and switch scenario of the Rituximab's biosimilar CT-P10. The model calculated the total number of patients based on the total national consumption of Rituximab per country. Accordingly, the model produced savings per each indication which were translated into the additional number of patients that would be permitted access to Rituximab's therapy as a result of these savings. In our modeling scenario, the total projected savings that will result from the uptake of Rituximab's biosimilar within the MENA region were estimated to be 46.59 million dollars. The cumulative savings in all 13 countries would allow access of Rituximab's therapy for a total of 6589 patients which is equivalent to a 14% increase in the number of patients benefiting from Rituximab's therapy. The introduction of Rituximab's biosimilar within the Middle East and North Africa region is associated with significant budgetary savings that will allow public national health authorities to reinvest such economic gains either in expanding access to Rituximab therapy or other costly lifesaving biologicals.


Nuclear diameters of breast cancer cells in tissue sections.
Nuclear diameters of breast cancer cells were measured on tissue sections in 100 cases. Processing the tissues for histology caused significant shrinkage and distortion of structures. Comparison between nuclear diameters measured on cytologic specimens and those measured on tissue sections must take into account a correction factor of 1.55 x. "Small nuclei only" were not found; in 19% of the tumors a "small nuclear type predominance" was evident. Twelve percent of the cases fell into the category of "more than 30% large nuclei" according to the cytologic criteria corrected for tissue sections. The importance of the correction factor is emphasized.


Secretion of tumor necrosis factor-alpha by mouse peritoneal macrophages in the presence of dental sealers, sealapex and endomethasone.
After filling root canals, the healing process depends on the chemical composition or physical-chemical properties of the material used, among other factors. All root canal sealers, whether solid or plastic, are foreign matter for the body if they remain in permanent contact with apical and periapical tissues. As a result, the first organic reaction that occurs is an attempt to phagocytize the material. During phagocytosis, macrophages release a large number of cell mediators into the area, among which are cytokines that are essential in intercellular communication and in many physiological and pathophysiological processes. One of these cytokines is tumor necrosis factor-alpha (TNF-alpha), which acts through links to specific receptors on the cell membrane initiating a cascade of events leading to induction, activation, or inhibition of numerous cytokine-regulated genes in the cell nucleus. The release of TNF-alpha in a cell culture of mouse peritoneal macrophages incubated with three concentrations (25, 50, and 100 mg/ml) of two endodontic sealers was measured. The solutions containing the calcium hydroxide-based root canal sealer (Sealapex) released fewer units of TNF-alpha than solutions containing the zinc oxide and eugenol-based sealer (Endomethasone).