Boron-doped peroxo-zirconium oxide dielectric for high-performance, low-temperature, solution-processed indium oxide thin-film transistor.
We developed a solution-processed indium oxide (In2O3) thin-film transistor (TFT) with a boron-doped peroxo-zirconium (ZrO2:B) dielectric on silicon as well as polyimide substrate at 200 °C, using water as the solvent for the In2O3 precursor. The formation of In2O3 and ZrO2:B films were intensively studied by thermogravimetric differential thermal analysis (TG-DTA), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FT IR), high-resolution X-ray diffraction (HR-XRD), and X-ray photoelectron spectroscopy (XPS). Boron was selected as a dopant to make a denser ZrO2 film. The ZrO2:B film effectively blocked the leakage current at 200 °C with high breakdown strength. To evaluate the ZrO2:B film as a gate dielectric, we fabricated In2O3 TFTs on the ZrO2:B dielectrics with silicon substrates and annealed the resulting samples at 200 and 250 °C. The resulting mobilities were 1.25 and 39.3 cm(2)/(V s), respectively. Finally, we realized a flexible In2O3 TFT with the ZrO2:B dielectric on a polyimide substrate at 200 °C, and it successfully operated a switching device with a mobility of 4.01 cm(2)/(V s). Our results suggest that aqueous solution-processed In2O3 TFTs on ZrO2:B dielectrics could potentially be used for low-cost, low-temperature, and high-performance flexible devices.


Health related quality of life after extremely preterm birth: a matched controlled cohort study.
The majority of infants born before the last trimester now grow up. However, knowledge on subsequent health related quality of life (HRQoL) is scarce. We therefore aimed to compare HRQoL in children born extremely preterm with control children born at term. Furthermore, we assessed HRQoL in relation to perinatal and neonatal morbidity and to current clinical and sociodemographic characteristics. The Child Health Questionnaire (CHQ-PF50) and a general questionnaire were applied in a population based cohort of 10 year old children born at gestational age < or = 28 weeks or with birth weight < or = 1000 grams in Western Norway in 1991-92 and in term-born controls, individually matched for gender and time of birth. The McNemar test and paired t-tests were used to explore group differences between preterms and matched controls. Paired regression models and analyses of interaction (SPSS mixed linear model) were used to explore potential effects of sociodemographic and clinical characteristics on HRQoL in the two groups. All 35 eligible preterm children participated. None had major impairments. Learning and/or attention problems were present in 71% of preterms and 20% of controls (odds ratio (OR): 7.0; 95% confidence interval (CI): 2.2 to 27.6). Insufficient professional support was described by 36% of preterm vs. 3% of control parents (OR: infinite; CI: 2.7 to infinite). Preterms scored lower on eight CHQ-PF50 sub-scales and the two summary scores, boys accounting for most of the deficits in areas of behavior, psychosocial functioning and parental burden. HRQoL was associated with learning and/or attention problems in both preterm and control children, significantly more so in preterms in areas related to health and parental burden. Within the preterm group, HRQoL was mostly unrelated to perinatal and neonatal morbidity. HRQoL for children born extremely preterm, and particularly for boys, was described by parents to be inferior to that of children born at term, and sufficiently poor to affect the daily life of the children and their families. Learning and/or attention problems were reported for a majority of preterms, strongly influencing their HRQoL.


Spectral irradiance model for tungsten halogen lamps in 340-850 nm wavelength range.
We have developed a physical model for the spectral irradiance of 1 kW tungsten halogen incandescent lamps for the wavelength range 340-850 nm. The model consists of the Planck's radiation law, published values for the emissivity of tungsten, and a residual spectral correction function taking into account unknown factors of the lamp. The correction function was determined by measuring the spectra of a 1000 W, quartz-halogen, tungsten coiled filament (FEL) lamp at different temperatures. The new model was tested with lamps of types FEL and 1000 W, 120 V quartz halogen (DXW). Comparisons with measurements of two national standards laboratories indicate that the model can account for the spectral irradiance values of lamps with an agreement better than 1% throughout the spectral region studied. We further demonstrate that the spectral irradiance of a lamp can be predicted with an expanded uncertainty of 2.6% if the color temperature and illuminance values for the lamp are known with expanded uncertainties of 20 K and 2%, respectively. In addition, it is suggested that the spectral irradiance may be derived from resistance measurements of the filament with lamp on and off.


Is a Blanket Elective Single Embryo Transfer Policy Defensible?
For the purpose of reducing maternal and neonatal morbidity, elective single transfer (eSET) in in vitro fertilization (IVF) was first proposed in 1999. The purpose of this review is to summarize recent oral debate between a proponent and an opponent of expanded eSET utilization in an attempt to determine whether a blanket eSET policy, as is increasingly considered, is defensible. While eSET is preferable when possible, and agreed upon by provider and patient, selective double embryo transfer (DET) must be seriously entertained if deemed more appropriate or is desired by the patient. Patient autonomy, let alone prolonged infertility and advancing age, demand nothing less. Importantly, IVF-generated twins represent only 15.7% of the national twin birth rate in the United States. Non-IVF fertility treatments have been identified as the main cause of all multiple births for quite some time. However, educational and regulatory efforts over the last decade, paradoxically, have exclusively only been directed at the practice of IVF, although IVF patient populations are rapidly aging. It is difficult to understand why non-IVF fertility treatments, usually applied to younger women, have so far escaped attention. This debate on eSET utilization in association with IVF may contribute to a redirection of priorities.


Using mobile phone text messaging for malaria surveillance in rural Kenya.
Effective surveillance systems are required to track malaria testing and treatment practices. A 26-week study "SMS for Life" was piloted in five rural districts of Kenya to examine whether SMS reported surveillance data could ensure real-time visibility of accurate data and their use by district managers to impact on malaria case-management. Health workers from 87 public health facilities used their personal mobile phones to send a weekly structured SMS text message reporting the counts of four basic surveillance data elements to a web-based system accessed by district managers. Longitudinal monitoring of SMS reported data through the web-based system and two rounds of cross-sectional health facility surveys were done to validate accuracy of data. Mean response rates were 96% with 87% of facilities reporting on time. Fifty-eight per cent of surveillance data parameters were accurately reported. Overall mean testing rates were 37% with minor weekly variations ranging from 32 to 45%. Overall test positivity rate was 24% (weekly range: 17-37%). Ratio of anti-malarial treatments to test positive cases was 1.7:1 (weekly range: 1.3:1-2.2:1). District specific trends showed fluctuating patterns in testing rates without notable improvement over time but the ratio of anti-malarial treatments to test positive cases improved over short periods of time in three out of five districts. The study demonstrated the feasibility of using simple mobile phone text messages to transmit timely surveillance data from peripheral health facilities to higher levels. However, accuracy of data reported was suboptimal. Future work should focus on improving quality of SMS reported surveillance data.


Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.
Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.


Effects of polyethylene glycol and a synthetic ice blocker during vitrification of immature porcine oocytes on survival and subsequent embryo development.
We evaluated the effects of polyethylene glycol (PEG) and Supercool X-1000 (SC) as supplements during the vitrification of immature cumulus-enclosed porcine oocytes in a solution based on 17.5% ethylene glycol + 17.5% propylene glycol. After warming, the oocytes were subjected to in vitro maturation, fertilization and embryo culture. In Experiment 1, equilibration and vitrification solutions were supplemented with or without 2% (w/v) PEG (PEG+ and PEG-, respectively). The survival rate, cleavage and blastocyst development were similar between PEG+ and PEG- groups; however, all values were lower than those in the non-vitrified control. In Experiment 2, vitrification solution was supplemented with or without 1% (v/v) SC (SC+ and SC-, respectively). The percentages of survival and blastocyst development were similar between SC+ and SC- groups but lower than those in the non-vitrified control. The percentage of cleavage in the SC- group was significantly lower than the control and the SC+ groups, which were in turn similar to one another. In both experiments, the cell numbers in blastocysts were not significantly different among the non-vitrified and vitrified groups. In conclusion, PEG did not improve oocyte survival and embryo development, whereas SC improved the ability of surviving oocytes to cleave but not to develop into blastocysts.


Overvalued ideation in adolescents with obsessive-compulsive disorder.
In Obsessive Compulsive Disorder (OCD), overvalued ideas (OVI) are considered poor prognostic indicators in adults. To date, OVI has not been studied in an adolescent population with OCD, nor has it been examined in relation to obsessive-compulsive beliefs. To investigate the relationship between OVI and specific cognitions, fifty-five adolescents with OCD (35 male; 20 female; age range 13-17 years; M=14.05 years, SD=1.75 years) participated. It was predicted that OVI would be associated with symptom severity and would moderate obsessive-compulsive beliefs and functional disability. Results showed that OVI was associated with symptom severity, but did not moderate the relationship with any OC beliefs or functional domains. To evaluate the role of OVI in treatment outcome, thirteen adolescents completed a cognitive-behavioral treatment program. Severity of their OCD symptoms, OVI, degree of functional impairment and quality of life were assessed. It was expected that all variables would change in response to treatment. Further, it was expected that OVI would mediate treatment outcome for all measures of obsessive-compulsive symptom and belief assessments. Results indicated that there was clinically significant change in symptom severity and functional disability, as well as beliefs regarding responsibility/overestimation of threat. Treatment, assessment, and methodological recommendations for this population are offered.


Treatment with higher dosages of heart failure medication is associated with improved outcome following cardiac resynchronization therapy.
Cardiac resynchronization therapy (CRT) is associated with improved morbidity and mortality in patients with chronic heart failure (CHF) on optimal medical therapy. The impact of CHF medication optimization following CRT, however, has never been comprehensively evaluated. In the current study, we therefore investigated the effect of CHF medication dosage on morbidity and mortality in CHF patients after CRT implantation. Chronic heart failure medication was assessed in 185 patients after CRT implantation. During an overall mean follow-up of 44.6 months, 83 patients experienced a primary endpoint (death, heart transplantation, assist device implantation, or hospitalization for CHF). Treatment with higher dosages of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blockers (ARBs) (P = 0.001) and beta-blockers (P < 0.001) as well as with lower dosages of loop diuretics (P < 0.001) was associated with a reduced risk for the primary combined endpoint as well as for all-cause mortality. Echocardiographic super-responders to CRT were treated with higher average dosages of ACE-I/ARBs (68.1 vs. 52.4%, P < 0.01) and beta-blockers (59 vs. 42.2%, P < 0.01). During follow-up, the average dosage of loop diuretics was decreased by 20% in super-responders, but increased by 30% in non-super-responders (P < 0.03). The use of higher dosages of neurohormonal blockers and lower dosages of diuretics is associated with reduced morbidity and mortality following CRT implantation. Our data imply a beneficial effect of increasing neurohormonal blockade whenever possible following CRT implantation.


Histone H3 K36 methylation is mediated by a trans-histone methylation pathway involving an interaction between Set2 and histone H4.
Set2-mediated H3 K36 methylation is an important histone modification on chromatin during transcription elongation. Although Set2 associates with the phosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII), the mechanism of Set2 binding to chromatin and subsequent exertion of its methyltransferase activity is relatively uncharacterized. We identified a critical lysine residue in histone H4 that is needed for interaction with Set2 and proper H3 K36 di- and trimethylation. We also determined that the N terminus of Set2 contains a histone H4 interaction motif that allows Set2 to bind histone H4 and nucleosomes. A Set2 mutant lacking the histone H4 interaction motif is able to bind to the phosphorylated CTD of RNAPII and associate with gene-specific loci but is defective for H3 K36 di- and trimethylation. In addition, this Set2 mutant shows increased H4 acetylation and resistance to 6-Azauracil. Overall, our study defines a new interaction between Set2 and histone H4 that mediates trans-histone regulation of H3 K36 methylation, which is needed for the preventative maintenance and integrity of the genome.


Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea.
During development, Sox2 is indispensable for cell division and differentiation, yet its roles in regenerating tissues are less clear. Here, we used combinations of transgenic mouse models to reveal that Sox2 haploinsufficiency (Sox2haplo) increases rather than impairs cochlear regeneration in vivo. Sox2haplo cochleae had delayed terminal mitosis and ectopic sensory cells, yet normal auditory function. Sox2haplo amplified and expanded domains of damage-induced Atoh1+ transitional cell formation in neonatal cochlea. Wnt activation via β-catenin stabilization (β-cateninGOF) alone failed to induce proliferation or transitional cell formation. By contrast, β-cateninGOF caused proliferation when either Sox2haplo or damage was present, and transitional cell formation when both were present in neonatal, but not mature, cochlea. Mechanistically, Sox2haplo or damaged neonatal cochleae showed lower levels of Sox2 and Hes5, but not of Wnt target genes. Together, our study unveils an interplay between Sox2 and damage in directing tissue regeneration and Wnt responsiveness and thus provides a foundation for potential combinatorial therapies aimed at stimulating mammalian cochlear regeneration to reverse hearing loss in humans.


Adherence to highly active antiretroviral treatment in HIV-infected Rwandan women.
Scale-up of highly active antiretroviral treatment therapy (HAART) programs in Rwanda has been highly successful but data on adherence is limited. We examined HAART adherence in a large cohort of HIV+ Rwandan women. The Rwanda Women's Interassociation Study Assessment (RWISA) was a prospective cohort study that assessed effectiveness and toxicity of ART. We analyzed patient data 12±3 months after HAART initiation to determine adherence rates in HIV+ women who had initiated HAART. Of the 710 HIV+ women at baseline, 490 (87.2%) initiated HAART. Of these, 6 (1.2%) died within 12 months, 15 others (3.0%) discontinued the study and 80 others (19.0%) remained in RWISA but did not have a post-HAART initiation visit that fell within the 12±3 month time points leaving 389 subjects for analysis. Of these 389, 15 women stopped their medications without being advised to do so by their doctors. Of the remaining 374 persons who reported current HAART use 354 completed the adherence assessment. All women, 354/354, reported 100% adherence to HAART at the post-HAART visit. The high self-reported level of adherence is supported by changes in laboratory measures that are influenced by HAART. The median (interquartile range) CD4 cell count measured within 6 months prior to HAART initiation was 185 (128, 253) compared to 264 (182, 380) cells/mm(3) at the post-HAART visit. Similarly, the median (interquartile range) MCV within 6 months prior to HAART initiation was 88 (83, 93) fL compared to 104 (98, 110) fL at the 12±3 month visit. Self-reported adherence to antiretroviral treatment 12±3 months after initiating therapy was 100% in this cohort of HIV-infected Rwandan women. Future studies should explore country-specific factors that may be contributing to high levels of adherence to HAART in this population.


Molecular cloning and chromosomal localization of the mouse decay-accelerating factor genes. Duplicated genes encode glycosylphosphatidylinositol-anchored and transmembrane forms.
Regulation of complement activation is essential in the prevention of damage to autologous tissue. This activity is mediated by the presence of specific complement regulatory proteins on the surface of host cells. In humans, one molecule involved in this regulation is a 70-kDa glycoprotein that has been designated decay-accelerating factor (DAF). We present the full-length cDNA sequence and chromosomal localization of the mouse genetic homologue of the human DAF gene. Interestingly, two classes of cDNA clones were obtained that, rather than representing alternately spliced mRNAs, were derived from two separate but closely related linked genes. Both genes encoded proteins with an amino-terminal signal sequence, followed by four short consensus repeats and a domain rich in serine and threonine. Hydrophilicity plots and alignment with human DAF predicted that one gene encoded a glycosylphosphatidylinositol-anchored form of mouse Daf with 64% nucleotide and 47% amino acid identity to human DAF. The product encoded by the second gene was predicted to have an alternate amino-terminal signal sequence and carboxyl-terminal membrane-spanning and cytoplasmic domains. The two mouse Daf genes share 85% nucleotide and 78% amino acid identities, and have been designated Daf-glycosylphosphatidylinositol and Daf-transmembrane to reflect the two alternate mechanisms of membrane attachment. mRNA expression analysis indicated that the two mouse Daf genes were differentially expressed in the adult mouse. Chromosome localization studies mapped the mouse Daf genes to chromosome 1, where they segregated with the C4-binding protein (C4bp) gene.


Acteoside suppresses RANKL-mediated osteoclastogenesis by inhibiting c-Fos induction and NF-κB pathway and attenuating ROS production.
Numerous studies have reported that inflammatory cytokines are important mediators for osteoclastogenesis, thereby causing excessive bone resorption and osteoporosis. Acteoside, the main active compound of Rehmannia glutinosa, which is used widely in traditional Oriental medicine, has anti-inflammatory and antioxidant potentials. In this study, we found that acteoside markedly inhibited osteoclast differentiation and formation from bone marrow macrophages (BMMs) and RAW264.7 macrophages stimulated by the receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL). Acteoside pretreatment also prevented bone resorption by mature osteoclasts in a dose-dependent manner. Acteoside (10 µM) attenuated RANKL-stimulated activation of p38 kinase, extracellular signal-regulated kinases, and c-Jun N-terminal kinase, and also suppressed NF-κB activation by inhibiting phosphorylation of the p65 subunit and the inhibitor κBα. In addition, RANKL-mediated increases in the expression of c-Fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and in the production of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 were apparently inhibited by acteoside pretreatment. Further, oral acteoside reduced ovariectomy-induced bone loss and inflammatory cytokine production to control levels. Our data suggest that acteoside inhibits osteoclast differentiation and maturation from osteoclastic precursors by suppressing RANKL-induced activation of mitogen-activated protein kinases and transcription factors such as NF-κB, c-Fos, and NFATc1. Collectively, these results suggest that acteoside may act as an anti-resorptive agent to reduce bone loss by blocking osteoclast activation.


Marrow culture in diffusion chambers in rabbits. II. Effect of competing demands for red cell and white cell production on cell growth.
Studies were done of cell production by marrow in diffusion chambers implanted in the peritoneal cavity of rabbits subjected to various stimuli to hematopoiesis. In chambers in neutropenic hosts and in hosts injected with endotoxin, animals presumed to have an increased stimulus to granulopoiesis, there was increased production of granulocytes but there was also increased production of red cells. Although red cell production was decreased in chambers in polycythemic hosts, granulocyte production was not different from that in controls. Stimulation of erythropoiesis by erythropoietin injections or by exposure to hypoxia increased red cell production by marrow in the implanted diffusion chambers without diminishing granulopoiesis. Only in chambers in hosts made anemic by bleeding was there an increase in red cell production accompanied by a decrease in granulocyte production. In these anemic hosts induction of neutropenia led to an increase in granulopoiesis without any depression of erythropoiesis.


Estimating drug consumption during a college sporting event from wastewater using liquid chromatography mass spectrometry.
Consumption of licit and/or illicit compounds during sporting events has traditionally been monitored using population surveys, medical records, and law enforcement seizure data. This pilot study evaluated the temporal and geospatial patterns in drug consumption during a university football game from wastewater using liquid chromatography tandem mass spectrometry (LC-MS/MS). Untreated wastewater samples were collected from three locations within or near the same football stadium every 30 min during a university football game. This analysis leveraged two LCMS/ MS instruments (Waters Acquity TQD and a Shimadzu 8040) to analyze samples for 58 licit or illicit compounds and some of their metabolites. Bayesian multilevel models were implemented to estimate mass load and population-level drug consumption, while accounting for multiple instrument runs and concentrations censored at the lower limit of quantitation. Overall, 29 compounds were detected in at least one wastewater sample collected during the game. The 10 most common compounds included opioids, anorectics, stimulants, and decongestants. For compounds detected in more than 50% of samples, temporal trends in median mass load were correlated with the timing of the game; peak loads for cocaine and tramadol occurred during the first quarter of the game and for phentermine during the third quarter. Stadium-wide estimates of the number of doses of drugs consumed were rank ordered as follows: oxycodone (n = 3246) > hydrocodone (n = 2260) > phentermine (n = 513) > cocaine (n = 415) > amphetamine (n = 372) > tramadol (n = 360) > pseudoephedrine (n = 324). This analysis represents the most comprehensive assessment of drug consumption during a university football game and indicates that wastewater-based epidemiology has potential to inform public health interventions focused on reducing recreational drug consumption during large-scale sporting events.


Increasing trees and high-albedo surfaces decreases heat impacts and mortality in Los Angeles, CA.
There is a pressing need for strategies to prevent the heat-health impacts of climate change. Cooling urban areas through adding trees and vegetation and increasing solar reflectance of roofs and pavements with higher albedo surface materials are recommended strategies for mitigating the urban heat island. We quantified how various tree cover and albedo scenarios would impact heat-related mortality, temperature, humidity, and oppressive air masses in Los Angeles, California, and quantified the number of years that climate change-induced warming could be delayed in Los Angeles if interventions were implemented. Using synoptic climatology, we used meteorological data for historical summer heat waves, classifying days into discrete air mass types. We analyzed those data against historical mortality data to determine excess heat-related mortality. We then used the Weather Research and Forecasting model to explore the effects that tree cover and albedo scenarios would have, correlating the resultant meteorological data with standardized mortality data algorithms to quantify potential reductions in mortality. We found that roughly one in four lives currently lost during heat waves could be saved. We also found that climate change-induced warming could be delayed approximately 40-70 years under business-as-usual and moderate mitigation scenarios, respectively.


Psychiatric disorders certified on death certificates in an English population.
Psychiatric disorders are sometimes certified on death certificates, but seldom selected as the underlying cause of death. The majority of deaths with a certified psychiatric cause are usually omitted from official mortality statistics, which are typically based on the underlying cause alone. To report on death rates for psychiatric disorders, as certified on death certificates, including all mentioned causes as well as the underlying cause of death. Analysis of database including all certified causes of death in 1979-1999, in three time periods defined by coding rule changes. Statistics on the underlying cause of death grossly under-estimated certified psychiatric disorders. For example, in the first period of our study they missed 88% of deaths in which schizophrenia was a certified cause, 98% of affective psychosis, and 96% of depression. Over time, considering all certified causes, age-standardised death rates for schizophrenia declined, those for affective psychosis showed no change, and those for depression and dementia increased. The decline in mortality rates for schizophrenia, and the increase for depression and dementia, may reflect real changes over time in disease prevalence at death, although other explanations are possible and are discussed.


A rapid and simple method for the quantitative determination of tolerance development to opiates in the guinea-pig ileum in vitro.
The rate and degree of tolerance development of morphine, normorphine and methadone were assessed in vitro on the guinea-pig ileum. After the half-maximal concentration to inhibit electrically induced contractions (IC50) for each compound was determined, tolerance to a fixed concentration representing 0.5, 1 or 2 times its IC50 was induced by incubation at 37 degrees C for 1, 2 or 4 hr. The IC50 was then redetermined and the ratio of the IC50 after and before incubation provided a quantitative index of the degree of tolerance development to each agonist. For any given concentration or time, morphine induced the highest, whereas normorphine the intermediate and methadone the lowest degree of tolerance. Tolerance to opiates was associated with some degree of physical dependence as evidenced by the fact that the application of naloxone at the end of each experiment elicited a muscular contraction. Specificity of tolerance development to opiates was demonstrated by several experiments. Coincubation of morphine with naloxone under the same conditions resulted in an inhibition of tolerance development. The stereospecificity of the process was demonstrated by the fact that levorphanol and I-methadone induced a high degree of tolerance, whereas, under the same conditions the less active d-isomers, dextrorphan and d-methadone, did not. Moreover, subsensitivity to acetylcholine, norepinephrine and adenosine monophosphate did not develop in the presence of tolerance to morphine. The validity of this method for investigating mechanisms involved in tolerance and physical dependence was further demonstrated by obtaining data compatible with earlier experiments in vivo that cyclic AMP enhances tolerance development and cycloheximide inhibits this phenomenon. The present method should facilitate studies on the mechanisms involved in opiate tolerance and physical dependence development.


Impact of regulatory changes on first- and second-generation antipsychotic drug consumption and expenditure in Italy.
In 1994 a change in drug reimbursement status was implemented in Italy according to cost-effectiveness criteria. The aim of this study was to examine the impact of these changes on the use of antipsychotic (AP) drugs. Data concerning actual quantities of antipsychotic agents dispensed in Italy from 1995 to June 2003 were obtained from the Italian Ministry of Health. For each antipsychotic agent, the number of defined daily doses (DDDs) per 1,000 inhabitants per day was calculated, as well as the annual expenditure in Euros. From 1995 to June 2003 prescriptions for first-generation antipsychotic agents (FGAs) progressively decreased from 2.54 to 2.0 DDD/1,000/day; in contrast, prescriptions for second-generation antipsychotic agents (SGAs) progressively rose up to 1.75 DDD/1,000/day in 2003. Overall, from 1995 to 2003 antipsychotic prescriptions rose from 2.54 to 3.75 DDD/1,000/day. In 2003 the antipsychotic drug most frequently used was haloperidol, followed by olanzapine and risperidone. In 2003 the use of SGAs accounted for nearly 50% of overall DDD/1,000/day of AP agents. The cost of these new drugs, however, accounted for more than 80% of the total AP expenditure. In Italy, the progressive increase in the utilisation of SGAs has been accompanied by a moderate decrease in the utilisation of phenothiazines and by an almost constant use of butyrophenones. The policy of reimbursing the use of SGAs only in subjects who could not tolerate FGAs eventually failed to significantly affect the pattern of antipsychotic consumption and expenditure; moreover, when this policy was eliminated at the beginning of 2001, the pattern of consumption and expenditure did not change.


Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE).
To disclose the mechanism of aberrant function of peripheral blood lymphocytes (PBL) in SLE, we focused on the catalytic function of CD45, and determined the CD45 PTPase activity in SLE patients. The sample population consisted of 32 SLE patients with different disease activity. PTPase activity of cell lysates immunoprecipitated by anti-CD45 MoAb was assayed against phosphotyrosine analogue PNPP, followed by measuring the release of para-nitro phenol at 410 nm. CD45 PTPase activity of PBL was significantly decreased in SLE patients, compared with that of normal controls and patients with systemic sclerosis (964 +/- 265, 1202 +/- 172, 1210 +/- 125, respectively; SLE versus normal, P<0.05). It was correlated with SLE Disease Activity Index (SLEDAI) score (r = 0.597, P = 0.0006), but not with the dose of prednisolone (r = 0.214, P = 0.2657), indicating that CD45 PTPase activity became reduced when the disease was active, but it was not affected by prednisolone. Moreover, it was not corrected by in vitro culture with or without stimulation. The expression of CD45 on PBL was comparable between normal and SLE, raising a possibility that it may be due to aberrant regulation of catalytic function of CD45 in SLE. Given the evidence that tyrosine phosphorylation of cellular proteins by tyrosine kinases and phosphatases is one of the key biochemical events in the signal transduction pathway, the decreased CD45 PTPase activity in SLE may account for the defective signal transduction via TCR/CD3, leading to dysregulated effector function of the lymphocytes.


Consumption of vegetables and fruits and risk of breast cancer.
The intake of vegetables and fruits has been thought to protect against breast cancer. Most of the evidence comes from case-control studies, but a recent pooled analysis of the relatively few published cohort studies suggests no significantly reduced breast cancer risk is associated with vegetable and fruit consumption. To examine the relation between total and specific vegetable and fruit intake and the incidence of breast cancer. Prospective study of 285,526 women between the ages of 25 and 70 years, participating in the European Prospective Investigation Into Cancer and Nutrition (EPIC) study, recruited from 8 of the 10 participating European countries. Participants completed a dietary questionnaire in 1992-1998 and were followed up for incidence of cancer until 2002. Relative risks for breast cancer by total and specific vegetable and fruit intake. Analyses were stratified by age at recruitment and study center. Relative risks were adjusted for established breast cancer risk factors. During 1,486,402 person-years (median duration of follow-up, 5.4 years), 3659 invasive incident breast cancer cases were reported. No significant associations between vegetable or fruit intake and breast cancer risk were observed. Relative risks for the highest vs the lowest quintile were 0.98 (95% confidence interval [CI], 0.84-1.14) for total vegetables, 1.09 (95% CI , 0.94-1.25) for total fruit, and 1.05 (95% CI , 0.92-1.20) for fruit and vegetable juices. For 6 specific vegetable subgroups no associations with breast cancer risk were observed either. Although the period of follow-up is limited for now, the results suggest that total or specific vegetable and fruit intake is not associated with risk for breast cancer.


Intimate partner violence after the diagnosis of sexually transmitted diseases.
OBJECTIVE To assess the prevalence and factors associated with intimate partner violence after the diagnosis of sexually transmitted diseases. METHODS This cross-sectional study was conducted in Fortaleza, CE, Northeastern Brazil, in 2012 and involved 221 individuals (40.3% male and 59.7% female) attended to at reference health care units for the treatment of sexually transmitted diseases. Data were collected using a questionnaire applied during interviews with each participant. A multivariate analysis with a logistic regression model was conducted using the stepwise technique. Only the variables with a p value < 0.05 were included in the adjusted analysis. The odds ratio (OR) with 95% confidence interval (CI) was used as the measure of effect. RESULTS A total of 30.3% of the participants reported experiencing some type of violence (27.6%, psychological; 5.9%, physical; and 7.2%, sexual) after the diagnosis of sexually transmitted disease. In the multivariate analysis adjusted to assess intimate partner violence after the revelation of the diagnosis of sexually transmitted diseases, the following variables remained statistically significant: extramarital relations (OR = 3.72; 95%CI 1.91;7.26; p = 0.000), alcohol consumption by the partner (OR = 2.16; 95%CI 1.08;4.33; p = 0.026), history of violence prior to diagnosis (OR = 2.87; 95%CI 1.44;5.69; p = 0.003), and fear of disclosing the diagnosis to the partner (OR = 2.66; 95%CI 1.32;5.32; p = 0.006). CONCLUSIONS Individuals who had extramarital relations, experienced violence prior to the diagnosis of sexually transmitted disease, feared disclosing the diagnosis to the partner, and those whose partner consumed alcohol had an increased likelihood of suffering violence. The high prevalence of intimate partner violence suggests that this population is vulnerable and therefore intervention efforts should be directed to them. Referral health care services for the treatment of sexually transmitted diseases can be strategic places to identify and prevent intimate partner violence.


On the low dimensionality of behavioral deficits and alterations of brain network connectivity after focal injury.
Traditional neuropsychological approaches emphasize the specificity of behavioral deficits and the modular organization of the brain. At the population level, however, there is emerging evidence that deficits are correlated resulting in a low dimensional structure of post-stroke neurological impairments. Here we consider the implications of low dimensionality for the three-way mapping between structural damage, altered physiology, and behavioral deficits. Understanding this mapping will be aided by large-sample studies that apply multivariate models and focus on explained percentage of variance, as opposed to univariate lesion-symptom techniques that report statistical significance. The low dimensionality of behavioral deficits following stroke is paralleled by widespread, yet relatively consistent, changes in functional connectivity (FC), including a reduction in modularity. Both are related to the structural damage to white matter and subcortical grey commonly produced by stroke. We suggest that large-scale physiological abnormalities following a stroke reduce the variety of neural states visited during task processing and at rest, resulting in a limited repertoire of behavioral states.


Evaluating the impact of air pollution on the incidence of out-of-hospital cardiac arrest in the Perth Metropolitan Region: 2000-2010.
Out-of-hospital cardiac arrest (OHCA) remains a major public health issue. Several studies have found that an increased level of ambient particulate matter (PM) smaller than 2.5 microns (PM2.5) is associated with an increased risk of OHCA. We investigated the relationship between air pollution levels and the incidence of OHCA in Perth, Western Australia. We linked St John Ambulance OHCA data of presumed cardiac aetiology with Perth air pollution data from seven monitors which recorded hourly levels of PM smaller than 2.5 and 10 microns (PM2.5/PM10), carbon monoxide (CO), sulfur dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3). We used a case-crossover design to estimate the strength of association between ambient air pollution levels and risk of OHCA. Between 2000 and 2010, there were 8551 OHCAs that met the inclusion criteria. Of these, 5624 (65.8%) occurred in men. An IQR increase in the 24 and 48 h averages of PM2.5 was associated with 10.6% (OR 1.106, 95% CI 1.038 to 1.180) and 13.6% (OR 1.136, 95% CI 1.051 to 1.228) increases, respectively, in the risk of OHCA. CO showed a consistent association with increased risk of an OHCA. An IQR increase in the 4 h average concentration of CO was associated with a 2.2% (OR 1.022, 95% CI 1.002 to 1.042) increase in risk of an OHCA. When we restricted our analysis of CO to arrests occurring between 6:00 and 10:00, we found a 4.4% (95% CI 1.1% to 7.8%) increase in risk of an OHCA. Elevated ambient PM2.5 and CO are associated with an increased risk of OHCA.


Transgenic crops: the current and next generations.
This chapter describes the present status and future prospects for transgenic (genetically modified) crops. It concentrates on the most recent data obtained from patent databases and field trial applications, as well as the usual scientific literature. By these means, it is possible to obtain a useful perspective into future commercial products and international trends. The various research areas are subdivided on the basis of those associated with input (agronomic) traits and those concerned with output (e.g., food quality) characteristics. Among the former group are new methods of improving stress resistance, and among the latter are many examples of producing pharmaceutical compounds in plants.


Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working Group.
Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.


[IRIS: a paradoxical inflammatory reaction in patients treated simultaneously for tuberculosis and HIV].
Co-infection with Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) represents a major threat to public health worldwide. The treatment of patients coinfected by Mtb and HIV is often complicated by the occurrence of an immune reconstitution inflammatory syndrome (IRIS), resulting in the unexpected resumption of tuberculosis symptoms after the initiation of antiretroviral therapy. IRIS is associated with a rapid reconstitution of CD4(+) T cell responses specific for Mtb, which is promoted by the control of HIV replication and a high concentration of available interleukin-7. Macrophages, whose activity is suddenly stimulated by CD4(+) T cell help, respond by an exacerbated inflammatory response in Mtb-rich tissues. A major research objective remains to identify biomarkers which could allow a reliable prediction of IRIS occurrence, in order to optimize medical care for the many patients affected by both HIV and tuberculosis in resource-limited settings.


Effects of Parsley (Petroselinum crispum) and its Flavonol Constituents, Kaempferol and Quercetin, on Serum Uric Acid Levels, Biomarkers of Oxidative Stress and Liver Xanthine Oxidoreductase Aactivity inOxonate-Induced Hyperuricemic Rats.
Increased serum uric acid is known to be a major risk related to the development of several oxidative stress diseases. The aim of this study was to investigate the effect of parsley, quercetin and kaempferol on serum uric acid levels, liver xanthine oxidoreductase activity and two non-invasive biomarkers of oxidative stress (total antioxidant capacity and malondialdehyde concentration) in normal and oxonate-induced hyperuricemic rats. A total of 60 male Wistar rats were randomly divided into ten equal groups; including 5 normal groups (vehicle, parsley, quercetin, kaempferol and allopurinol) and 5 hyperuricemic groups (vehicle, parsley, quercetin, kaempferol and allopurinol). Parsley (5 g/Kg), quercetin (5 mg/Kg), kaempferol (5 mg/Kg) and allopurinol (5 mg/Kg) were administrated to the corresponding groups by oral gavage once a day for 2 weeks. The results showed that parsley and its flavonol did not cause any significant reduction in the serum uric acid levels in normal rats, but significantly reduced the serum uric acid levels of hyperuricemic rats in a time-dependent manner. All treatments significantly inhibited liver xanthine oxidoreductase activity. Parsley, kaempferol and quercetin treatment led also to a significant increase in total antioxidant capacity and decrease in malondialdehyde concentration in hyperuricemic rats. Although the hypouricemic effect of allopurinol was much higher than that of parsley and its flavonol constituents, it could not significantly change oxidative stress biomarkers. These features of parsley and its flavonols make them as a possible alternative for allopurinol, or at least in combination therapy to minimize the side effects of allopurinol to treat hyperuricemia and oxidative stress diseases.


Modifier Ontologies for frequency, certainty, degree, and coverage phenotype modifier.
Background: When phenotypic characters are described in the literature, they may be constrained or clarified with additional information such as the location or degree of expression, these terms are called "modifiers". With effort underway to convert narrative character descriptions to computable data, ontologies for such modifiers are needed. Such ontologies can also be used to guide term usage in future publications. Spatial and method modifiers are the subjects of ontologies that already have been developed or are under development. In this work, frequency (e.g., rarely, usually), certainty (e.g., probably, definitely), degree (e.g., slightly, extremely), and coverage modifiers (e.g., sparsely, entirely) are collected, reviewed, and used to create two modifier ontologies with different design considerations. The basic goal is to express the sequential relationships within a type of modifiers, for example, usually is more frequent than rarely, in order to allow data annotated with ontology terms to be classified accordingly. Method: Two designs are proposed for the ontology, both using the list pattern: a closed ordered list (i.e., five-bin design) and an open ordered list design. The five-bin design puts the modifier terms into a set of 5 fixed bins with interval object properties, for example, one_level_more/less_frequently_than, where new terms can only be added as synonyms to existing classes. The open list approach starts with 5 bins, but supports the extensibility of the list via ordinal properties, for example, more/less_frequently_than, allowing new terms to be inserted as a new class anywhere in the list. The consequences of the different design decisions are discussed in the paper. CharaParser was used to extract modifiers from plant, ant, and other taxonomic descriptions. After a manual screening, 130 modifier words were selected as the candidate terms for the modifier ontologies. Four curators/experts (three biologists and one information scientist specialized in biosemantics) reviewed and categorized the terms into 20 bins using the Ontology Term Organizer (OTO) (http://biosemantics.arizona.edu/OTO). Inter-curator variations were reviewed and expressed in the final ontologies. Results: Frequency, certainty, degree, and coverage terms with complete agreement among all curators were used as class labels or exact synonyms. Terms with different interpretations were either excluded or included using "broader synonym" or "not recommended" annotation properties. These annotations explicitly allow for the user to be aware of the semantic ambiguity associated with the terms and whether they should be used with caution or avoided. Expert categorization results showed that 16 out of 20 bins contained terms with full agreements, suggesting differentiating the modifiers into 5 levels/bins balances the need to differentiate modifiers and the need for the ontology to reflect user consensus. Two ontologies, developed using the Protege ontology editor, are made available as OWL files and can be downloaded from https://github.com/biosemantics/ontologies. Contribution: We built the first two modifier ontologies following a consensus-based approach with terms commonly used in taxonomic literature. The five-bin ontology has been used in the Explorer of Taxon Concepts web toolkit to compute the similarity between characters extracted from literature to facilitate taxon concepts alignments. The two ontologies will also be used in an ontology-informed authoring tool for taxonomists to facilitate consistency in modifier term usage.


Endocardial fibroelastosis in children with special reference to the lesions of cardiac ganglia.
In all cases of primary endocardial fibroelastosis investigated diffuse degenerative changes in the ganglion cells were detected. Thickened endocardium was formed by the proliferation of mesenchymal cells located under the endothelial endocardium and of the mesenchyme surrounding the necrobiotic muscle cells. In some cases ;axial' vacuolar degeneration, necrobiosis, and necrosis of muscle cells, interstitial oedema, and dilatation of capillaries and lymphatic spaces were found in the whole myocardium. In all cases these changes were in the subendocardial layer.In the cases discussed morphological changes in the endocardium were seen to be secondary to lesions in myocardial and possibly in neural structures.


Nanoparticles made of multi-block copolymer of lactic acid and ethylene glycol containing periodic side-chain carboxyl groups for oral delivery of cyclosporine A.
The purpose of this study was to evaluate the potential of new carboxylated multi-block copolymer of lactic acid and ethylene glycol (EL14) for nanoparticle (NP) formation and their ability to deliver high molecular weight hydrophobic drug--cyclosporine A (CsA). CsA-loaded EL14 NPs were compared with traditional poly(lactide-co-glycolide) (PLGA) NPs, both prepared by emulsion-diffusion-evaporation process. On the one hand, the increase in drug payload from 10 to 30 per cent for EL14 NPs showed no difference in particle size, however the entrapment efficiency tends to decrease from 50 to 43 per cent; on the other hand, the more hydrophobic PLGA showed an increasing trend in entrapment efficiency from 20 to 62 per cent with increasing particle size. Over 90 per cent of CsA was released in vitro from both the nanoparticulates; however, the release was much slower in the case of more hydrophobic PLGA. On in vivo evaluation in rats, the NPs made of EL14 showed a higher C(max), a faster T(max) and enhanced tissue levels to that of PLGA that are crucial for CsA's activity and toxicity; however, the overall bioavailability of the nanoparticulates was similar and higher than Neoral. Together these data demonstrate the feasibility of NPs made of low molecular weight, hydrophilic polymer EL14 for efficient delivery of CsA.


Hierarchical superstructures from a star-shaped molecule consisting of a cyclic oligosiloxane with cyanobiphenyl moieties.
Unconventional star-shaped liquid crystals (abbreviated as SiLCs) were successfully synthesized by chemically connecting four cyanobiphenyl anisotropic mesogens to the periphery of a super-hydrophobic and ultra-flexible cyclic tetramethyltetrasiloxane ring with flexible hexyl chains. Based on the combined experimental techniques of differential scanning calorimetry (DSC), cross-polarized optical microscopy (POM), solid-state carbon-13 ((13)C) nuclear magnetic resonance (NMR) spectroscopy and one-dimensional (1D) wide-angle X-ray diffraction (WAXD), it was found that the SiLC molecule exhibited the monotropic phase transition from a LC phase to a crystalline phase. The crystalline phase was only detected during slow heating processes above its glass transition temperature, while a LC phase was formed both during cooling and during heating processes. The hierarchical superstructures were identified from the structure-sensitive 2D WAXD of the macroscopically oriented SiLC film and confirmed by selected area electron diffraction (SAED) of the SiLC single crystals. The molecular packing symmetry in the monoclinic unit cell was further investigated by computer simulations on the real and reciprocal spaces. Macroscopically oriented SiLC hierarchical superstructures on the different length scales may provide the targeted physical properties, which can allow us to apply SiLC molecules in the fields of electro-optical devices and nonlinear optics.


Stimulation of cyclic adenosine monophosphate accumulation causes breakdown of the blood-retinal barrier.
Pigmented rabbits were given an intravitreous injection of 0.1 ml of various concentrations of test drug, and vitreous fluorophotometry was done 6 and 24 hr after injection. Dibutyryl cyclic adenosine monophosphate (AMP) and 8-bromo-cyclic AMP caused reversible intravitreous fluorescein leakage only at relatively high concentrations. Adrenergic agents that are effective stimulators of adenylate cyclase (epinephrine, isoproterenol, and norepinephrine) caused transient intravitreous fluorescein leakage (2.3-3.1-fold above baseline) that was significantly greater than that caused by phenylephrine (1.1-fold above baseline), an adrenergic agent that is a poor stimulator of adenylate cyclase. Prostaglandins E1 and E2, which are good stimulators of adenylate cyclase, caused striking disruption of the blood-ocular barriers, and prostaglandins that are not good stimulators of adenylate cyclase had little or no effect on these barriers. The magnitude of the prostaglandin E1 effect (9.3-fold above baseline) was similar to that of N-ethylcarboxamidoadenosine (NECA), the most potent adenosine agonist, and was greater than one would predict based on its effect on adenylate cyclase in vitro. Prostaglandin E1, like NECA, also caused retinal vasodilation and hemorrhages. These data suggest that stimulation of intracellular cyclic AMP accumulation may be a common feature of mediators that cause breakdown of the blood-retinal barrier, but there may be another as yet unexplained feature shared by PGE1 and NECA that makes them particularly effective and capable of causing retinal vasodilation and hemorrhages.


Rotational spin Hall effect in a uniaxial crystal.
We have considered the propagation process of the phase-matched array of singular beams through a uniaxial crystal. We have revealed that local beams in the array are rotated when propagating. However the right and left rotations are unequal. There are at least two processes responsible for the array rotation: the interference of local beams and the spatial depolarization. The interference takes place in the vortex birth and annihilation events forming the symmetrical part of the rotation. The depolarization process contributes to the asymmetry of the rotation that is called the rotational spin Hall effect. It can be brought to light due to the difference between the envelopes of the dependences of the angular displacement on the inclination angle of the local beams or the crystal length reaching the value of some angular degree. The direction of the additional array rotation is exclusively defined by the handedness of the circular polarization in the initial beam array.


Role of the Built and Online Social Environments on Expression of Dining on Instagram.
Online social communities are becoming windows for learning more about the health of populations, through information about our health-related behaviors and outcomes from daily life. At the same time, just as public health data and theory has shown that aspects of the built environment can affect our health-related behaviors and outcomes, it is also possible that online social environments (e.g., posts and other attributes of our online social networks) can also shape facets of our life. Given the important role of the online environment in public health research and implications, factors which contribute to the generation of such data must be well understood. Here we study the role of the built and online social environments in the expression of dining on Instagram in Abu Dhabi; a ubiquitous social media platform, city with a vibrant dining culture, and a topic (food posts) which has been studied in relation to public health outcomes. Our study uses available data on user Instagram profiles and their Instagram networks, as well as the local food environment measured through the dining types (e.g., casual dining restaurants, food court restaurants, lounges etc.) by neighborhood. We find evidence that factors of the online social environment (profiles that post about dining versus profiles that do not post about dining) have different influences on the relationship between a user's built environment and the social dining expression, with effects also varying by dining types in the environment and time of day. We examine the mechanism of the relationships via moderation and mediation analyses. Overall, this study provides evidence that the interplay of online and built environments depend on attributes of said environments and can also vary by time of day. We discuss implications of this synergy for precisely-targeting public health interventions, as well as on using online data for public health research.


[Screening of LDLR gene mutations in nine patients with familial hypercholesterolemia].
To screen for LDLR gene mutations in 9 patients with familial hypercholesterolemia (FH). All exons of the LDLR gene and flanking intronic sequences were amplified by PCR and subjected to automatic DNA sequencing. For patients with homozygous or compound heterozygous mutations, parental DNA sequencing or T cloning sequencing was carried out to determine the parental origin of the mutant alleles. Direct sequencing of PCR products revealed 8 LDLR variants in 7 patients, which included c.259T>G, c.513delC, c.530C>T, c.682G>T, c.763C>T, c.1187-10G>A, c.1948delG, and c.1730G>A, among which c.1948delG was novel. Four patients have carried heterozygous mutations, two carried homozygous mutations, and one carried compound heterozygous mutations. The patients with biallelic mutations presented with a more severe phenotype compared those carrying heterozygous mutations. LDLR mutations were identified in 7 out of 9 patients with FH. Among the 8 identified LDLR mutations, c.1948delG was firstly reported. Above findings have expanded the mutation spectrum of LDLR gene.


Middle-Aged Diabetic Females and Males Present Distinct Susceptibility to Alzheimer Disease-like Pathology.
Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. Currently, it is estimated that T2D affects 422 million people worldwide with a rapidly increasing prevalence. During the past two decades, T2D has been widely shown to have a major impact in the brain. This, together with the cognitive decline and increased risk for dementia upon T2D, may arise from the complex interaction between normal brain aging and central insulin signaling dysfunction. Among the several features shared between T2D and some neurodegenerative disorders (e.g., Alzheimer disease (AD)), the impairment of insulin signaling may be a key link. However, these may also involve changes in sex hormones' function and metabolism, ultimately contributing to the different susceptibilities between females and males to some pathologies. For example, female sex has been pointed as a risk factor for AD, particularly after menopause. However, less is known on the underlying molecular mechanisms or even if these changes start during middle-age (perimenopause). From the above, we hypothesized that sex differentially affects hormone-mediated intracellular signaling pathways in T2D brain, ultimately modulating the risk for neurodegenerative conditions. We aimed to evaluate sex-associated alterations in estrogen/insulin-like growth factor-1 (IGF-1)/insulin-related signaling, oxidative stress markers, and AD-like hallmarks in middle-aged control and T2D rat brain cortices. We used brain cortices homogenates obtained from middle-aged (8-month-old) control Wistar and non-obese, spontaneously T2D Goto-Kakizaki (GK) male and female rats. Peripheral characterization of the animal models was done by standard biochemical analyses of blood, plasma, or serum. Steroid sex hormones, oxidative stress markers, and AD-like hallmarks were given by specific ELISA kits and colorimetric techniques, whereas the levels of intracellular signaling proteins were determined by Western blotting. Albeit the high levels of plasma estradiol and progesterone observed in middle-aged control females suggested that they were still under their reproductive phase, some gonadal dysfunction might be already occurring in T2D ones, hence, anticipating their menopause. Moreover, the higher blood and lower brain cholesterol levels in female rats suggested that its dysfunctional uptake into the brain cortex may also hamper peripheral estrogen uptake and/or its local brain steroidogenic metabolism. Despite the massive drop in IGF-1 levels in females' brains, particularly upon T2D, they might have developed some compensatory mechanisms towards the maintenance of estrogen, IGF-1, and insulin receptors function and of the subsequent Akt- and ERK1/2-mediated signaling. These may ultimately delay the deleterious AD-like brain changes (including oxidative damage to lipids and DNA, amyloidogenic processing of amyloid precursor protein and increased tau protein phosphorylation) associated with T2D and/or age (reproductive senescence) in female rats. By demonstrating that differential sex steroid hormone profiles/action may play a pivotal role in brain over T2D progression, the present study reinforces the need to establish sex-specific preventive and/or therapeutic approaches and an appropriate time window for the efficient treatment against T2D and AD.


Electrohydrodynamic properties of succinoglycan as probed by fluorescence correlation spectroscopy, potentiometric titration and capillary electrophoresis.
The electrostatic, hydrodynamic and conformational properties of aqueous solutions of succinoglycan have been analyzed by fluorescence correlation spectroscopy (FCS), proton titration, and capillary electrophoresis (CE) over a large range of pH values and electrolyte (NaCl) concentrations. Using the theoretical formalism developed previously for the electrokinetic properties of soft, permeable particles, a quantitative analysis for the electro-hydrodynamics of succinoglycan is performed by taking into account, in a self-consistent manner, the measured values of the diffusion coefficients, electric charge densities, and electrophoretic mobilities. For that purpose, two limiting conformations for the polysaccharide in solution are tested, i.e. succinoglycan behaves as (i) a spherical, random coil polymer or (ii) a rodlike particle with charged lateral chains. The results show that satisfactory modeling of the titration data for ionic strengths larger than 50 mM can be accomplished using both geometries over the entire range of pH values. Electrophoretic mobilities measured for sufficiently large pH values (pH > 5-6) are in line with predictions based on either model. The best manner to discriminate between these two conceptual models is briefly discussed. For low pH values (pH < 5), both models indicate aggregation, resulting in an increase of the hydrodynamic permeability and a decrease of the diffusion coefficient.


Manganese dosimetry: species differences and implications for neurotoxicity.
Manganese (Mn) is an essential mineral that is found at low levels in food, water, and the air. Under certain high-dose exposure conditions, elevations in tissue manganese levels can occur. Excessive manganese accumulation can result in adverse neurological, reproductive, and respiratory effects in both laboratory animals and humans. In humans, manganese-induced neurotoxicity (manganism) is the overriding concern since affected individuals develop a motor dysfunction syndrome that is recognized as a form of parkinsonism. This review primarily focuses on the essentiality and toxicity of manganese and considers contemporary studies evaluating manganese dosimetry and its transport across the blood-brain barrier, and its distribution within the central nervous system (CNS). These studies have dramatically improved our understanding of the health risks posed by manganese by determining exposure conditions that lead to increased concentrations of this metal within the CNS and other target organs. Most individuals are exposed to manganese by the oral and inhalation routes of exposure; however, parenteral injection and other routes of exposure are important. Interactions between manganese and iron and other divalent elements occur and impact the toxicokinetics of manganese, especially following oral exposure. The oxidation state and solubility of manganese also influence the absorption, distribution, metabolism, and elimination of manganese. Manganese disposition is influenced by the route of exposure. Rodent inhalation studies have shown that manganese deposited within the nose can undergo direct transport to the brain along the olfactory nerve. Species differences in manganese toxicokinetics and response are recognized with nonhuman primates replicating CNS effects observed in humans while rodents do not. Potentially susceptible populations, such as fetuses, neonates, individuals with compromised hepatic function, individuals with suboptimal manganese or iron intake, and those with other medical states (e.g., pre-parkinsonian state, aging), may have altered manganese metabolism and could be at greater risk for manganese toxicity.


Unrelated allogeneic bone marrow transplantation using high-dose busulfan and cyclophosphamide (BU-CY) for the preparative regimen.
This study reviews results of a radiation-free preparative regimen consisting of busulfan and cyclophosphamide in 65 unrelated allogeneic bone marrow transplant recipients. Thirty-eight patients had chronic myelogenous leukemia (17 patients chronic phase, 13 patients accelerated phase, eight patients blast phase), 19 patients had acute leukemia (second complete remission or relapse) and eight patients had myelodysplasia. The patients were transplanted at four different medical centers from July 1988 to November 1992. Ages ranged 4-48 years (median 32). Fifty-seven patients received busulfan 16 mg/kg and cyclophosphamide 120 mg/kg, and eight received busulfan at doses between 15 and 17 mg/kg and cyclophosphamide at doses 100-200 mg/kg as preparative regimens. All patients received cyclosporine for graft-versus-host disease prophylaxis; in addition 46 patients received corticosteroid, 38 methotrexate, six anti-CD5 ricin A-immunotoxin, and four T cell-depleted bone marrow. Median follow-up of survivors was 53 months (range 15-68 months). Four year actuarial survival was 24 +/- 12%. Four-year survival based on disease was 29 +/- 27% for chronic myelogenous leukemia (CML) in chronic phase, 20 +/- 9% for chronic myelogenous leukemia in accelerated phase, 0% for chronic myelogenous leukemia in blast phase, 32 +/- 40% for acute leukemia, and 38 +/- 34% for myelodysplasia. Actuarial survival was 66 +/- 40% in patients age < 20 years, vs 23 +/- 13% for patients ages 20 to 40, and 10 +/- 14% for patients age > 40 years. Fifty patients (88%) engrafted. Graft failure occurred in eight patients. Acute graft-versus-host disease grade II-IV occurred in 36 (72%). Two patients relapsed after engraftment with the donor cells and died of leukemia within a month of relapse. The most common causes of death were graft-versus-host disease (37%), and transplant-related toxicity (59%); relapse (4%) was a rare cause of death. Busulfan/cyclophosphamide is an effective preparative regimen in unrelated bone marrow transplantation permitting adequate engraftment and a low relapse rate. Best results are observed in patients less than 20 years old.


Unstable Carotid Plaque as a Phenotype of Chronic Systemic Inflammation Enhances Renal Insufficiency.
Chronic systemic inflammation is prevalent in patients with chronic kidney disease (CKD) and is linked to the development of cerebrovascular disease. In this study, we explored the association between the unstable plaques and preoperative CKD in patients who underwent carotid endarterectomy (CEA)/carotid artery stenting (CAS). Furthermore, this study also aimed to explore whether there is a difference in the aggravation of renal function with the presence of stable or unstable plaques. The study included 90 patients who underwent CEA/CAS for carotid artery stenosis. Multivariate analysis was performed to determine the risk factors for CKD. Kaplan-Meier estimation was employed to evaluate the aggravation of renal function following CEA/CAS. Multivariate analysis revealed that contralateral carotid occlusive disease (odds ratio [OR], 4.45; 95% confidence interval [CI], 1.36-14.6), and T1 high-intensity carotid plaque (OR, 3.26; 95% CI, 1.2-8.86) were independent factors of CKD. Kaplan-Meier estimation demonstrated a higher aggravation of renal function in the T1 high-intensity group compared to those in the iso-intensity (P =.03). Following CEA/CAS, the time until aggravation of renal insufficiency was 12.0 ± 9.4 months in the T1 high-intensity group and 24.5 ± 9.6 months in the iso-intensity group (P =.03). This study demonstrated that contralateral carotid artery stenosis and T1 high-intensity plaques are more frequently observed in patients with CKD. T1 high-intensity carotid plaque is well linked to CKD development in future.


Developing a core outcome set for hand fractures and joint injuries in adults: a systematic review.
This study identifies the treatment outcome domains used in recently published studies on the treatment of hand fractures and joint injuries with the aim to inform development of a core outcome set. Seven databases were searched from January 2014 to March 2019 for randomized and quasi-randomized studies and large prospective observational studies. We identified 1777 verbatim outcomes in 160 eligible studies. From the verbatim outcomes we distinguished 639 unique outcomes, which we categorized into 74 outcome domains based on the World Health Organization International Classification of Functioning, Disability, and Health framework. The primary outcome was appropriately identified in only 65% (72/110) of randomized and quasi-randomized controlled trials. Of the 72 studies with a primary outcome identified, 74% (53/72) had an appropriate power calculation. The vast heterogeneity in outcome selection across studies highlights the need for a core outcome set of what outcomes to measure in future clinical research on hand fractures and joint injuries.


Challenges in systematic reviews of complementary and alternative medicine topics.
The use of complementary and alternative medicine (CAM) continues to grow in the United States. The Agency for Healthcare Research and Quality has devoted a substantial proportion of the Evidence-based Practice Center (EPC) program to systematic reviews of CAM. Such syntheses present different challenges from those conducted on western medicine topics, and in many ways are more difficult. We discuss 3 challenges: identifying evidence about CAM, assessing the quality of individual studies, and addressing rare serious adverse events. We use illustrations from EPC evidence reports to show readers approaches to the 3 areas and then present specific recommendations for each issue.


Patient characteristics of untreated chronic central serous chorioretinopathy patients with focal versus diffuse leakage.
To describe the characteristics and potential differences between focal and diffuse phenotypes of untreated chronic central serous chorioretinopathy (cCSC). For this study, patients were divided in two groups. Focal leakage was defined as 1 "hot spot" of leakage, whereas diffuse leakage was defined as either > 1 hot spot or a larger area of widespread leakage on FA. Clinical characteristics were assessed at presentation. After Bonferroni correction, P values < 0.00125 were deemed statistically significant. The focal leakage group included 68 eyes (53 males), and the diffuse leakage group included 105 eyes (88 males). Mean best-corrected visual acuity (BCVA) was 77.1 ± 8.1 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters in the focal group and 76.0 ± 9.6 ETDRS letters in the diffuse group (p = 0.440). In the focal group, mean age was 46.9 ± 8.8 years, whereas this was 49.7 ± 8.3 years in the diffuse group (p = 0.033). Mean central foveal thickness was 107.1 ± 21.3 μm in the focal group and 106.2 ± 27.3 μm in the diffuse group (p = 0.818). Mean choroidal thickness was 407.5 ± 114.8 μm in the focal group and 419.1 ± 113.9 μm in the diffuse group (p = 0.578). In the focal group, subretinal fluid was present in the fellow eye in 16% of the patients, as compared to 29% in the diffuse group (p = 0.067). In untreated cCSC patients with focal or diffuse leakage on FA, no marked differences in clinical characteristics were found. Extensive choroidal abnormalities may be present in both groups, which are presumed to lie at the basis of the development of cCSC.


The Present and Future Opportunities of the Rare Cancer Network: An International Consortium for Advancement of Oncologic Care.
To date, the Rare Cancer Network (RCN) has initiated more than 90 studies and 54 peer-reviewed publications were produced as a result. The Second International Symposium of the Rare Cancer Network recently took place in Istanbul, Turkey on April 17-18, 2015, and update was given on multiple currently ongoing projects, while also giving room for new proposals which will shape the direction of future studies for the group. This companion issue of the RCN Proceedings summarized the findings of this meeting, while also serving as a call for fresh projects and papers which will continue to energize the group and advance the oncologic science. A brief introduction to the principles, history, and vision of the RCN was also included. To review, the academic year of 2014-15 marked an enormous success for the international members of the RCN, with the generation of 8 fully published papers and more than 12 newly proposed topics. By the collective efforts of all RCN members, in the future, we look forward to the upcoming opportunities in continuing to advance the standard of chemo- and radiotherapeutic oncologic care for selected rare tumor topics. The studies of these rare cancers often do not allow the design and execution of prospectively enrolled trials; however, these uncommon malignancies do impact the humankind and add to its suffering globally in significant ways.


In vivo histopathologic comparison of the acute injury following treatment with five fractional ablative laser devices.
Both erbium (Er:YAG) and carbon dioxide (CO(2)) devices are commonly-used, efficient laser systems for aggressive skin resurfacing procedures. The devices each have different adjustable parameters (density, spot size, number of pulses, pattern, etc) and utilize variable energy capabilities to tailor individual treatments depending on the skin pathology and goals of treatment. Overall, the consensus has been that multiple-pass erbium treatments needed for efficacious wrinkle reduction had similar downtime and comorbidity to the traditional CO(2) treatments. Unfortunately, there were limited data comparing the histological differences and changes throughout the wound-healing process over time between the two treatment methods. The authors compare the difference in injury following treatment with five novel fractional ablative laser systems in vivo. Differences in damage pattern, treatment depth, and degree of surrounding cellular injury following treatment with each device at common clinical settings are evaluated in a side-by-side histopathologic comparison. Prior to planned excisional surgery, the panni of 20 abdominoplasty patients were treated with five novel ablative fractional carbon dioxide or Er:YAG laser systems at various clinical parameters, in accordance with the manufacturers' treatment guidelines. After tissue removal two to four hours later, the skin was biopsied and processed for histopathologic evaluation. Specimens were stained with hematoxylin and eosin, along with a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay, to highlight the degree of irreversible cellular injury. The acute damage profile differed between the fractional Er:YAG and CO(2) devices with respect to depth of penetration and extension of coagulation surrounding the microcolumns. The damage pattern was dependent on the parameters set with each device (eg, fluence, pulses, density, pulse width). The TUNEL-stained sections demonstrated more collateral cellular injury surrounding the ablated columns with the CO(2) devices than with the Er:YAG systems. Following treatment with the fractional Er:YAG and CO(2) devices, deep tissue injury with various coagulative and ablative properties was observed, and it was confirmed that carbon dioxide and erbium devices result in different patterns of injury. As such, each may be better suited for different clinical situations. It is important for practitioners to understand the limitations of a specific device, as well as the tissue injury following a given treatment pattern or protocol, to appropriately tailor their treatment algorithm for a given patient. This extensive histopathologic evaluation of the acute characterization of injury across devices is helpful in clarifying the differences/similarities in laser-tissue interaction following treatment in an in vivo human model.


An introduction to nucleoside and nucleotide analogues.
The introduction of newer and more potent agents has diverted attention away from the importance of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack the virological potency of either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, due largely to their competitive mode of inhibition and requirement for metabolic activation. However, neither NNRTIs nor PIs alone can maintain the complete suppression of HIV replication required for extended therapy, and both suffer from serious class cross-resistance on therapeutic failure. Thus, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, both for their contribution to a regimen's virological potency and the subsequent preservation of the more potent drug classes used with them. However, it has become apparent in recent years that the current NRTIs exhibit duration-dependent adverse events as a class, which may limit the length of time for which they can be safely used. An independent contribution to peripheral fat wasting in lipodystrophy syndrome has been established for the use of NRTI drugs. Of greater clinical concern is their established association with potentially fatal lactic acidaemia and hepatic steatosis. Both these class events, as well as several individual drug events, such as peripheral; neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of confidence. Mitochondrial toxicity, due in large part to the high affinity of several NRTI agents for uptake by mitochondrial DNA polymerase gamma, has been demonstrated both in vitro and in vivo. New chain-terminating agents are urgently needed that address issues of improved virological potency, greater efficacy in NRTI-experienced individuals, and greater long-term safety. The nucleotide class of reverse transcriptase inhibitor (NtRTI), currently under clinical development, addresses improved potency by abbreviating the intracellular activation pathway to allow a more rapid and complete conversion to the active agent. These nucleoside monophosphate analogues are taken as masked prodrugs bearing labile lipophilic groups to facilitate penetration of target cell membranes. Subsequent unmasking by endogenous chemolytic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along the developmental process is tenofovir disoproxil fumarate (TDF), an orally available acyclic adenine phosphonate analogue, currently in Phase III clinical trials. This agent has shown high potency and an unusually durable response in trials of single-agent therapy intensification in highly treatment-experienced individuals, and its active metabolite, tenofovir diphosphate, exhibits a long intracellular half-life in both resting and activated peripheral blood mononuclear cells that permits once daily dosing. Tenofovir diphosphate also exhibits a very low affinity for DNA polymerase gamma in vitro, suggesting a low degree of in vivo mitochondrial toxicity may be observed on long-term follow-up, although clinical data to support this inference are not yet available. The introduction of TDF and other NtRTIs as 'second-generation' nucleoside analogues carefully evaluated for potential long-term toxicity, can be expected to significantly improve the therapeutic options for both those currently on HAART and those yet to begin.


Thermal drift compensation method for microbolometer thermal cameras.
We propose a new method of compensation for drifts in thermal cameras using a filter in place of a shutter. The latter method requires periodically closing the camera, thus causing the images to appear frozen frequently. Our technique of replacing the shutter with a filter eliminates this frozen image problem. In this paper we discuss the principles of the new method and present the obtained results.


Oxygen therapy for acute myocardial infarction.
Oxygen (O(2)) is widely recommended for patients with myocardial infarction yet a narrative review has suggested it may do more harm than good. Systematic reviews have concluded that there was insufficient evidence to know whether oxygen reduced, increased or had no effect on the heart ischaemia or infarct size. To review the evidence from randomised controlled trials to establish whether routine use of inhaled oxygen in acute myocardial infarction (AMI) improves patient-centred outcomes, in particular pain and death. The following bibliographic databases were searched (to the end of February 2010): Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, MEDLINE In-Process, EMBASE, CINAHL, LILACS and PASCAL, British Library ZETOC, Web of Science ISI Proceedings. Experts were also contacted to identify any studies. No language restrictions were applied. Randomised controlled trials of people with suspected or proven AMI, less than 24 hours after onset, in which the intervention was inhaled oxygen (at normal pressure) compared to air and regardless of co-therapies provided these were the same in both arms of the trial. Two review authors independently reviewed the titles and abstracts of identified studies to see if they met the inclusion criteria and independently undertook the data extraction. The quality of studies and the risk of bias were assessed according to guidance in the Cochrane Handbook. The primary outcomes were death, pain and complications. The measure of effect used was the relative risk (RR). Three trials involving 387 patients were included and 14 deaths occurred. The pooled RR of death was 2.88 (95% CI 0.88 to 9.39) in an intention-to-treat analysis and 3.03 (95% CI 0.93 to 9.83) in patients with confirmed AMI. While suggestive of harm, the small number of deaths recorded meant that this could be a chance occurrence. Pain was measured by analgesic use. The pooled RR for the use of analgesics was 0.97 (95% CI 0.78 to 1.20). There is no conclusive evidence from randomised controlled trials to support the routine use of inhaled oxygen in patients with acute AMI. A definitive randomised controlled trial is urgently required given the mismatch between trial evidence suggestive of possible harm from routine oxygen use and recommendations for its use in clinical practice guidelines.


Clinical Safety and Immunogenicity of Tumor-Targeted, Plant-Made Id-KLH Conjugate Vaccines for Follicular Lymphoma.
We report the first evaluation of plant-made conjugate vaccines for targeted treatment of B-cell follicular lymphoma (FL) in a Phase I safety and immunogenicity clinical study. Each recombinant personalized immunogen consisted of a tumor-derived, plant-produced idiotypic antibody (Ab) hybrid comprising the hypervariable regions of the tumor-associated light and heavy Ab chains, genetically grafted onto a common human IgG1 scaffold. Each immunogen was produced in Nicotiana benthamiana plants using twin magnICON vectors expressing the light and heavy chains of the idiotypic Ab. Each purified Ab was chemically linked to the carrier protein keyhole limpet hemocyanin (KLH) to form a conjugate vaccine. The vaccines were administered to FL patients over a series of ≥6 subcutaneous injections in conjunction with the adjuvant Leukine (GM-CSF). The 27 patients enrolled in the study had previously received non-anti-CD20 cytoreductive therapy followed by ≥4 months of immune recovery prior to first vaccination. Of 11 patients who became evaluable at study conclusion, 82% (9/11) displayed a vaccine-induced, idiotype-specific cellular and/or humoral immune response. No patients showed serious adverse events (SAE) related to vaccination. The fully scalable plant-based manufacturing process yields safe and immunogenic personalized FL vaccines that can be produced within weeks of obtaining patient biopsies.


Multi-ethnic genome-wide association study for atrial fibrillation.
Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.


Association Between Entrustable Professional Activities and Milestones Evaluations: Real-time Assessments Correlate With Semiannual Reviews.
Entrustable professional activities (EPAs) have been developed to refine competency-based education. The American Board of Surgery has initiated a 2-year pilot study to evaluate the impact of EPAs on the evaluation and feedback of surgical residents. The ACGME Milestones in Surgery is a semiannual competency-based evaluation program to measure resident progression through 16 professional attributes across 8 practice domains. The correlation between these 2 evaluation tools remains unclear. The purpose of this study is to evaluate this correlation through comparison of an EPA with the corresponding elements of the ACGME Milestones. From July, 2018 to October, 2019, all residents submitting EPA evaluations for gall bladder disease were evaluated for preoperative, intraoperative, and/or postoperative entrustability. The ratings were converted to a numerical rank from 0 to 4. Milestones scores from May 2019 and November 2019 were obtained for each resident, with scores ranging from 0 to 4. The gall bladder EPA incorporates the operative PC3 and MK2 and nonoperative PC1, PC2, and ICS3 components. Spearman rank correlation was conducted to evaluate the association between each resident's median EPA ranking and his/her milestones scores. SUNY Upstate Medical University, Syracuse, NY, a university-based hospital. General surgery residents. Among 24 residents, 106 intraoperative EPA evaluations were. For both the May and November milestones, significant positive correlations were noted for PC3 (correlation coefficient ρ = 0.690, p < 0.001; ρ = 0.876, p < 0.001). Similarly, for MK2, a significant positive correlation was noted (ρ = 0.882, p < 0.001; ρ = 0.759, p < 0.001). Interestingly, significant positive correlations were also identified between the 3 nonoperative milestones and the intraoperative entrustability ranking. We observed significant correlations between EPAs for cholecystectomy and associated milestones evaluation scores. These findings indicate that EPAs may provide more timely and specific feedback than existing tools and, on aggregate, may improve upon existing formative feedback practices provided through the biannual evaluation of surgical residents.


A synthetic peptide from transforming growth factor beta type III receptor inhibits liver fibrogenesis in rats with carbon tetrachloride liver injury.
Transforming growth factor beta1 (TGF-beta1) is a pleiotropic cytokine, which displays potent profibrogenic effects and is highly expressed in fibrotic livers. For this reason, development of TGF-B1 inhibitors might be of great importance to control liver fibrogenesis as well as other undesired side effects due to this cytokine. Potential peptide inhibitors of TGF-beta1 (derived from TGF-beta1 and from its type III receptor) were tested in vitro and in vivo using different assays. Peptides P11 and P12, derived from TGF-beta1, and P54 and P144, derived from its type III receptor, prevented TGF-beta1-dependent inhibition of MV1Lu proliferation in vitro and markedly reduced binding of TGF-beta1 to its receptors. P144 blocked TGF-beta1-dependent stimulation of a reporter gene under the control of human alpha2(I) collagen promoter. Intraperitoneal administration of P144 also showed potent antifibrogenic activity in vivo in the liver of rats receiving CCl4. These rats also showed a significant decrease in the number of activated hepatic stellate cells as compared with those treated with saline only. These results suggest that short synthetic peptides derived from TGF-beta1 type III receptor may be of value in reducing liver fibrosis in chronic liver injury.


Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu.
Recent studies have demonstrated that plasticity of naturally occurring CD4(+)Foxp3(+) regulatory T cells (nTregs) may account for their inability to control chronic inflammation in established autoimmune diseases. All-trans retinoic acid (atRA), the active derivative of vitamin A, has been demonstrated to promote Foxp3(+) Treg differentiation and suppress Th17 development. In this study, we report a vital role of atRA in sustaining the stability and functionality of nTregs in the presence of IL-6. We found that nTregs treated with atRA were resistant to Th17 and other Th cell conversion and maintained Foxp3 expression and suppressive activity in the presence of IL-6 in vitro. atRA decreased IL-6R expression and signaling by nTregs. Of interest, adoptive transfer of nTregs even from arthritic mice treated with atRA suppressed progression of established collagen-induced arthritis. We suggest that nTregs treated with atRA may represent a novel treatment strategy to control established chronic immune-mediated inflammatory diseases.


The role of sediment-transport evaluations for development of modeled instream flows: policy and approach in Texas.
Instream-flow scientists embrace streamflow as the master variable driving aquatic and riparian ecosystems, and that natural flow variability is imperative for river conservation and restoration efforts. Sediment transport, which is critical for maintenance of physical habitats in rivers and floodplains, has received less direct attention from instream-flow practitioners. This article serves to highlight the roles of sediment-transport evaluations in modifying or verifying instream-flow prescriptions based on hydrology alone. Two examples of sediment-transport evaluations are discussed in relation to the Texas Senate Bill 3 Environmental Flows allocation process, a mandate to "develop environmental flow analyses and a recommended flow regime" that "maintain(s) the viability of the state's streams, rivers, and bay and estuary systems" using "reasonably available science". The first example provides an evaluation of effective discharge of suspended-sediment load of the lower Brazos River. The magnitude and frequency of effective discharge occurs between typical high-flow pulses and overbank flows, indicating that hydrologic and physical processes are not optimally coupled in some flow-regime models. The second example utilizes the Hydrology-Based Environmental Flow Regime (HEFR) model to prescribe instream flows for the lower Sabine River, and compares modeled bed-material loads for observed and HEFR-prescribed flow regimes. Results indicate that annual water and sediment yields are greatly reduced for the modeled flow regime. It should be noted, however, that different input variables to the HEFR model would have resulted in different computations of water and sediment yields, reinforcing that instream-flow practitioners should exercise great caution when applying rule-of-thumb procedures to generate flow prescriptions.


The Persevering Cytotaxonomy: Discovery of a Unique XX/XY Sex Chromosome System in Catfishes Suggests the Existence of a New, Endemic and Rare Species.
The genus Hypostomus has a broad geographic distribution in Brazilian rivers and comprises armored catfishes with a very complicated taxonomy due to the absence of morphological autapomorphies. The existence of nearly 10 allopatric populations with different karyotypes suggests that Hypostomusancistroides represents a species complex in the Upper Paraná River basin. In this paper, an unusual karyotype of an isolated H. aff. ancistroides population was investigated. All specimens of this sample have 2n = 66 chromosomes except for 1 male with 2n = 67, most likely due to a supernumerary chromosome. In this population, the sexes are dimorphic, the males are heterogametic, and an XX/XY sex chromosome system is present. Phylogenetic analysis using mitochondrial and nuclear DNAs indicated that this population forms a monophyletic group separate from the other populations of H.ancistroides and may represent an incipient species.


C-reactive protein: adjunct to cardiovascular risk assessment.
The study aimed to investigate whether elevated plasma high sensitivity C-reactive protein (hs-CRP) levels are independently associated with an increased risk of cardiovascular disease (CVD) and to then assess the effectiveness of the addition of hs-CRP testing to cardiovascular risk assessment by standard lipid screening. A retrospective hospital-based case-control study was designed. All patients attending Cross Crossing Medical Centre (CCMC) for routine cardiovascular assessment or emergency treatment were included. Cases were defined as patients with a cardiovascular event and controls as those without an event. Data collected included blood measurements of hs-CRP and cholesterol, demographic data, drug and risk factor history. Odds ratio of 1.84 (95% CI 1.00, 3.38) indicated that a patient with elevated hs-CRP is 1.84 times more at risk of CVD than one with normal hs-CRP. Additionally, the association between hs-CRP and CVD was found to be independent of the other risk factors (p = 0.058). Hs-CRP ranked fourth as an indicator of risk above smoking and diabetes, and patients with both high hs-CRP and high cholesterol (OR = 9.5) were 3.5 times more at risk of CVD than someone with high cholesterol alone (OR = 6.0). Hs-CRP testing enhanced the clinical identification of patients at risk of cardiovascular events. It can therefore contribute to timely implementation of effective lifestyle modification and pharmaceutical intervention.


Identification of spirochetes (treponemes) in endodontic infections.
The purpose of this study was to determine the prevalence of spirochetes in asymptomatic infected root canals and in endodontic abscesses/cellulitis. Aseptic clinical samples were collected using paper points from 54 infected root canals and from aspirates of 84 abscesses/cellulitis. Oligonucleotide primers were produced for PCR identification of Treponema vincentii, T. pectinovorum, T. medium, T. amylovorum, T. denticola, T. maltophilum, and T. socranskii. PCR detected spirochetes in 51 of 84 (60.7%) samples from abscesses/cellulitis and in 20 of 54 (37.0%) samples from asymptomatic infected root canals. T. socranskii was the most frequently detected (44.9%), followed by T. maltophilum (29.7%), T. denticola (28.9%), T. pectinovorum (13.7%), and T. vincentii (5.1%). The number of treponema species detected ranged from 1 to 5 species per sample. The mean numbers of species detected were 2.3 in abscesses/cellulitis and 2.6 in infected root canals. Significant association among species was found between T. maltophilum and T. socranskii, as well as between T. maltophilum and T. denticola by determining the odds ratio (> 2.0).