Estimated future HIV prevalence, incidence, and potential infections averted in the United States: a multiple scenario analysis.
To estimate the potential future burden of HIV in the United States under different intervention scenarios. We modeled future HIV incidence, prevalence, and infections averted using 2006 estimates of HIV incidence (55,400 new infections per year), prevalence (1,107,000 persons living with HIV), and transmission rate (5.0 per 100 persons living with HIV). We modeled 10-year trends for 3 base-case scenarios (steady incidence, steady transmission rate, declining transmission rate based on the 2000-2006 trend) and 2 intensified HIV intervention scenarios (50% reduction in transmission rate within 10 and 5 years). Base-case scenarios predicted HIV prevalence increases of 24%-38% in 10 years. Reducing the transmission rate by 50% within 10 years reduces incidence by 40%; prevalence increases 20% to an estimated 1,329,000 persons living with HIV. Halving the transmission rate within 5 years reduces incidence by 46%; prevalence increases 13%, to 1,247,000. Although in year 10 incidence is similar regardless of the intervention time frame, more infections are averted when halving the transmission rate within 5 years. HIV prevalence will likely increase creating additional demands for health care services. These analyses are instructive for setting HIV prevention goals for the nation and assessing potential cost savings of intensified HIV prevention efforts.


Genetic Load and Potential Mutational Meltdown in Cancer Cell Populations.
Large genomes with elevated mutation rates are prone to accumulating deleterious mutations more rapidly than natural selection can purge (Muller's ratchet). As a consequence, it may lead to the extinction of small populations. Relative to most unicellular organisms, cancer cells, with large and nonrecombining genome and high mutation rate, could be particularly susceptible to such "mutational meltdown." However, the most common type of mutation in organismal evolution, namely, deleterious mutation, has received relatively little attention in the cancer biology literature. Here, by monitoring single-cell clones from HeLa cell lines, we characterize deleterious mutations that retard the rate of cell proliferation. The main mutation events are copy number variations (CNVs), which, estimated from fitness data, happen at a rate of 0.29 event per cell division on average. The mean fitness reduction, estimated reaching 18% per mutation, is very high. HeLa cell populations therefore have very substantial genetic load and, at this level, natural population would likely face mutational meltdown. We suspect that HeLa cell populations may avoid extinction only after the population size becomes large enough. Because CNVs are common in most cell lines and tumor tissues, the observations hint at cancer cells' vulnerability, which could be exploited by therapeutic strategies.


Atomistic simulations of P(NDI2OD-T2) morphologies: from single chain to condensed phases.
We investigate theoretically the structure, crystallinity, and solubility of a high-mobility n-type semiconducting copolymer, P(NDI2OD-T2), and we propose a set of new force field parameters. The force field is reparametrized against density functional theory (DFT) calculations, with the aim to reproduce the correct torsional angles that govern the polymer chain flexibility and morphology. We simulate P(NDI2OD-T2) oligomers in different environments, namely, in vacuo, in the bulk phase, and in liquid toluene and chloronaphthalene solution. The choice of these solvents is motivated by the fact that they induce different kinds of molecular preaggregates during the casting procedures, resulting in variable device performances. Our results are in good agreement with the available experimental data; the polymer bulk structure, in which the chains are quite planar, is correcly reproduced, yet the isolated chains are flexible enough to fold in vacuo. We also calculate the solubility of P(NDI2OD-T2) in toluene and chloronaphthalene, predicting a much better solubility of the polymer in the latter, also in accordance to experimental observations. Different morphologies and dynamics of the oligomers in the two solvents have been observed. The proposed parameters make it possible to obtain the description of P(NDI2OD-T2) in different environments and can serve as a basis for extensive studies of this polymer semiconductor, such as, for example, the dynamics of aggregation in solvent.


The Frontal Assessment Battery (FAB) in Parkinson's disease and correlations with formal measures of executive functioning.
The Frontal Assessment Battery (FAB) is a short tool for the assessment of executive functions consisting of six subtests that explore different abilities related to the frontal lobes. Several studies have indicated that executive dysfunction is the main neuropsychological feature in Parkinson's disease (PD). To evaluate the clinical usefulness of the FAB in identifying executive dysfunction in PD; to determine if FAB scores in PD are correlated with formal measures of executive functions; and to provide normative data for the Portuguese version of the FAB. The study involved 122 healthy participants and 50 idiopathic PD patients. We compared FAB scores in normal controls and in PD patients matched for age, education and Mini-Mental State Examination (MMSE) score. In PD patients, FAB results were compared to the performance on tests of executive functioning. In the healthy subjects, FAB scores varied as a function of age, education and MMSE. In PD, FAB scores were significantly decreased compared to normal controls, and correlated with measures of executive functions such as phonemic and semantic verbal fluency tests, Wisconsin Card Sorting Test and Trail Making Test Part A and Part B. The FAB is a useful tool for the screening of executive dysfunction in PD, showing good discriminant and concurrent validities. Normative data provided for the Portuguese version of this test improve the accuracy and confidence in the clinical use of the FAB.


Chemometric analysis for the detection of biogenic amines in Chilean Cabernet Sauvignon wines: a comparative study between organic and nonorganic production.
In this work, the presence of biogenic amines (BAs) was correlated with the type of wine grape culture (traditional or organic) and their concentration in the different stages of winemaking (must, alcoholic fermentation [AF] and malolactic fermentation [MLF]). The formation of BA occurred mainly during MLF in which the percentages for putrescine, cadaverine, phenylethylamine, histamine, and tyramine were 100%, 70%, 13%, 61%, and 44% for the wines produced with traditional grapes and 100%, 94%, 25%, 88%, and 13% for the wines produced with organic grapes, respectively. In general, these latter wines exhibited a lower concentration of total amines. The principal component analysis and partial least-square discriminate analysis indicated that the generation of BA has a certain behavioral pattern in the wines analyzed, which is associated with the different stages of wine production and with the type of culture (traditional or organic) used in the wine grapes. Chemometrics tools can be useful as a method of characterization and classification in a global overview of the process variables involved in the development of toxic chemicals in foods, such as the production of BA in wine.


[Ultrastructure of osteoid islets in mixed-type hepatoblastoma].
Composite morphological studies established that "osteoid" may consist of various portions of finely granular nonparticular basic substance and fibrous structures resembling collagen fibers and randomly interwoven in different directions. This substance was found to be synthesized by myoepithelial-like cells contacting by desmosomes and desmosome-like contacts and having in their cytoplasm abundant bundles of microfibrils, developed granular endoplasmic reticulum, and Golgi zones. The regularities of histotopographic location of such islets suggest that polygonal cells of forming bile ducts subject to cataplasia participate in the synthesis of intercellular "osteoid-like" substance. The similarity between hepatoblastoma of the mixed type and pleomorphic adenoma of the salivary gland is indicated.


Diagnosis of Tuberculous Meningitis Using a Combination of Peripheral Blood T-SPOT.TB and Cerebrospinal Fluid Interferon-γ Detection Methods.
To evaluate the effectiveness of combined peripheral blood T-SPOT.TB and cerebrospinal fluid interferon-γ (cIFN-γ) detection methods in the diagnosis of tuberculous meningitis (TBM). A total of 30 individuals with TBM and 39 control individuals without TBM participated in this study. IFN-γ-secreting T cells were detected by enzyme-linked immunospot (ELISPOT), and cIFN-γ was detected by enzyme-linked immunosorbent assay (ELISA). We collected cerebrospinal fluid from 10 patients in the TBM group on initial visit and at 4 weeks, to observe changes. The sensitivity and specificity of peripheral-blood T-SPOT.TB testing in the diagnosis of TBM were 70% and 87%, respectively. The area under the ROC curve of cIFN-γ for TBM diagnosis was 0.819, and the corresponding sensitivity and specificity were 83% and 85%, respectively. When T-SPOT.TB and cIFN-γ results were positive, the specificity and positive predictive value of TBM diagnosis reached 100%. Combined use of T-SPOT.TB and cIFN-γ could improve the diagnosis efficiency of TBM. Dynamic observation of cIFN-γ is also important in monitoring TBM because the level of this analyte significantly decreases after treatment.


Structure of the processive human Pol δ holoenzyme.
In eukaryotes, DNA polymerase δ (Pol δ) bound to the proliferating cell nuclear antigen (PCNA) replicates the lagging strand and cooperates with flap endonuclease 1 (FEN1) to process the Okazaki fragments for their ligation. We present the high-resolution cryo-EM structure of the human processive Pol δ-DNA-PCNA complex in the absence and presence of FEN1. Pol δ is anchored to one of the three PCNA monomers through the C-terminal domain of the catalytic subunit. The catalytic core sits on top of PCNA in an open configuration while the regulatory subunits project laterally. This arrangement allows PCNA to thread and stabilize the DNA exiting the catalytic cleft and recruit FEN1 to one unoccupied monomer in a toolbelt fashion. Alternative holoenzyme conformations reveal important functional interactions that maintain PCNA orientation during synthesis. This work sheds light on the structural basis of Pol δ's activity in replicating the human genome.


Management of pregnancy-related issues in multiple sclerosis patients: the need for an interdisciplinary approach.
Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS), most probably autoimmune in origin, usually occurring in young adults with a female/male prevalence of approximately 3:1. Women with MS in the reproductive age may face challenging issues in reconciling the desire for parenthood with their condition, owing to the possible influence both on the ongoing or planned treatment with the possible consequences on the disease course and on the potential negative effects of treatments on foetal and pregnancy outcomes. At MS diagnosis, timely counselling should promote informed parenthood, while disease evolution should be assessed before making therapeutic decisions. Current guidelines advise the discontinuation of any treatment during pregnancy, with possible exceptions for some treatments in patients with very active disease. Relapses decline during pregnancy but are more frequent during puerperium, when MS therapy should be promptly resumed in most of the cases. First-line immunomodulatory agents, such as interferon-β (IFN-β) and glatiramer acetate (GA), significantly reduce the post-partum risk of relapse. Due to substantial evidence of safety with the use of GA during pregnancy, a recent change in European marketing authorization removed the pregnancy contraindication for GA. This paper reports a consensus of Italian experts involved in MS management, including neurologists, gynaecologists and psychologists. This consensus, based on a review of the available scientific evidence, promoted an interdisciplinary approach to the management of pregnancy in MS women.


CHKB-AS1 enhances proliferation and resistance to NVP-BEZ235 of renal cancer cells via regulating the phosphorylation of MAP4 and PI3K/AKT/mTOR signaling.
Targeted therapy is pivotal in renal carcinoma treatment, and the dual-inhibitor NVP-BEZ235 has emerged as a promising candidate in preliminary studies. Its effectiveness against renal carcinoma and the mechanisms underlying potential resistance, however, warrant further exploration. This study aims to elucidate these aspects, enhancing our understanding of NVP-BEZ235's future clinical utility. To investigate resistance mechanisms, renal cancer cell lines were exposed to progressively increasing concentrations of NVP-BEZ235, leading to the development of stable resistance. These resistant cells underwent extensive RNA-sequencing analysis. We implemented gene interference techniques using plasmid vectors and lentivirus and conducted regular IC50 assessments. To pinpoint the role of LncRNAs, we utilized FISH and immunofluorescence staining assays, supplemented by RNA pull-down and RIP assays to delineate interactions between LncRNA and its RNA-binding protein (RBP). Further, Western blotting and qRT-PCR were employed to examine alterations in signaling pathways, with an animal model providing additional validation. Our results show a marked increase in the IC50 of NVP-BEZ235 in resistant cell lines compared to their parental counterparts. A significant revelation was the role of LncRNA-CHKB-AS1 in mediating drug resistance. We observed dysregulated expression of CHKB-AS1 in both clinical samples of clear cell renal cell carcinoma (ccRCC) and cell lines. In vivo experiments further substantiated our findings, showing that CHKB-AS1 overexpression significantly enhanced tumor growth and resistance to NVP-BEZ235 in a subcutaneous tumorigenesis model, as evidenced by increased tumor volume and weight, whereas CHKB-AS1 knockdown led to a marked reduction in these parameters. Critically, CHKB-AS1 was identified to interact with MAP4, a key regulator in the phosphorylation of the PI3k/Akt/mTOR pathway. This interaction contributes to a diminished antitumor effect of NVP-BEZ235, highlighting the intricate mechanism through which CHKB-AS1 modulates drug resistance pathways, potentially impacting therapeutic strategies against renal carcinoma.


Species occurrence of the potentially toxigenic diatom genus Pseudo-nitzschia and the associated neurotoxin domoic acid in the Argentine Sea.
The marine diatom genus Pseudo-nitzschia, the major known producer of the neurotoxin domoic acid (DA) responsible for the amnesic shellfish poisoning (ASP) syndrome in humans and marine mammals, is globally distributed. The genus presents high species richness in the Argentine Sea and DA has been frequently detected in the last few years in plankton and shellfish samples, but the species identity of the producers remains unclear. In the present work, the distribution and abundance of Pseudo-nitzschia species and DA were determined from samples collected on two oceanographic cruises carried out through the Argentine Sea (∼39-47°S) during summer and spring 2013. Phytoplankton composition was analysed by light and electron microscopy while DA was determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The genus Pseudo-nitzschia was recorded in 71 and 86% of samples collected in summer and spring, respectively, whereas DA was detected in only 42 and 21% of samples, respectively. Microscopic analyses revealed at least five potentially toxic species (P. australis, P. brasiliana, P. fraudulenta, P. pungens, P. turgidula), plus putatively non-toxigenic P. dolorosa, P. lineola, P. turgiduloides and unidentified specimens of the P. pseudodelicatissima complex. The species P. australis showed the highest correlation with DA occurrence (r=0.55; p<0.05), suggesting its importance as a major DA producer in the Argentine Sea. In the northern area and during summer, DA was associated with the presence of P. brasiliana, a species recorded for the first time in the Argentine Sea. By contrast, high concentrations of P. fraudulenta, P. pungens and P. turgidula did not correspond with DA occurrence. This study represents the first successful attempt to link toxigenicity with Pseudo-nitzschia diversity and cell abundance in field plankton populations in the south-western Atlantic.


Height and body mass index distribution in children and adolescents with and without spina bifida.
Children with spina bifida (SB) are at risk for stunting and overweight. However, height and Body Mass Index (BMI) z-score distribution in children and adolescents with SB are unclear. The aim of this study was to examine height and BMI z-score distribution in Brazilian children and adolescents with and without SB. This study further aimed to examine whether height and BMI z-scores differ between individuals with and without SB. This study included 101 participants (SB: n = 18; non-SB: n = 83, aged 7-16 years). The World Health Organization (WHO) AnthroPlus software was used to calculate height and BMI z-scores. AnthroPlus z-score distribution graphs were used to examine individual z-scores based on the 2007 WHO normal distribution curve. Effects of the group (SB vs non-SB) on height and BMI z-scores were examined with sequential regression. In the WHO distribution graph analysis, height z-scores of participants with SB were slightly left-shifted compared to the WHO normal distribution curve. In the regression analysis, group (SB vs non-SB) was a significant predictor of height z-scores after controlling for sex and age (ΔR2 = 0.064, p = 0.010). BMI z-scores of participants with SB were right-shifted compared to the WHO normal curve. However, there was no contribution of the group to BMI z-scores (ΔR2 = 0.011, p = 0.301). These findings suggest that Brazilian children and adolescents with SB may be at risk for reduced height and increased BMI.


Evaluation of the Effectiveness of Risperidone in Treating Breath-Holding Spells in Children.
Breath holding spells (BHS) are a type of syncope in children that is commonly seen in the first years of life. Although these attacks do not cause serious damage to the child's brain, in severe or repeated cases, they expose the brain to hypoxia and cause a lot of stress in parents. In these cases, the clinician should consider therapy. The purpose of this study is to investigate the effectiveness of Risperidone in the treatment of BHS in children visiting the neurology clinic of the Children's Medical Center Hospital. In this randomized clinical trial, the statistical population included patients with the history of Breath Holding spells grades 2 to 3 (after ruling out of seizure disorders) over one year old, visiting the neurology clinic of Tehran Children's Medical Center in 2019. The subjects were randomly selected from patients visiting the clinic using a table of random numbers from the admit ion list. After providing the necessary explanations and obtaining informed consent from their parents, they were treated with low-dose Risperidone (maximum 1 mg) for three months. The patients were observed for three months in terms of frequency and severity of spells monthly. In this study, the median (25th and 75th percentile) age of subjects was 2.3 (2.0-2.6) years. Both the number and severity of seizures in the subjects had a statistically significant decrease in the period after treatment with Risperidone (P<0.001). The studied boys and girls experienced statistically significant decrease in terms of both the frequency of spells (P-value of 0.002 and 0.039) and intensity of seizures (P=0.016) and P=0.008), respectively after treatment with Risperidone. Also, in the studied children under 2 years old and over 2 years old, both the frequency (P=0.021 and P=0.004) and intensity of spells (P=0.008) 0.016 for subjects under and over 2 years, respectively) had a statistically significant decrease after treatment with risperidone compared to pretreatment. According to the results of this study, it seems that both the frequency and the intensity of spells in children (regardless of gender and age group), experienced a statistically significant decrease after treatment with Risperidone. We suggest conducting a more comprehensive study considering a larger sample size in order to estimate this issue more correctly.


Soliton content in the standard optical OFDM signal.
The nonlinear Schrödinger equation (NLSE) is often used as a master path-average model for fiber-optic transmission lines. In general, the NLSE describes the co-existence of dispersive waves and soliton pulses. The propagation of a signal in such a nonlinear channel is conceptually different from linear systems. We demonstrate here that the conventional orthogonal frequency-division multiplexing (OFDM) input optical signal at powers typical for modern communication systems might have soliton components statistically created by the random process corresponding to the information content. Applying the Zakharov-Shabat spectral problem to a single OFDM symbol with multiple subcarriers, we quantify the effect of the statistical soliton occurrence in such an information-bearing optical signal. Moreover, we observe that at signal powers optimal for transmission, an OFDM symbol incorporates multiple solitons with high probability. The considered optical communication example is relevant to a more general physical problem of the generation of coherent structures from noise.


Orbitofrontal morphology in people at high risk of developing schizophrenia.
Abnormalities of orbitofrontal cortex (OFC) sulcogyral patterns have been reported in schizophrenia, but it is not known if these predate psychosis. Hundred and forty-six subjects at high genetic risk of schizophrenia, 34 first episode of schizophrenia patients (SZ) and 36 healthy controls were scanned and clinically assessed. Utilising the classification system proposed by Chiavaras, we categorised OFC patterns and compared their distribution between the groups, as well as between those high risk subjects who did, and did not develop schizophrenia. The relationship between OFC pattern and schizotypy was explored in high risk subjects. We refined Chiavaras' classification system, with the identification of a previously unreported variant of OFC surface structure. There were significant differences in distribution of OFC patterns between high risk subjects who did or did not develop schizophrenia as well as between the first episode of schizophrenia group and healthy controls. Within the high risk group, possession of OFC Type III was associated with higher ratings on the Structured Inventory for Schizotypy (SIS) psychotic factor. Our results suggest that OFC Type III is associated with psychotic features before the development of schizophrenia. Characterisation of OFC morphology may have a role in the identification of those at greatest risk of developing schizophrenia.


Isolated large third-trimester intracranial cyst on fetal ultrasound: fact or fiction?
To distinguish the fact from artifact of an isolated, large, intracranial cyst on prenatal sonography (PSG). The use of PSG is rapidly increasing with most obstetric ultrasounds occurring in general community settings like small hospitals and clinics with personnel who have variable training, experience, and interest levels. In contrast, most PSG articles and books are produced in large subspecialty centers with concentrated referral bases plus both highly-trained and experienced personnel. We report a series of 2 normal newborn patients who had a large prenatal unilateral intracranial cyst diagnosed by PSG in the 10 years between July of 1989 and 1999 at a rural community hospital. The newborns had imaging studies at birth and their neurodevelopmental progress was followed for several years. Textbook, bibliography and computerized Medline (1966-present) searches including prenatal ultrasound, observer variation, diagnostic errors, reproducibility of results, sensitivity and specificity, accuracy, central nervous system, false-positive, prenatal diagnosis, and brain were examined starting in August 1996 for reports. There were 4079 obstetric ultrasounds performed in 3.5 years, January 1996 through July 1999 at this rural community facility. This rate extrapolates to a total of 11 654 obstetric ultrasounds over the 10-year study period in which the 2 cases of intracranial cyst artifact occurred. Thus, the incidence of 2 intracranial cyst artifacts was estimated as 2/11 654 PSG, a .0002% false-positive rate. This is the first report of the occurrence of PSG artifacts in a community facility. Artifact is a real problem and needs to be specified in differential diagnoses. There are ways to decrease sonographic artifact-or at least to recognize it-so our estimates at a community hospital for its occurrence are presented with the relevant technical and ethical issues. None of these issues have been previously reported in the pediatric literature. Our false-positive rate for large intracranial cyst compares favorably with other reports. Our estimate may inflate our denominator by reporting scans rather than the number of fetuses scanned, and our numerator may miss cases that moved from the community. Confusion differentiating PSG artifact from reality often occurs when interpreting static or frozen real-time images. The signs that sonogram images may be artifacts include defects that: extend outside the fetal body; change shape, size and echogenecity with different scan planes; are not seen on all examinations; and are isolated in an otherwise normal fetus. Failure to offer quality PSG in clinical settings where it is available restricts access of pregnant women to the diagnosis of fetal anomalies, and therefore restricts access to the options of pregnancy termination, fetal therapy like fetal surgery, and delivery options of timing, setting, and mode. We suggest a multidisciplinary approach to prenatal abnormalities like isolated third trimester unilateral intracranial cyst in both primary and tertiary care settings aids interpretation followed by expectant conservative management without elaborate, risky, or terminal interventions.


Abducens (sixth) nerve palsy presenting as a rare case of isolated brainstem metastasis from a primary breast carcinoma.
Most isolated abducens (sixth) nerve palsies are ischaemic in nature. However, there are other causes that can mimic an abducens nerve palsy, which requires aggressive diagnostic management. A 56-year-old hypertensive woman presented with a right abduction deficit. Her past history revealed that she had undergone a mastectomy and completed a course of chemo- and radiation therapy for breast carcinoma. She was well until she develped binocular diplopia five months later. Magnetic resonance imaging showed a right pontine mass. Stereotactic biopsy was performed, and histopathology revealed a metastatic carcinoma that was compatible with an origin from the breast primary. We conclude that identifying and managing patients with metastatic lesions involves a multidisciplinary approach. Thorough history-taking and neuro-ophthalmologic evaluation would help physicians in establishing the primary differentials, which could not only be sight-saving but life-saving as well.


Overuse injuries in runners of different abilities-a one-year prospective study.
The aim of this prospective study was to investigate differences in participant characteristics, previous injury, running dynamics during a long-distance run, and training between injured and uninjured runners in runners of different abilities. Center-of-mass acceleration data were collected during a long-distance overground run. Runners were then divided into four groups (elite, advanced, intermediate and slow) based on their finishing time. Participants completed training diaries and were monitored for 1 year. Seventy-six runners completed the prospective study with 39 (51.3%) sustaining a running injury (44% elite, 42% advanced, 54% intermediate, 59% slow). Differences between injured and uninjured runners within each group related to injury included: (1) elite injured runners ran with longer contact times and (2) more slow injured runners reported an injury in previous year, were heavier, had higher body mass and body mass index, ran with lower step frequencies, and ran a greater weekly distance. Advanced injured runners exhibited fatigue changes in step regularity and peak braking during the run that may be related to injury. These findings suggest that runners of different abilities may have different factors related to injury however due to the small sample sizes in the groups this needs to be explored further.


Cell kill kinetics of several nogalamycin analogs and adriamycin for Chinese hamster ovary, L1210 leukemia, and B16 melanoma cells in culture.
Nogalamycin is an anthracycline antibiotic which was markedly cytotoxic in vitro and was active against several tumor systems in vivo. We compare here the lethality of several nogalamycin analogs against Chinese hamster ovary (CHO), mouse leukemia (L1210), and mouse melanoma (B16) cells in culture. 7-con-O-Methylnogarol (7-con-OMEN) was the most lethal of all the analogs tested. Thus, for CHO cells exposed for two hr to the drug, the 50% lethal doses of 7-con-OMEN, nogalamycin, and dis-nogamycin were 0.25, 2.7, and 5.8 micrograms/ml, respectively. In general, CHO cells were less sensitive than B16 or L1210 cells to most compounds. All compounds gave dose-survival curves which consisted of a shoulder region followed by a region of exponential decline in survival. The nogalamycin analogs nogalamycin, dis-nogamycin, 7-con-O-methylnogalarol, and 7-con-OMEN were selected for further study because of their greater lethality in vitro and antitumor activity in vivo. The lethality of these compounds was compared to that of Adriamycin. 7-con-OMEN was more toxic to CHO cells than was Adriamycin but was less toxic to B16 and L1210 cells. All of these compounds (except 7-con-O-methylnogalarol which was not tested) were more lethal to exponentially growing cells than to plateau-phase cells. The survival response after different periods of exposure to these drugs was compared. In order to make valid comparisons of the time-survival response to different drugs, the drug concentrations chosen were such that they were equitoxic after a two-hr exposure. Under these conditions, the order of lethality after long-term exposure (8 hr to 24 hr) was nogalamycin > dis-nogamycin > 7-con-OMEN, Adriamycin > 7-con-O-methylnogalarol. With all the drugs, the rate of cell death increased with increasing drug concentrations.


Varying Modes of Selection Among Toxin Families in the Venoms of the Giant Desert Hairy Scorpions (Hadrurus).
Venoms are primarily believed to evolve under strong diversifying selection resulting from persistent coevolution between predator and prey. Recent research has challenged this hypothesis, proposing that venoms from younger venomous lineages (e.g., snakes and cone snails) are governed predominantly by diversifying selection, while venoms from older venomous lineages (e.g., centipedes, scorpions, and spiders) are under stronger purifying selection. However, most research in older lineages has tested selection at more diverse phylogenetic scales. Although these tests are important for evaluating broad macroevolutionary trends underlying venom evolution, they are less equipped to detect species-level evolutionary trends, which likely have large impacts on venom variation seen at more diverse phylogenetic scales. To test for selection among closely related species from an older venomous lineage, we generated high-throughput venom-gland transcriptomes and venom proteomes for four populations of Giant Desert Hairy Scorpions (Hadrurus), including three Hadrurus arizonensis populations and one Hadrurus spadix population. We detected significant episodic and pervasive diversifying selection across a highly abundant toxin family that likely has a major role in venom function ([Formula: see text]KTxs), providing a contrast to the stronger purifying selection identified from other studies on scorpion venoms. Conversely, we detected weak episodic diversifying and/or stronger purifying selection in four toxin families (non-disulfide bridged peptides, phospholipase A2s, scorpine-like antimicrobial peptides, and serine proteases), most of which were less abundant and likely have ancillary functional roles. Finally, although we detected several major toxin families at disproportionate transcriptomic and/or proteomic abundances, we did not identify significant sex-based variation in Hadrurus venoms.


Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2.
One of the hallmarks of human pancreatic ductal adenocarcinoma (PDAC) is its pronounced type I collagen-rich fibrotic reaction. Although recent reports have shown that the fibrotic reaction can limit the efficacy of gemcitabine chemotherapy, the underlying mechanisms remain poorly understood. In this article, we show that the type I collagen allows PDAC cells to override checkpoint arrest induced by gemcitabine. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3-dimensional collagen microenvironment have minimal Chk1 phosphorylation and continue to proliferate in the presence of gemcitabine. Collagen increases membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent ERK1/2 phosphorylation to limit the effect of gemcitabine. Collagen also increases MT1-MMP-dependent high mobility group A2 (HMGA2) expression, a nonhistone DNA-binding nuclear protein involved in chromatin remodeling and gene transcription, to attenuate the effect of gemcitabine. Overexpression of MT1-MMP in the collagen microenvironment increases ERK1/2 phosphorylation and HMGA2 expression, and thereby further attenuates gemcitabine-induced checkpoint arrest. MT1-MMP also allows PDAC cells to continue to proliferate in the presence of gemcitabine in a xenograft mouse model. Clinically, human tumors with increased MT1-MMP show increased HMGA2 expression. Overall, our data show that collagen upregulation of MT1-MMP contributes to gemcitabine resistance in vitro and in a xenograft mouse model, and suggest that targeting MT1-MMP could be a novel approach to sensitize pancreatic tumors to gemcitabine.


An Irgafos® 168 story: When the ubiquity of an additive prevents studying its leaching from plastics.
Plastic pollution is a source of chemical to the environment and wildlife. Despite the ubiquity of plastic pollution and thus plastic additive in the environment, plastic additives have been studied to a limited extend. As a prerequisite to a study aiming to evaluate the leaching of a common additive used as an antioxidant (Irgafos® 168) from polyethylene microparticles, an inventory of the potential background contamination of the laboratory workplace was done. In this study, Irgafos® 168 (tris(2,4-ditert-butylphenyl) phosphite) and its oxidized form (tris (2,4-ditert-butylphenyl) phosphate) were quantified in different laboratory reagents, including the plastic packaging and the powders, using Pyrolysis-GC/MS. At least one form of Irgafos® 168 was detected in all tested laboratory reagents with higher concentrations in caps and bottles as compared to the powders. Additionally, oxidized Irgafos® 168 was also found in the reverse osmosed and deionized water container used in the laboratory. The same profile of contamination, i.e. higher concentration of the oxidized form and higher concentrations in acidic reagents, was observed when comparing the reagent and their respective containers suggesting that the additive is leaching from the container into the powder. Overall, this study demonstrates that the antioxidant additive Irgafos® 168 is ubiquitous in the laboratory workplace. Plastic additives such as Irgafos® 168 can therefore largely interfere and biased ecotoxicological and toxicological studies especially using environmentally relevant concentrations of microplastics. The source, fate and effects of plastic additive from plastic debris should be carefully considered in future studies that require setting up methods to overcome these contaminations.


Stabilisation of an amorphous form of ROY through a predicted co-former interaction.
The highly polymorphic compound ROY, notorious for the colour of its crystals, was the subject of an optimised high-throughput ultrasound-based co-crystal screen. This screen involved a computational pre-screen which highlighted an interaction between ROY and the potential co-former pyrogallol. We have shown that the presence of pyrogallol stabilises the amorphous form of ROY, highlighting the potential for future prediction of co-amorphous behaviours.


Improvement on storage stability of iron-fortified soybean powder by microencapsulation.
Full-fat soybean powder was a more difficult-to-fortify food vehicle than cereal flour and powdered milk products because of a large quantity of unsaturated fatty acids, particularly when iron was necessary to be fortified. Minimizing oxidation of lipids was extremely valuable in the fortified-food industry. However, very limited data were available on the effect of microencapsulation of iron compounds on lipid oxidation in full-fat soybean powder. In our study, ferric pyrophosphate (FP) was microencapsulated by the emulsifying-gelation technique and its effect on the storage stability of Yingyangbao (YYB) was evaluated. The results showed that microencapsulated FP (MFP) was regularly spherical and uniformly distributed. MFP could significantly (P < 0.05) decrease the sensory score of rancid odor for YYB. The formation of lipid oxidation products such as carbonyl compounds, malondialdehyde, pentanal, and hexanal in YYB during the accelerated test was significantly retarded, improving oxidative stability and delaying the sensory deterioration. The E-nose analysis showed that YYB with MFP had significantly (P < 0.05) lower levels of response values on the specific sensors than YYB containing FP with or without ascorbyl palmitate. MFP could significantly (P < 0.05) improve the sensory and oxidative stability of iron-fortified full-fat soybean powder such as YYB.


Clavulanate and beta-lactamase induction.
Concern has been expressed that clavulanate can antagonize ticarcillin against enterobacteria and pseudomonads that have inducible expression of chromosomal 'Class I' beta-lactamases. It is suggested that clavulanate-induced enzyme inactivates ticarcillin, which itself is a feeble inducer. We confirmed that this mechanism applied, showing that antagonism was abolished in beta-lactamase-basal mutants of inducible strains. Antagonism has been reported in double disc tests with strains of Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, Serratia spp. and indole-positive Proteeae. Only with some strains of Ent. cloacae and Morganella morganii, however, did the presence of 1-32 mg/l clavulanate elevate the MIC of ticarcillin by more than one or two dilutions in chequerboard studies. Clavulanate was synergistic with ticarcillin against Proteus vulgaris strains, being a potent inhibitor of the unusual Class I enzyme of this species. Induction-determined antagonism was not reduced in Ent. cloacae transconjugants that produced the plasmid-mediated TEM-1 beta-lactamase, despite the ability of this enzyme to bind clavulanate. Our results suggest that Ent. cloacae and M. morganii strains should be confirmed not to be more sensitive to ticarcillin alone than to ticarcillin/clavulanate, before the latter combination is used clinically. Otherwise, it appears that beta-lactamase induction is unlikely to cause significant antagonism. It is emphasized that induction is reversible, causing, at worst, a transient resistance. It should not be confused with the selection of stably-derepressed mutants that can occur, for example, in the clinical use of newer cephalosporins.


Viability of carbon-based life as a function of the light quark mass.
The Hoyle state plays a crucial role in the helium burning of stars that have reached the red giant stage. The close proximity of this state to the triple-alpha threshold is needed for the production of carbon, oxygen, and other elements necessary for life. We investigate whether this life-essential condition is robust or delicately fine-tuned by measuring its dependence on the fundamental constants of nature, specifically the light quark mass and the strength of the electromagnetic interaction. We show that there exist strong correlations between the alpha-particle binding energy and the various energies relevant to the triple-alpha process. We derive limits on the variation of these fundamental parameters from the requirement that sufficient amounts of carbon and oxygen be generated in stars. We also discuss the implications of our results for an anthropic view of the Universe.


Pathways curriculum and family interventions to promote healthful eating and physical activity in American Indian schoolchildren.
Pathways, a multisite school-based study aimed at promoting healthful eating and increasing physical activity, was a randomized field trial including 1704 American Indian third to fifth grade students from 41 schools (21 intervention, 20 controls) in seven American Indian communities. The intervention schools received four integrated components: a classroom curriculum, food service, physical activity, and family modules. The curriculum and family components were based on Social Learning Theory, American Indian concepts, and results from formative research. Process evaluation data were collected from teachers (n=235), students (n=585), and families. Knowledge, Attitudes, and Behavior Questionnaire data were collected from 1150 students including both intervention and controls. There were significant increases in knowledge and cultural identity in children in intervention compared to control schools with a significant retention of knowledge over the 3 years, based on the results of repeating the third and fourth grade test items in the fifth grade. Family members participated in Family Events and take-home activities, with fewer participating each year. A culturally appropriate school intervention can promote positive changes in knowledge, cultural identity, and self-reported healthful eating and physical activity in American Indian children and environmental change in school food service.


Pergolide interactions with nicotine and pilocarpine in rats on the radial-arm maze.
Antagonists of nicotinic and muscarinic acetylcholinergic (ACh) receptors have significant interactions with dopaminergic (DA) ligands with regard to radial-arm maze choice accuracy. The current studies examined the interactions of agonists of nicotinic and muscarinic ACh receptors with the DA agonist pergolide. Pergolide given in a range from 0.03-1.0 mg/kg had no detectable effect on radial-arm maze choice accuracy when given alone. With this dose range there was a linear increase in response latency. Pergolide had significant interactive effects with the nicotinic and muscarinic agonists nicotine and pilocarpine. Given together with nicotine, pergolide produced a significantly elevated linear increase in accuracy relative to when it was given alone. With pilocarpine, pergolide had an inverted U-shaped effect improving choice accuracy at low to moderate doses of 0.03 and 0.1 mg/kg. These results support previous findings of DA-ACh interactions with regard to radial-arm maze choice accuracy. Combined DA-ACh treatment may be a useful treatment of cognitive dysfunction.


Health system decarbonization on obstetric and newborn units.
The healthcare industry makes up 4.6 % of greenhouse gas (GHS) emissions worldwide. Although it is not known what proportion of GHGs come from obstetric and newborn units, newborns and pregnant individuals are likely to face some of the largest consequences from climate change. We review the literature in the areas of decarbonization on labor and delivery (L&D) and neonatal units and describe innovations from the fields of surgery and anesthesia. Best practices for L&D include refining disposable equipment packs, decreasing the use of single-use medical devices, adequately triaging waste, and decreasing the use of potent anesthetic gases such as nitrous oxide and desflurane. In neonatal settings, similarly triaging waste and decreasing the use of plastics containing endocrine disrupting chemicals can lower the carbon and environmental footprint and improve neonatal health. Additionally, avoiding unnecessary cesarean deliveries and increasing breastfeeding practices are also likely to improve the carbon footprint of L&D and neonatal units.


[Detoxification of aflatoxin B1 by different chemical methods and evaluation of the effectiveness of the treatments applied].
Different chemical treatments were applied to solutions of Aflatoxin B1 in order to compare their efficacy for the detoxification of AfB1: sodium sulfite, sodium hydrogen sulfate, sodium hydroxide, ammonia, sodium hypochlorite, hydrogen peroxide. The rate of the detoxification of AfB1 has been followed by three experimental approaches: 1. Quantitative estimation of the unmodified AfB1 by HPLC chromatography. 2. Quantitative estimation of the most toxic metabolite. AfB1-epoxide by chemical transformation into the trishydroxy AfB1 derivative followed by HPLC analysis. 3. Determination of the bacterial mutagenic activity, following the Ames' test. Among the different detoxification methods that were compared, the treatment with sodium sulfite proved to be the most efficient and seems thus to be recommended for foods contaminated by AfB1.


Evaluating the Prediction of Brain Maturity From Functional Connectivity After Motion Artifact Denoising.
The ability to make individual-level predictions from neuroanatomy has the potential to be particularly useful in child development. Previously, resting-state functional connectivity (RSFC) MRI has been used to successfully predict maturity and diagnosis of typically and atypically developing individuals. Unfortunately, submillimeter head motion in the scanner produces systematic, distance-dependent differences in RSFC and may contaminate, and potentially facilitate, these predictions. Here, we evaluated individual age prediction with RSFC after stringent motion denoising. Using multivariate machine learning, we found that 57% of the variance in individual RSFC after motion artifact denoising was explained by age, while 4% was explained by residual effects of head motion. When RSFC data were not adequately denoised, 50% of the variance was explained by motion. Reducing motion-related artifact also revealed that prediction did not depend upon characteristics of functional connections previously hypothesized to mediate development (e.g., connection distance). Instead, successful age prediction relied upon sampling functional connections across multiple functional systems with strong, reliable RSFC within an individual. Our results demonstrate that RSFC across the brain is sufficiently robust to make individual-level predictions of maturity in typical development, and hence, may have clinical utility for the diagnosis and prognosis of individuals with atypical developmental trajectories.


Variable neuroendocrine responses to ecologically-relevant challenges in sticklebacks.
Variable neuroendocrine responses to ecologically-relevant challenges in sticklebacks. PHYSIOL BEHAV 00(0) 000-000, 2006. Here, we compare the behavioral, endocrine and neuroendocrine responses of individual sticklebacks exposed to either an unfamiliar conspecific or to a predator. We found that the two stressors elicited a similar hypothalamic-pituitary-interrenal response as assessed by whole-body concentrations of cortisol, but produced quite different patterns of change in brain monoamine and monoamine metabolite content as assessed by concentrations of serotonin (5-HT), dopamine (DA), norepinephrine (NE) and the monoamine metabolites 5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA) and 3-4-dihydroxyphenylacetic acid (DOPAC). For example, relative to baseline levels, NE levels were elevated in individuals exposed to a predator but were lower in individuals confronted by a challenging conspecific. Levels of monoamine neurotransmitters in specific regions of the brain showed extremely close links with behavioral characteristics. Frequency of attacking a conspecific and inspecting a predator were both positively correlated with concentrations of NE. However, whereas serotonin was negatively correlated with frequency of attacking a conspecific, it was positively associated with predator inspection. The data indicate that the qualitative and quantitative nature of the neuroendocrine stress response of sticklebacks varies according to the nature of the stressor, and that interindividual variation in behavioural responses to challenge are reflected by neuroendocrine differences.


Adaptive time-frequency matrix features for T wave alternans analysis.
T wave alternans (TWA) has been associated with ventricular arrhythmias. Hence, TWA detection can risk stratify patients with heart disease who may experience sudden death from ventricular arhythmias. However, accurate TWA detection is technically challenging due to the low microvolt TWA signal and the confounding effect of biological noise such as movement, myopotentials or respiration. In this paper, we propose nonnegative matrix factorization (NMF)-Adaptive spectral method to increase the robustness of TWA detection in ambulatory electrocardiograms (ECGs). The proposed method applies a non-linear time-frequency (TF) analysis and NMF to the aligned ST-T waveforms. This method separates the TWA signal from the other non-desired ECG signal components, and detects TWA with high accuracy. The performance of our proposed method is validated in a clinical study using ECGs which confirms a TWA detection of 92% compared to 47% using the conventional spectral method.


Phosphorylation of tau by glycogen synthase kinase 3beta affects the ability of tau to promote microtubule self-assembly.
To study the effects of phosphorylation by glycogen synthase kinase-3beta (GSK-3beta) on the ability of the microtubule-associated protein tau to promote microtubule self-assembly, tau isoform 1 (foetal tau) and three mutant forms of this tau isoform were investigated. The three mutant forms of tau had the following serine residues, known to be phosphorylated by GSK-3, replaced with alanine residues so as to preclude their phosphorylation: (1) Ser-199 and Ser-202 (Ser-199/202-->Ala), (2) Ser-235 (Ser-235-->Ala) and (3) Ser-396 and Ser-404 (Ser-396/404-->Ala). Wild-type tau and the mutant forms of tau were phosphorylated with GSK-3beta, and their ability to promote microtubule self-assembly was compared with the corresponding non-phosphorylated tau species. In the non-phosphorylated form, wild-type tau and all of the mutants affected the mean microtubule length and number concentrations of assembled microtubules in a manner consistant with enhanced microtubule nucleation. Phosphorylation of these tau species with GSK-3beta consistently reduced the ability of a given tau species to promote microtubule self-assembly, although the affinity of the tau for the microtubules was not greatly affected by phosphorylation since the tau species remained largely associated with the microtubules. This suggests that the regulation of microtubule assembly can be controlled by phosphorylation of tau at sites accessible to GSK-3beta by a mechanism that does not necessarily involve the dissociation of tau from the microtubules.


Mdivi1 ameliorates mitochondrial dysfunction in non-alcoholic steatohepatitis by inhibiting JNK/MFF signaling.
Mitochondrial dysfunction plays a crucial role in the progression of non-alcoholic steatohepatitis (NASH). Mitochondrial division inhibitor 1 (Mdivi1) is a potential inhibitor of dynamin-related protein (Drp1) and mitochondrial fission. However, the therapeutic effect of Mdivi1 against NASH and its underlying molecular mechanisms remain unclear. In this study, we established mouse models of NASH by inducing high-fat/high-cholesterol (HFHC) or methionine- and choline-deficient (MCD) diets and treated the animals with 5 mg/kg/day Mdivi1 or placebo. Treatment with Mdivi1 significantly alleviated diet-induced fatty liver phenotypes, including increased liver weight/body weight ratio, insulin resistance, hepatic lipid accumulation, steatohepatitis, and liver injury. Furthermore, Mdivi1 treatment suppressed HFHC or MCD diet-induced changes in the expression of genes related to lipid metabolism and inflammatory cytokines. Additionally, Mdivi1 reduced macrophage infiltration in the injured liver and promoted polarization of macrophages towards the M1 phenotype. At the molecular level, Mdivi1 attenuated mitochondrial fission by reducing Drp1 activation and expression, thereby decreasing mitochondrial reactive oxygen species accumulation and mitochondrial DNA damage. Moreover, Mdivi1-treated mice exhibited elevated levels of phosphorylated-c-Jun N-terminal kinase (p-JNK), mitochondrial fission factor (MFF), cleaved caspase 3 protein, and TUNEL-positive cell expression in the liver, suggesting that Mdivi1 might ameliorate mitochondrial dysfunction and reduce hepatocyte apoptosis by inhibiting the JNK/MFF pathway. Collectively, Mdivi1 protected against diet-induced NASH by restoring mitochondrial homeostasis and function, potentially through its inhibitory effect on the JNK/MFF pathway. Consequently, further investigation of Mdivi1 as a promising drug for NASH treatment is warranted.


Mining and Tailings Dam Detection in Satellite Imagery Using Deep Learning.
This work explores the combination of free cloud computing, free open-source software, and deep learning methods to analyze a real, large-scale problem: the automatic country-wide identification and classification of surface mines and mining tailings dams in Brazil. Locations of officially registered mines and dams were obtained from the Brazilian government open data resource. Multispectral Sentinel-2 satellite imagery, obtained and processed at the Google Earth Engine platform, was used to train and test deep neural networks using the TensorFlow 2 application programming interface (API) and Google Colaboratory (Colab) platform. Fully convolutional neural networks were used in an innovative way to search for unregistered ore mines and tailing dams in large areas of the Brazilian territory. The efficacy of the approach is demonstrated by the discovery of 263 mines that do not have an official mining concession. This exploratory work highlights the potential of a set of new technologies, freely available, for the construction of low cost data science tools that have high social impact. At the same time, it discusses and seeks to suggest practical solutions for the complex and serious problem of illegal mining and the proliferation of tailings dams, which pose high risks to the population and the environment, especially in developing countries.


Imaging of the Postoperative Anterior Cruciate Ligament: Emphasis on New Surgical and Imaging Methods.
The aim of anterior cruciate ligament (ACL) reconstruction is to restore normal function of the knee, but unfortunately abnormal kinematics and a predisposition to knee osteoarthritis occur in a significant percentage of patients. So there is an ongoing need to improve treatment options and long-term outcome of patients with a ruptured ACL. With the recent advancements in the field of ACL tissue engineering, the focus of treatment for ACL injuries is changing from resection and reconstruction toward repair and regeneration. Several new ACL repair methods were recently introduced as an alternative to traditional ACL reconstructive procedures. Radiologists must become familiar with these new surgical methods to interpret their appearance correctly on postoperative imaging studies. This article provides an overview of the latest advancements in ACL surgical methods and discusses the role of imaging to assess the postoperative ACL including both standard and advanced imaging methods.


Non-local validated parametrization of an agent-based model of local-scale Taenia solium transmission in North-West Peru.
The pork tapeworm, Taenia solium, is the cause of a preventable zoonotic disease, cysticercosis, affecting both pigs and humans. Continued endemic transmission of T. solium is a major contributor of epilepsy and other neurologic morbidity, and the source of important economic losses, in many rural areas of developing countries. Simulation modelling can play an important role in aiding the design and evaluation of strategies to control or even eliminate transmission of the parasite. In this paper, we present a new agent based model of local-scale T. solium transmission and a new, non-local, approach to the model calibration to fit model outputs to observed human taeniasis and pig cysticercosis prevalence simultaneously for several endemic villages. The model fully describes all relevant aspects of T. solium transmission, including the processes of pig and human infection, the spatial distribution of human and pig populations, the production of pork for human consumption, and the movement of humans and pigs in and out in several endemic villages of the northwest of Peru. Despite the high level of uncertainty associated with the empirical measurements of epidemiological data associated with T. solium, the non-local calibrated model parametrization reproduces the observed prevalences with an acceptable precision. It does so not only for the villages used to calibrate the model, but also for villages not included in the calibration process. This important finding demonstrates that the model, including its calibrated parametrization, can be successfully transferred within an endemic region. This will enable future studies to inform the design and optimization of T. solium control interventions in villages where the calibration may be prevented by the limited amount of empirical data, expanding the possible applications to a wider range of settings compared to previous models.


Structural insight into mechanism and diverse substrate selection strategy of L-ribulokinase.
The araBAD operon encodes three different enzymes required for catabolism of L-arabinose, which is one of the most abundant monosaccharides in nature. L-ribulokinase, encoded by the araB gene, catalyzes conversion of L-ribulose to L-ribulose-5-phosphate, the second step in the catabolic pathway. Unlike other kinases, ribulokinase exhibits diversity in substrate selectivity and catalyzes phosphorylation of all four 2-ketopentose sugars with comparable k(cat) values. To understand ribulokinase recognition and phosphorylation of a diverse set of substrates, we have determined the X-ray structure of ribulokinase from Bacillus halodurans bound to L-ribulose and investigated its substrate and ATP co-factor binding properties. The polypeptide chain is folded into two domains, one small and the other large, with a deep cleft in between. By analogy with related sugar kinases, we identified (447)GGLPQK(452) as the ATP-binding motif within the smaller domain. L-ribulose binds in the cleft between the two domains via hydrogen bonds with the side chains of highly conserved Trp126, Lys208, Asp274, and Glu329 and the main chain nitrogen of Ala96. The interaction of L-ribulokinase with L-ribulose reveals versatile structural features that help explain recognition of various 2-ketopentose substrates and competitive inhibition by L-erythrulose. Comparison of our structure to that of the structures of other sugar kinases revealed conformational variations that suggest domain-domain closure movements are responsible for establishing the observed active site environment.


Problems with tense marking in children with specific language impairment: not how but when.
Many children with specific language impairment (SLI) have persisting problems in the correct use of verb tense, but there has been disagreement as to the underlying reason. When we take into account studies using receptive as well as expressive language tasks, the data suggest that the difficulty for children with SLI is in knowing when to inflect verbs for tense, rather than how to do so. This is perhaps not surprising when we consider that tense does not have a transparent semantic interpretation, but depends on complex relationships between inflections and hierarchically organized clauses. An explanation in terms of syntactic limitations contrasts with a popular morpho-phonological account, the Words and Rules model. This model, which attributes problems to difficulties with applying a rule to generate regular inflected forms, has been widely applied to adult-acquired disorders. There are striking similarities in the pattern of errors in adults with anterior aphasia and children with SLI, suggesting that impairments in appreciation of when to mark tense may apply to acquired as well as developmental disorders.


Sex and gender matters : A sex-specific analysis of original articles published in the Wiener klinische Wochenschrift between 2013 and 2015.
The variables sex and gender are significantly related to health and disease of women and men. Aiming at quality research, biomedical publications need to account for the key variables sex and gender. All original articles published in the Wiener klinische Wochenschrift between 2013 and 2015 were extracted into a database. As a result, the 195 published articles were selected for review led by the Sex and Gender Equity in Research Guidelines (SAGER) by the European Association of Science Editors (EASE). The slightest indications of mentioning sex and/or gender were assessed by two reviewers independently from one another. Of the 195 publications 4 specified sex and/or gender in the title, and 62 in the abstract. None of the authors reported whether the variables sex and/or gender may have relevance and were taken into account in the design of the study. Of the 195 publications 48 mentioned the potential implications of sex and/or gender on the study results. In the time span studied most of the selected articles of this journal did not account for the variables sex and/or gender systematically or adequately. For future research the existing guidelines can help authors and editors to overcome gender bias due to inadequate methods. Applying sex and gender-sensitive methods to biomedical and health research is necessary for high quality and as a precondition for results which are generalizable and applicable to both women and men.


Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma.
Local delivery of carmustine (BCNU) from biodegradable polymers prolongs survival against experimental brain tumors. Moreover, paracrine administration of interleukin-2 (IL-2) has been shown to elicit a potent antitumor immune response and to improve survival in animal brain tumor models. We report the use of a novel polymeric microsphere delivery vehicle to release IL-2. We demonstrate both in vitro release of cytokine from the microspheres and histological evidence of the inflammatory response elicited by IL-2 released from the microspheres in the rat brain. These microspheres are used to deliver IL-2, and biodegradable polymer wafers are used to deliver BCNU, directly at the site of an intracranially implanted glioma in the rat. The two agents administered locally show a synergistic effect. Fischer 344 rats challenged intracranially with 9L gliosarcoma received an intracranial implant of either empty microspheres or microspheres containing IL-2 (IL-2 MS). Five days later, animals in each group were randomized to receive polymer implants loaded with 0, 3.8, or 10% BCNU at the tumor site. Animals that received the combination of IL-2 MS and 3.8% BCNU polymer (median survival, 28.5 d) or IL-2 MS and 10% BCNU polymer (median survival, 45.5 d) showed significantly improved survival compared with animals that received monotherapy with IL-2 microspheres (median survival, 24 d), 3.8% BCNU polymer (median survival, 24 d), or 10% BCNU polymer (median survival, 32.5 d). Control animals had a median survival of 18 days. The combination of either 3.8 or 10% BCNU polymer with IL-2 MS resulted in 7 and 25% long-term survivors, respectively. By showing synergy of IL-2 and BCNU in an animal glioma model and using a reproducible synthetic delivery system for each agent (i.e., one that did not rely on genetically engineered cells or viruses), we hope that the combination of local immunotherapy and chemotherapy can take an important step closer to clinical application in patients with malignant brain tumors.


Current problems of nonionizing radiation.
Electromagnetic radiation in the radiofrequency range is the most common type of nonionizing radiation. The accelerated development in telecommunications and the introduction of power transmission lines, as well as glue drying and plastic heating in the wood and plastic industries, cause both occupational and nonoccupational systematic exposure to electromagnetic radiation in the radiofrequency range. For the hygienic rating of radiowave exposure it is necessary to use biological models to evaluate, in depth, the mechanisms and effects of electromagnetic radiation. The ultra- and superhigh frequency range is the most active in causing biological responses. The high frequency range is less active. Physical characteristics (continuous and impulse) and the combined effect of the electromagnetic field with other factors, eg, elevated air temperature, etc, have an effect on biological responses.


Liver transplantation for primary biliary cirrhosis and primary sclerosing cholangitis: predicting outcomes with natural history models.
In patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), risk score models that reflect disease severity have been developed and can serve as an objective measurement to assess and evaluate the effect of the severity of liver disease on the outcome of liver transplantation. Thus, using the established Mayo risk scores for PBC and PSC, one not only can estimate survival for the individual patient but can measure disease activity as well. Indeed, several studies have suggested that the optimal timing of liver transplantation with use of the Mayo PBC model may be an important tool to improve survival, decrease morbidity, and decrease overall related costs. Likewise, studies in patients with PSC have yielded similar results. This review explores how prognostic mathematical survival models for PBC and PSC might be applied to individual patients in need of liver transplantation. The following question is addressed: How can the timing of liver transplantation be optimized to increase survival, decrease postoperative morbidity, and ultimately, decrease the overall resource utilization involved in this procedure?


Characterization of a new megabirnavirus that confers hypovirulence with the aid of a co-infecting partitivirus to the host fungus, Rosellinia necatrix.
A new virus termed Rosellinia necatrix megabirnavirus 2 (RnMBV2) was molecularly and biologically characterized. RnMBV2 was originally harbored in isolate W8 of R. necatrix co-infected with the previously reported virus Rosellinia necatrix partitivirus 1 (RnPV1). RnMBV2 has molecular features similar and different from precedent megabirnaviruses, Rosellinia necatrix megabirnavirus 1 (RnMBV1) and Sclerotinia sclerotiorum megabirnavirus 1 (SsMBV1). The two genomic segments of RnMBV2 (9.0-kbp dsRNA1 and 8.0-kbp dsRNA2) each possess two open reading frames (ORF1 and 2 on dsRNA1 and ORF3 and 4 on dsRNA2), with a well conserved 5'-long untranslated region (UTR) of 1.7-1.8kb between the segments, and relatively short 3'-UTR. The RnMBV2 dsRNA1-coded capsid protein (CP) and RNA-dependent RNA polymerase (RdRp) show higher sequence identity to those of SsMBV1 than to those of RnMBV1, whereas the RnMBV2 ORF3-coded protein is more closely related to the counterpart of RnMBV1. No significant amino acid sequence similarity was detected among ORF4-coded sequences of the three megabirnaviruses. Virion transfection and co-culturing allowed for single and double infection of mycelial incompatible isolates W37 and W97 by RnMBV2 and/or RnPV1. Their comparative analyses showed RnMBV2 to be able to confer hypovirulence with the aid of a co-infecting RnPV1, while the individual viruses exhibited asymptomatic infections. Interestingly, RnPV1 accumulation appeared to be increased in co-infected fungal strain with two segments of RnMBV2 relative to singly infected fungal strains. Furthermore, the dispensability of RnMBV2 dsRNA2 was demonstrated to be similar to that of the other two megabirnaviruses.


Facial Cellulitis Caused by Candida Guilliermondi in an Immunocompetent Patient: A Rare Case Report.
Candida cellulitis is a rare disease, primarily reported in immunocompromised patients. Atypical Candida spp. infections are increasing, largely due to the growing number of immunocompromised patients. This case report describes a 52-year-old immunocompetent patient with facial cellulitis caused by Candida guilliermondi. Candida guilliermondi has not previously been reported as a cause of facial cellulitis in either immunocompromised or immunocompetent patients. A 52-year-old, otherwise healthy, male patient presented with facial cellulitis that did not respond to intravenous antibiotics. Culture of the drained pus revealed Candida guilliermondi. The patient was successfully treated with intravenous fluconazole. This case highlights the possibility of atypical Candida spp. causing deep facial infections in immunocompetent patients. Candida guilliermondi has not been previously reported as a cause of facial cellulitis in either immunocompromised or immunocompetent patients. Healthcare providers should consider atypical Candida spp. infections in the differential diagnosis of deep facial infections in both immunocompromised and immunocompetent patients. Candida guilliermondi can cause facial cellulitis in immunocompetent patients. This has not been previously reported.Atypical Candida spp. infections should be considered in the differential diagnosis of deep facial infections in both immunocompromised and immunocompetent patients.Healthcare providers should be aware of the increasing incidence of non-Candida albicans Candida species infections, especially in immunocompromised patients.


Acute alcohol effects on inhibitory control and implicit cognition: implications for loss of control over drinking.
Alcohol impairs inhibitory control, and it alters implicit alcohol cognitions including attentional bias and implicit associations. These effects are seen after doses of alcohol which do not lead to global impairments in cognitive performance. We review studies which demonstrate that the effects of alcohol on inhibitory control are associated with the ability of alcohol to prime alcohol-seeking behavior. We also hypothesize that alcohol-induced changes in implicit alcohol cognitions may partially mediate alcohol-induced priming of the motivation to drink. Based on contemporary theoretical models and conceptualizations of executive function, impulsivity, and the motivational salience of alcohol-related cues, we speculate on other aspects of cognition that may underlie alcohol's effects on alcohol seeking. Inconsistencies in existing research and priorities for future research are highlighted, including dose effects and the potential interactions between chronic heavy drinking and the acute effects of alcohol on these cognitive processes.


Steroid therapy is associated with decreased numbers of dendritic cells and fibroblasts, and increased numbers of satellite cells, in the dystrophic skeletal muscle.
The possible therapeutic benefits of using steroids to enhance muscle strength and slow disease progression in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) has been examined previously. In this investigation, it was hypothesised that steroid therapy is associated with morphological changes in the dystrophic muscle. To test this hypothesis, two muscle biopsies were obtained (one biopsy before treatment, and the second 6 months following prednisone therapy) from 24 patients with dystrophies (18 DMD, 6 BMD). The participants were categorised into: control (6 specimens, normal muscle), untreated and treated groups. The muscle was evaluated for ultrastructural changes using transmission electron microscopy (TEM). In the untreated group, the muscle fibres were degenerated and of variable sizes. The myofibrils were thin with either complete loss of bands and/or abnormal banding patterns. The Z-lines were irregularly spaced and loosely registered. The mitochondria of the myofibrils were small, few, spherical and irregularly distributed. Numerous dendritic cells (DCs) with euchromatic nuclei, and multiple and long dendrites, were seen among the myofibrils. The collagen fibres among the muscle fibres (endomysium) were numerous and large. The satellite cells had euchromatic nuclei with clumps of heterochromatin. In the treated group, the muscle fibres had a relatively uniform size with occasional fibres showing partial degeneration. The myofibrils had a relatively similar diameter comparable to that of normal muscle .The degenerated areas were small in size with occasional foci showing loss of banding pattern, and abnormal short bands with thick and hazy Z-lines. The mitochondria of the myofibrils were numerous, spherical, small in size and regularly arranged between the myofibrils. Few DCs, with heterochromatic nuclei, and few and short dendrites appeared between the myofibrils. The collagen fibres between the muscle fibres (endomysium) were numerous and large. As compared with the treated group, there was a statistically significant increase (p<0.05) in the numbers of DCs (0.7+/-0.2 vs 1.6+/-0.3) and fibroblasts (1.9+/-0.2 vs 2.9 +/-0.3) in the untreated group. Alternatively, there was a statistically significant decrease (p<0.05) in the numbers of satellite cells (1.2+/-0.2 vs 0.6+/-0.1). The ability of steroids to induce ultrastructural features of improvement supports the notion that they have beneficial therapeutic role. The clinical ramifications of these observations mandate further studies.


Extracting binaural information from simultaneous targets and distractors: effects of amplitude modulation and asynchronous envelopes.
When different components of a stimulus carry different binaural information, processing of binaural information in a target component is often affected. The present experiments examine whether such interference is affected by amplitude modulation and the relative phase of modulation of the target and distractors. In all experiments, listeners attempted to discriminate interaural time differences of a target stimulus in the presence of distractor stimuli with ITD=0. In Experiment 1, modulation of the distractors but not the target reduced interference between components. In Experiment 2, synthesized musical notes exhibited little binaural interference when there were slight asynchronies between different streams of notes (31 or 62 ms). The remaining experiments suggested that the reduction in binaural interference in the previous experiments was due neither to the complex spectra of the synthesized notes nor to greater detectability of the target in the presence of modulated distractors. These data suggest that this interference is reduced when components are modulated in ways that result in the target appearing briefly in isolation, not because of segregation cues. These data also suggest that modulation and asynchronies between modulators that might be encountered in real-world listening situations are adequate to reduce binaural interference to inconsequential levels.


Land Cover of Early-Life Environment Modulates the Risk of Type 1 Diabetes.
Environmental microbial exposures have been implicated to protect against immune-mediated diseases such as type 1 diabetes. Our objective was to study the association of land cover around the early-life dwelling with the development of islet autoimmunity and type 1 diabetes to evaluate the role of environmental microbial biodiversity in the pathogenesis. Association between land cover types and the future risk of type 1 diabetes was studied by analyzing land cover types classified according to Coordination of Information on the Environment (CORINE) 2012 and 2000 data around the dwelling during the first year of life for 10,681 children genotyped for disease-associated HLA-DQ alleles and monitored from birth in the Type 1 Diabetes Prediction and Prevention (DIPP) study. Land cover was compared between children who developed type 1 diabetes (n = 271) or multiple diabetes-associated islet autoantibodies (n = 384) and children without diabetes who are negative for diabetes autoantibodies. Agricultural land cover around the home was inversely associated with diabetes risk (odds ratio 0.37, 95% CI 0.16-0.87, P = 0.02 within a distance of 1,500 m). The association was observed among children with the high-risk HLA genotype and among those living in the southernmost study region. Snow cover on the ground seemed to block the transfer of the microbial community indoors, leading to reduced bacterial richness and diversity indoors, which might explain the regional difference in the association. In survival models, an agricultural environment was associated with a decreased risk of multiple islet autoantibodies (hazard ratio [HR] 1.60, P = 0.008) and a decreased risk of progression from single to multiple autoantibody positivity (HR 2.07, P = 0.001) compared with an urban environment known to have lower environmental microbial diversity. The study suggests that exposure to an agricultural environment (comprising nonirrigated arable land, fruit trees and berry plantations, pastures, natural pastures, land principally occupied by agriculture with significant areas of natural vegetation, and agroforestry areas) early in life is inversely associated with the risk of type 1 diabetes. This association may be mediated by early exposure to environmental microbial diversity.


Experimental analysis of biparental inbreeding in a self-fertilizing plant.
Localized dispersal and mating may genetically structure plant populations, resulting in matings among related individuals. This biparental inbreeding has significant consequences for the evolution of mating systems, yet is difficult to estimate in natural populations. We estimated biparental inbreeding in two populations of the largely self-fertilizing plant Aquilegia canadensis using standard inference as well as a novel experiment comparing apparent selfing between plants that were randomly relocated within populations to experimental control plants. Using two allozyme markers, biparental inbreeding (b) inferred from the difference between single-locus and multilocus estimates of selfing (b = s(s) - s(m)) was low. Less than 3% of matings involved close relatives (mean b = 0.029). In contrast, randomly relocating plants greatly reduced apparent selfing (mean s(s) = 0.674) compared to control plants that had been dug up and replanted in their original locations (s(s) = 0.953, P = 0.002). Based on this difference in s(s), we estimated that approximately 30% of all matings involved close relatives (mean b = 0.279, 95% CL = 0.072-0.428). Inference from s(s) - s(m) underestimated b in these populations by more than an order of magnitude. Biparental inbreeding is thought to influence the evolution of self-fertilization primarily through reducing the genetic cost of outcrossing. This is unlikely to be of much significance in A. canadensis because inbreeding depression (a major cost of selfing) is much stronger than the cost of outcrossing. However, biparental inbreeding combined with strong inbreeding depression may influence selection on dispersal.


[Changes in the transepithelial potential and spike responses of the ampullae of Lorenzini to temperature stimulation in the skate].
Electrical responses of the sensory epithelium of Lorenzinian ampullae as well as their nerve fibres frequency reactions to thermal stimulation were studied in Black Sea skates, Raja clavata. Electrically isolated ampullae with input resistance 500-800 K omega were used. They were loaded through a feedback circuit to a controllable resistance. Heating of the ampulla caused a lumen-negative shift of the transepithelial potential, its amplitude being approximately linearly dependent on the input resistance of the preparation (R1). Frequency responses of the nerve fibres were also dependent on R1. With R1 more (less) than 400-500 K omega there was an increase (decrease) in spike frequency during heating of the ampulla. Two temperature-dependent potential sources in sensory epithelium affecting spike frequency in the opposite ways are suggested.


The cigarette smoke components induced the cell proliferation and epithelial to mesenchymal transition via production of reactive oxygen species in endometrial adenocarcinoma cells.
Cigarette smoke (CS) causes about 480,000 deaths each year worldwide and is well-known to have harmful effects on the human body, leading to heart disease, stroke, lung cancer, and cardiovascular problems. In the present study, the effects of acrylonitrile (AN), benzo(a)pyrene (B(a)P), formaldehyde (FOR), isoprene (ISO), nicotine-derived nitrosamine ketone (NNK), which are the main components of CS, on the proliferation, invasion, and the epithelial-mesenchymal transition (EMT) process of human Ishikawa endometrial adenocarcinoma cells were investigated. Treating Ishikawa cells with CS components resulted in increased cell growth and altered expression of cell cycle-related genes: the protein expression of cyclin D & E increased, while the levels of p21 & p27 were reduced following treatment of these five CS components. In addition, CS components increased the invasion capacity of Ishikawa cells. The expression of the epithelial markers, E-cadherin and occludin, were significantly decreased, while the expression of the mesenchymal marker, N-cadherin, was significantly increased by CS components. In dichloro-dihydro-fluorescein diacetate (H2DCF-DA) assay, ROS production increased by treatment of CS components. The CS components activated the ROS-p38 MAPK-EMT pathway by increasing the level of phosphorylated p38 MAPK and p44/42 (ERK1/2), and by up-regulating Snail and Slug, the transcription factors for EMT. Taken together, these results indicate that CS components can promote progression of endometrial adenocarcinoma via increasing cell proliferation and the ROS-mediated EMT process.


Transference: The Matrix of the Frame.
I use the clinical example of a traumatized adolescent to talk about how a transference experience creates the frame where the analytic work occurs. Out of the external boundaries of the relationships with an object, the internal frame, the womb of transformation processes, is created. The analyst's capacity to wait is essential for the transformation that creates and shapes the transference experience, which, like playing, becomes the matrix of the frame where it happens as it happens. As the traumatic experiences find their place in the transference and begin to be integrated, the adolescent becomes more present and real in the session.


Thrombopoietin and hematopoietic stem cells.
Thrombopoietin (TPO) is the cytokine that is chiefly responsible for megakaryocyte production but increasingly attention has turned to its role in maintaining hematopoietic stem cells (HSCs). HSCs are required to initiate the production of all mature hematopoietic cells, but this differentiation needs to be balanced against self-renewal and quiescence to maintain the stem cell pool throughout life. TPO has been shown to support HSC quiescence during adult hematopoiesis, with the loss of TPO signaling associated with bone marrow failure and thrombocytopenia. Recent studies have shown that constitutive activation mutations in Mpl contribute to myeloproliferative disease. In this review, we will discuss TPO signaling pathways, regulation of TPO levels and the role of TPO in normal hematopoiesis and during myeloproliferative disease.


Opioid receptor subtypes: fact or artifact?
There is a vast amount of pharmacological evidence favouring the existence of multiple subtypes of opioid receptors. In addition to the primary classification of µ (mu: MOP), δ (delta: DOP), κ (kappa: KOP) receptors, and the nociceptin/orphanin FQ peptide receptor (NOP), various groups have further classified the pharmacological µ into µ(1-3), the δ into δ(1-2)/δ(complexed/non-complexed), and the κ into κ(1-3). From an anaesthetic perspective, the suggestions that µ(1) produced analgesia and µ(2) produced respiratory depression are particularly important. However, subsequent to the formal identification of the primary opioid receptors (MOP/DOP/KOP/NOP) by cloning and the use of this information to produce knockout animals, evidence for these additional subtypes is lacking. Indeed, knockout of a single gene (and hence receptor) results in a loss of all function associated with that receptor. In the case of MOP knockout, analgesia and respiratory depression is lost. This suggests that further sub-classification of the primary types is unwise. So how can the wealth of pharmacological data be reconciled with new molecular information? In addition to some simple misclassification (κ(3) is probably NOP), there are several possibilities which include: (i) alternate splicing of a common gene product, (ii) receptor dimerization, (iii) interaction of a common gene product with other receptors/signalling molecules, or (iv) a combination of (i)-(iii). Assigning variations in ligand activity (pharmacological subtypes) to one or more of these molecular suggestions represents an interesting challenge for future opioid research.


Continuous glucose monitoring--a study of the Enlite sensor during hypo- and hyperbaric conditions.
The performance and accuracy of the Enlite(™) (Medtronic, Inc., Northridge, CA) sensor may be affected by microbubble formation at the electrode surface during hypo- and hyperbaric conditions. The effects of acute pressure changes and of prewetting of sensors were investigated. On Day 1, 24 sensors were inserted on the right side of the abdomen and back in one healthy individual; 12 were prewetted with saline solution, and 12 were inserted dry. On Day 2, this procedure was repeated on the left side. All sensors were attached to an iPro continuous glucose monitoring (CGM) recorder. Hypobaric and hyperbaric tests were conducted in a pressure chamber, with each test lasting 105 min. Plasma glucose values were obtained at 5-min intervals with a HemoCue(®) (Ängelholm, Sweden) model 201 glucose analyzer for comparison with sensor glucose values. Ninety percent of the CGM systems operated during the tests. The mean absolute relative difference was lower during hyperbaric than hypobaric conditions (6.7% vs. 14.9%, P<0.001). Sensor sensitivity was slightly decreased (P<0.05) during hypobaric but not during hyperbaric conditions. Clarke Error Grid Analysis showed that 100% of the values were found in the A+B region. No differences were found between prewetted and dry sensors. The Enlite sensor performed adequately during acute pressure changes and was more accurate during hyperbaric than hypobaric conditions. Prewetting the sensors did not improve accuracy. Further studies on type 1 diabetes subjects are needed under various pressure conditions.


Use of a medication-based risk adjustment index to predict mortality among veterans dually-enrolled in VA and medicare.
There is systemic undercoding of medical comorbidities within administrative claims in the Department of Veterans Affairs (VA). This leads to bias when applying claims-based risk adjustment indices to compare outcomes between VA and non-VA settings. Our objective was to compare the accuracy of a medication-based risk adjustment index (RxRisk-VM) to diagnostic claims-based indices for predicting mortality. We modified the RxRisk-V index (RxRisk-VM) by incorporating VA and Medicare pharmacy and durable medical equipment claims in Veterans dually-enrolled in VA and Medicare in 2012. Using the concordance (C) statistic, we compared its accuracy in predicting 1 and 3-year all-cause mortality to the following models: demographics only, demographics plus prescription count, or demographics plus a diagnostic claims-based risk index (e.g., Charlson, Elixhauser, or Gagne). We also compared models containing demographics, RxRisk-VM, and a claims-based index. In our cohort of 271,184 dually-enrolled Veterans (mean age = 70.5 years, 96.1% male, 81.7% non-Hispanic white), RxRisk-VM (C = 0.773) exhibited greater accuracy in predicting 1-year mortality than demographics only (C = 0.716) or prescription counts (C = 0.744), but was less accurate than the Charlson (C = 0.794), Elixhauser (C = 0.80), or Gagne (C = 0.810) indices (all P < 0.001). Combining RxRisk-VM with claims-based indices enhanced its accuracy over each index alone (all models C ≥ 0.81). Relative model performance was similar for 3-year mortality. The RxRisk-VM index exhibited a high level of, but slightly less, accuracy in predicting mortality in comparison to claims-based risk indices. Its application may enhance the accuracy of studies examining VA and non-VA care and enable risk adjustment when diagnostic claims are not available or biased. Level 3.


Ferroelectric Field Effect in Epitaxial Thin Film Oxide SrCuO2/Pb(Zr0.52Ti0.48)O3 Heterostructures.
A ferroelectric field effect in epitaxial thin film SrCuO(2)/Pb(Zr(0.52)Ti(0.48))O(3) heterostructures was observed. A 3.5 percent change in the resistance of a 40 angstrom SrCuO(2) layer (a parent high-temperature superconducting compound) was measured when the polarization field of the Pb(Zr(0.52)Ti(0.48))O(3) layer was reversed by the application of a pulse of small voltage (<5 volts). This effect, both reversible and nonvolatile, is attributed to the electric field-induced charge at the interface of SrCuO(2) and Pb(Zr(0.52)Ti(0.48))O(3). This completely epitaxial thin film approach shows the possibility of making nonvolatile, low-voltage ferroelectric field effect devices for both applications and fundamental studies of field-induced doping in novel compounds like SrCuO(2).


When antihypertensive monotherapy fails: fixed-dose combination therapy.
Antihypertensive monotherapy fails to control blood pressure in many patients. Data on the efficacy and tolerance of fixed dose angiotensin-converting enzyme (ACE) inhibitor/calcium antagonist combinations were reviewed, since they are the most widely prescribed medications for hypertension. A fixed-dose combination of two drug classes is an option for hypertension treatment. Four fixed-dose ACE inhibitor/calcium antagonist combinations are available. They achieve superior blood pressure control with no increase in adverse events compared with their monotherapy components. In addition, they antagonize some class-specific adverse effects and may exhibit beneficial effects on target organ disease, such as renal dysfunction and left ventricular hypertrophy. Fixed-dose combination therapy is an attractive option when reasonable doses of initial antihypertensive monotherapy fail. Use of such combinations could increase patient compliance, by virtue of better tolerance compared with increased-dose monotherapy and simplicity of administration.


Soft truncation thresholding for gene set analysis of RNA-seq data: application to a vaccine study.
Gene set analysis (GSA) has been used for analysis of microarray data to aid the interpretation and to increase statistical power. With the advent of next-generation sequencing, the use of GSA is even more relevant, as studies are often conducted on a small number of samples. We propose the use of soft truncation thresholding and the Gamma Method (GM) to determine significant gene set (GS), where a generalized linear model is used to assess per-gene significance. The approach was compared to other methods using an extensive simulation study and RNA-seq data from smallpox vaccine study. The GM was found to outperform other proposed methods. Application of the GM to the smallpox vaccine study found the GSs to be moderately associated with response, including focal adhesion (p = 0.04) and extracellular matrix receptor interaction (p = 0.05). The application of GSA to RNA-seq data will provide new insights into the genomic basis of complex traits.


Antibodies against outer membrane proteins in rabbit antisera prepared against Escherichia coli O26 K60.
Antibodies directed against the protein constituents of the outer envelope membrane of Escherichia coli O26 K60 were demonstrated in antisera elicited in rabbits against three different preparations of the bacterium. Outer membraned solubilized by sodium dodecyl sulphate were applied to the antisera in an interfacial precipitin test, followed by polyacrylamide gel electrophoretic analysis of the resulting immunecomplexes. Protein profiles showed a complete outer membrane protein pattern, indicating the antigenic character of these proteins. Antisera containing antibodies against outer membrane proteins and free of reactive antibodies against lipopolysaccharide showed relatively low agglutinating activities against the bacteria. The antibodies against the protein constituents of the outer membrane belong mainly to the 7S class immunoglobulins, as indicated by 2-mercaptoethanol treatment of the antisera.


Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors.
Neuroendocrine tumors (NETs) of the digestive tract are a heterogeneous group of rare malignancies. Three major subgroups can be defined: pancreatic endocrine tumors, carcinoid tumors, and poorly differentiated gastroenteropancreatic NETs. Classically, digestive NETS have been considered to have an indolent course characterized for prolonged stabilizations or slow progressions, but there are clear differences in terms of aggressiveness, clinical course, and response to treatment among them. Retrospective studies have identified several clinicopathological and immunohistochemical factors as angioinvasion and proliferative index assessed by Ki-67 expression, which predict biological behavior and correlate with survival. Chemotherapy regimens based on the combination of several active drugs such as streptozocin, doxorubicin, 5-fluorouracil, dacarbazine, and temozolomide show low response rates, which sets the need to improve the results of the medical treatment of these malignancies. This review will analyze the role of Ki-67 in digestive NETs under a clinical perspective and will suggest future fields for development of this approach that enable a better patient selection for chemotherapy. Also a comprehensive review of the literature about chemotherapy in NETs is presented.


Clinical analysis of cerebrospinal fluid interleukin-6 in neuropsychiatric systemic lupus erythematosus.
To clarify the clinical usefulness of cerebrospinal fluid (CSF) interleukin-6 (IL-6) measurement in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), we studied CSF IL-6 levels in patients with NPSLE and analyzed the association between CSF IL-6 levels and other clinical findings of NPSLE. We retrospectively analyzed records of 37 patients (33 females and four males) with NPSLE admitted to our hospital between January 2003 and December 2008. All patients showed neuropsychiatric symptoms. Fourteen patients showed abnormalities in brain magnetic resonance imaging (MRI) and 12 patients had abnormal findings in electroencephalography (EEG). Increased CSF cell counts and elevated levels of CSF IL-6 were found in 11 and 30 patients, respectively. Elevated levels of CSF IL-6 were not statistically correlated with specific abnormalities in the blood analysis, in increased CSF cell counts, and in abnormalities in the brain MRI and EEG. In addition, a group of NPSLE patients positive for antiphospholipid antibodies (aPL) showed lower CSF IL-6 than the patients negative for aPL. These results indicated that CSF IL-6 might be useful in diagnosis of NPSLE. However, general assessments of patients based on various factors (clinical manifestations, imaging findings and CSF examinations) are also required.


Health Risk Behaviors after Disaster Exposure Among Older Adults.
The aim of this study was to examine the extent to which an exposure to disaster is associated with change in health behaviors. Federal disaster declarations were matched at the county-level to self-reported behaviors for participants in the Health and Retirement Study (HRS), 2000-2014. Multivariable logistic regression was used to evaluate the relationship between disaster and change in physical activity, body mass index (BMI), and cigarette smoking. The sample included 20,671 individuals and 59,450 interviews; 1,451 unique disasters were declared in counties in which HRS respondents lived during the study period. Exposure to disaster was significantly associated with weight gain (unadjusted RRR=1.19; 95% CI, 1.11-1.27; adjusted RRR=1.21; 95% CI, 1.13-1.30). Vigorous physical activity was significantly lower among those who had experienced a disaster compared to those who had not (unadjusted OR=0.89; 95% CI, 0.84-0.95; adjusted OR=0.84; 95% CI, 0.79-0.89). No significant difference in cigarette smoking was found. This study found an increase in weight gain and decrease in physical activity among older adults after disaster exposure. Adverse health behaviors such as these can contribute to functional decline among older adults.BellSA, ChoiH, LangaKM, IwashynaTJ. Health risk behaviors after disaster exposure among older adults. Prehosp Disaster Med. 2019;34(1):95-97.