Production of a class II two-component lantibiotic of Streptococcus pneumoniae using the class I nisin synthetic machinery and leader sequence.
Recent studies showed that the nisin modification machinery can successfully dehydrate serines and threonines and introduce lanthionine rings in small peptides that are fused to the nisin leader sequence. This opens up exciting possibilities to produce and engineer larger antimicrobial peptides in vivo. Here we demonstrate the exploitation of the class I nisin production machinery to generate, modify, and secrete biologically active, previously not-yet-isolated and -characterized class II two-component lantibiotics that have no sequence homology to nisin. The nisin synthesis machinery, composed of the modification enzymes NisB and NisC and the transporter NisT, was used to modify and secrete a putative two-component lantibiotic of Streptococcus pneumoniae. This was achieved by genetically fusing the propeptide-encoding sequences of the spr1765 (pneA1) and spr1766 (pneA2) genes to the nisin leader-encoding sequence. The chimeric prepeptides were secreted out of Lactococcus lactis, purified by cation exchange fast protein liquid chromatography, and further characterized. Mass spectrometry analyses demonstrated the presence and partial localization of multiple dehydrated serines and/or threonines and (methyl)lanthionines in both peptides. Moreover, after cleavage of the leader peptide from the prepeptides, both modified propeptides displayed antimicrobial activity against Micrococcus flavus. These results demonstrate that the nisin synthetase machinery can be successfully used to modify and produce otherwise difficult to obtain antimicrobially active lantibiotics.


Mechanisms and fitness costs of resistance to antimicrobial peptides LL-37, CNY100HL and wheat germ histones.
Antimicrobial peptides (AMPs) represent a potential new class of antimicrobial drugs with potent and broad-spectrum activities. However, knowledge about the mechanisms and rates of resistance development to AMPs and the resulting effects on fitness and cross-resistance is limited. We isolated antimicrobial peptide (AMP) resistant Salmonella typhimurium LT2 mutants by serially passaging several independent bacterial lineages in progressively increasing concentrations of LL-37, CNY100HL and Wheat Germ Histones. Significant AMP resistance developed in 15/18 independent bacterial lineages. Resistance mutations were identified by whole genome sequencing in two-component signal transduction systems (pmrB and phoP) as well as in the LPS core biosynthesis pathway (waaY, also designated rfaY). In most cases, resistance was associated with a reduced fitness, observed as a decreased growth rate, which was dependent on growth conditions and mutation type. Importantly, mutations in waaY decreased bacterial susceptibility to all tested AMPs and the mutant outcompeted the wild type parental strain at AMP concentrations below the MIC for the wild type. Our data suggests that resistance to antimicrobial peptides can develop rapidly through mechanisms that confer cross-resistance to several AMPs. Importantly, AMP-resistant mutants can have a competitive advantage over the wild type strain at AMP concentrations similar to those found near human epithelial cells. These results suggest that resistant mutants could both be selected de novo and maintained by exposure to our own natural repertoire of defence molecules.


Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior.
Pathological modifications in the highly conserved and ubiquitously expressed heterogeneous ribonucleoprotein TDP-43 were recently associated to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a late-onset disorder that affects predominantly motoneurons [Neumann, M. et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133, Sreedharan, J. et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672, Kabashi, E. et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572-574]. However, the function of TDP-43 in vivo is unknown and a possible direct role in neurodegeneration remains speculative. Here, we report that flies lacking Drosophila TDP-43 appeared externally normal but presented deficient locomotive behaviors, reduced life span and anatomical defects at the neuromuscular junctions. These phenotypes were rescued by expression of the human protein in a restricted group of neurons including motoneurons. Our results demonstrate the role of this protein in vivo and suggest an alternative explanation to ALS pathogenesis that may be more due to the lack of TDP 43 function than to the toxicity of the aggregates.


Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing.
Human amnion/chorion tissue derived from the placenta is rich in cytokines and growth factors known to promote wound healing; however, preservation of the biological activities of therapeutic allografts during processing remains a challenge. In this study, PURION® (MiMedx, Marietta, GA) processed dehydrated human amnion/chorion tissue allografts (dHACM, EpiFix®, MiMedx) were evaluated for the presence of growth factors, interleukins (ILs) and tissue inhibitors of metalloproteinases (TIMPs). Enzyme-linked immunosorbent assays (ELISA) were performed on samples of dHACM and showed quantifiable levels of the following growth factors: platelet-derived growth factor-AA (PDGF-AA), PDGF-BB, transforming growth factor α (TGFα), TGFβ1, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), placental growth factor (PLGF) and granulocyte colony-stimulating factor (GCSF). The ELISA assays also confirmed the presence of IL-4, 6, 8 and 10, and TIMP 1, 2 and 4. Moreover, the relative elution of growth factors into saline from the allograft ranged from 4% to 62%, indicating that there are bound and unbound fractions of these compounds within the allograft. dHACM retained biological activities that cause human dermal fibroblast proliferation and migration of human mesenchymal stem cells (MSCs) in vitro. An in vivo mouse model showed that dHACM when tested in a skin flap model caused mesenchymal progenitor cell recruitment to the site of implantation. The results from both the in vitro and in vivo experiments clearly established that dHACM contains one or more soluble factors capable of stimulating MSC migration and recruitment. In summary, PURION® processed dHACM retains its biological activities related to wound healing, including the potential to positively affect four distinct and pivotal physiological processes intimately involved in wound healing: cell proliferation, inflammation, metalloproteinase activity and recruitment of progenitor cells. This suggests a paracrine mechanism of action for dHACM when used for wound healing applications.


Opioids for chronic pain: molecular and genomic basis of actions and adverse effects.
Opioid analgesics are being increasingly used for pain control in both cancer and noncancer patients. Despite thousands of years of their use, the biological basis of their action and adverse effects are only now being understood. It is important to understand these agents better so that the potentially large sections of the population who may eventually be eligible to receive therapeutic opioids are treated rationally and safely. Recent advances in pain physiology, molecular biology of neurotransmission, in-vivo neuroimaging and the study of genomic influences on drug receptors and metabolism are beginning to clarify how opioids work, how they differ from each other and how they may cause harm. Understanding the biological basis of how opioids work and produce adverse effects should help us to make better choices of which drugs to use for specific populations. Identifying individual genetic differences in opioid receptors and drug metabolism pathways may also pave the way to more targeted and safer medication in the future.


Comparison of ethical judgments exhibited by clients and ethics consultants in Japan.
Healthcare professionals must make decisions for patients based on ethical considerations. However, they rely on clinical ethics consultations (CEC) to review ethical justifications of their decisions. CEC consultants support the cases reviewed and guide medical care. When both healthcare professionals and CEC consultants face ethical problems in medical care, how is their judgment derived? How do medical judgments differ from the ethical considerations of CECs? This study examines CECs in Japan to identify differences in the ethical judgment of clients and CEC consultants. The CEC request and response documents of all 60 cases reviewed across Japan between October 2006 and the end of October 2011 were classified in terms of the presence of decisional capacity in the patient. We conducted a qualitative content analysis of the differences in reasoning between client and CEC consultants. Reasoned judgments were verified in individual cases to classify the similarities or differences of opinion between CEC clients and teams. As the result of classification of the decisional capacity and the difference of opinion regarding medical care, the most frequent category was 25 cases (41.7%) of "uncertain decisional capacity," and 23 cases (38.3%) of "withholding of decision-making." A chi-square analysis was performed on presence of decisional capacity and agreement in decision-making, yielding a statistically significant difference (p < 0.05). The CEC consultants' reasoning was based on "patient's preference was ambiguous," "validity of family as a surrogate," "estimation of patient preference," and "patient's best interest," whereas the CEC client's reasoning was based on "consistent family preference was shown/not shown" and "appropriate therapeutic methods to manage patient safety." Differences in opinions were found in cases classified according to decisional capacity. Furthermore, the reasoning behind judgments differed between CEC clients and CEC consultants. The reasoning of CEC consultants was critical and reflective, while for clients it was situational and pragmatic.


Schooling in adolescence raises IQ scores.
Although some scholars maintain that education has little effect on intelligence quotient (IQ) scores, others claim that IQ scores are indeed malleable, primarily through intervention in early childhood. The causal effect of education on IQ at later ages is often difficult to uncover because analyses based on observational data are plagued by problems of reverse causation and self-selection into further education. We exploit a reform that increased compulsory schooling from 7 to 9 y in Norway in the 1960s to estimate the effect of education on IQ. We find that this schooling reform, which primarily affected education in the middle teenage years, had a substantial effect on IQ scores measured at the age of 19 y.


Decision-Making under Risk: Conditions Affecting the Risk Preferences of Politicians in Digitalization.
Public officials are constantly facing decisions under risk, particularly in digitalization policies, the consequences of which are hard to predict given their multiple dimensional nature. Since scholarly research has not yet addressed this phenomenon, we do not know what influences the risk preferences of politicians in digitalization policies. Prospect theory-widely used to explain political decisions-can help us describe politicians' potential risk references and the conditions affecting their decisions. Accordingly, this paper aims to answer the following question: what are the conditions affecting the risk preferences of politicians in digitalization policies? I address this question by employing two important assumptions of prospect theory: the value function and the probability weighting function. Particularly, I discuss the effects of loss/gain frames and probability weighting on the risk preferences of politicians in digitalization with outcomes in multiple dimensions (e.g., data privacy and economy). I argue that whether an outcome is perceived as a gain or as a loss depends on how the situation is framed and how the probabilities are weighted. I conclude with a brief discussion of how prospect theory can leverage our understanding of political decisions in highly complex policy environments.


Functional significance of overlapping transcripts of crtEF, bchCA, and puf photosynthesis gene operons in Rhodobacter capsulatus.
The Rhodobacter capsulatus crtEF, bchCA, and puf operons each encode products that function together to produce photosynthetic pigment-protein complexes. The crtEF operon encodes two enzymes of the carotenoid biosynthetic pathway, the bchCA operon encodes two enzymes of the bacteriochlorophyll biosynthetic pathway, and the puf operon contains six genes, four of which are known to code for proteins that bind pigment cofactors and position them in the intracytoplasmic membrane. These operons are adjacent on the chromosome and are transcribed in the same direction. Although each of these operons can be expressed from its own promoter, it is possible for transcription to begin at the crtEF promoter and continue through the bchCA and puf operons. We herein present the results of experiments which demonstrate that this overlapping transcriptional arrangement is important for establishment of normal levels of transcripts of the bchCA and puf operons and that read-through transcription from the bchCA operon contributes significantly to the expression of a pufB'::lac'Z gene fusion. Growth studies of crtF and bchC interposon mutants show that this read-through transcription is necessary for efficient transition from respiratory to photosynthetic growth modes.


Combination plots as graphical tools in the study of enzyme inhibition.
Although statistical regression has become the method of choice in the analysis of enzyme kinetics, graphical methods continue to be useful on account of their illustrative capabilities. It is pointed out in this paper that enzyme inhibition data may be presented more efficiently as a single linear plot than the traditional way as a family of lines. This approach has been taken previously by Hunter and Downs [Hunter and Downs (1945) J. Biol. Chem. 157, 427-446] but has remained neglected. A new version of this type of plot (combination plot) has been devised which is linear for competitive, non-competitive, uncompetitive and linear mixed inhibition and has a characteristic appearance for each type of inhibition behaviour. The slopes and intercepts not only indicate directly the dissociation constant but also provide quantitative criteria for the nature of inhibition. This plot should serve as a useful graphical tool in enzyme research as well as in biochemical education.


[The hierarchy of approaches to tobacco control]
Tobacco represents the single most preventable cause of disease and death in the world today. Of 260 million male deaths in the developed world between 1950 and 2000, it is estimated that 50 million will be due to smoking. In the oral and craniofacial region tobacco use has been associated with the occurrence of cleft palate, periodontal disease and tooth loss, and a variety of soft tissue lesions including oral cancer. For example, smoking is estimated to account for 92% of cancers of the lip, oral cavity and pharynx. Few studies have examined relative efficiency of the many different approaches to tobacco control but, in general, legislative approaches such as increasing tobacco taxes and prohibiting advertising are most effective and those based on printed educational materials and cessation groups, the least effective. In all cases, advice or intervention by health care professionals ranked among the most effective non-legislative approaches to control. A very wide range of professionally-based interventions have been described, including pharmacologic interventions, behavioral approaches and group counseling. The dental profession has a unique opportunity to influence tobacco use by their patients. Its use is almost always immediately evident to the dentist or dental assistant in terms of odor, staining, poor oral hygiene or obvious oral disease. There is also a tendency for the length of personal contact with the dentist to be greater than with a physician. Guidelines are now available that provide the dental professional with advice on the best approaches to tobacco control with their patients.


Coping Strategies in mothers of children with autism spectrum disorder and their relation to maternal stress and depression.
Having a child with autism may have a strong impact on the family, especially on mothers, who are usually the primary caregivers of children with autism. Parents of children with autism report more mental health problems compared to parents of children with typical development or other developmental disabilities. Parental copying strategies may play a significant role when parents have to overcome stressful situations during the child development. The present study aimed to investigate the coping strategies used by mothers of children with autism spectrum disorder (ASD), and their relation to maternal stress and depression. One hundred and forty-three (143) mothers (mean age 42.7 years) of children with ASD (6-17years), who attended the ASD Outpatient Clinic of the Department of Child Psychiatry, at a Children's Hospital, participated in the current study. Mothers completed a series of questionnaires: a demographic characteristics questionnaire, the Center for Epidemiologic Studies Depression Scale (CES-D), the Family Crisis Oriented Personal Scales (F-COPES), and the Parenting Stress Index Short-Form (PSI-SF). Mothers with higher educational level scored significantly lower in total F-COPES and its subscale "reframing". Increased daily hours related to child care and the child's medication were additional factors significantly associated with lower scores on "reframing". Reframing subscale was also negatively correlated with "parental distress", whereas "passive appraisal" was positively correlated with depressive symptoms. Lower scores on "mobilizing family to acquire" and "accept help" were associated with family life being more seriously affected. Coping strategies of mothers of children with ASD are associated with a number of factors related to personal characteristics of caregivers, child treatment and family characteristics. Mental health professionals should examine factors that may strengthen coping strategies that handle the challenges of having a child with ASD.


Effect of the alpha-amino group on peptide retention behaviour in reversed-phase chromatography. Determination of the pK(a) values of the alpha-amino group of 19 different N-terminal amino acid residues.
We have examined the contribution of the alpha-amino group to retention behaviour for peptides in reversed-phase chromatography using two series of peptide analogues, one containing an N alpha-acetylated terminal and the other containing an alpha-amino group (non-acetylated). The effect of the alpha-amino group, at pH 2, on the hydrophobicity of the side-chain of the N-terminal residue was obtained by referencing the retention time of the acetylated or non-acetylated peptide to the retention time of a glycine analogue. It was shown that the presence of an alpha-amino group could decrease or increase the hydrophobicity of the side-chain of the N-terminal residue with respect to the hydrophobicity of the side-chain in the absence of an alpha-amino group. The effect was also shown to be sequence dependent, with respect to the N-terminal residue. Increasing pH was shown to increase retention time dramatically for the non-acetylated analogues, through the deprotonation of the alpha-amino group. By separating pairs of acetylated/non-acetylated analogues over the pH range 2-9, it was possible to determine the pK(a) of the alpha-amino group, where it was shown that the pK(a) was dependent on two probable factors: (1) the inherent hydrophobicity of the stationary phase; and (2) the amino acid substituted in the N-terminal position. Interestingly, the pK(a) values determined were very similar to that found in proteins. It was also possible to determine the pK(a) values of some of the substituted amino acids containing ionizable side-chains. This study shows that, in order to understand fully the retention behaviour of peptides containing an alpha-amino group in reversed-phase chromatography, one must incorporate an alpha-amino group contribution and its effect on the hydrophobicity of the side-chain of the N-terminal residue.


Structure of the O18 antigen from Acinetobacter baumannii.
The polymeric O antigen was obtained from lipopolysaccharide extracted from isolated, defatted cell walls of the reference strain for Acinetobacter baumannii serogroup O18. Monosaccharide analyses and NMR spectra established that the polymer had a regular structure with a repeating unit based on residues of D-galactose (2), N-acetyl-D-galactosamine (1), and N-acetyl-D-mannosamine (1). Further interpretation of the NMR spectra, combined with the results of methylation analysis and a Smith degradation, showed that the repeating unit had the following structure. beta-D-ManpNAc-(1-->4)-alpha-D-Galp 1 decreases 4 -->3)-beta-D-GalpNAc-(1-->3)-beta-D-Galp-(1-->.


Microanatomical and histological features in the long bones of Mosasaurine mosasaurs (Reptilia, Squamata)--implications for aquatic adaptation and growth rates.
During their evolution in the Late Cretaceous, mosasauroids attained a worldwide distribution, accompanied by a marked increase in body size and open ocean adaptations. This transition from land-dwellers to highly marine-adapted forms is readily apparent not only at the gross anatomic level but also in their inner bone architecture, which underwent profound modifications. The present contribution describes, both qualitatively and quantitatively, the internal organization (microanatomy) and tissue types and characteristics (histology) of propodial and epipodial bones in one lineage of mosasauroids; i.e., the subfamily Mosasaurinae. By using microanatomical and histological data from limb bones in combination with recently acquired knowledge on the inner structure of ribs and vertebrae, and through comparisons with extant squamates and semi-aquatic to fully marine amniotes, we infer possible implications on mosasaurine evolution, aquatic adaptation, growth rates, and basal metabolic rates. Notably, we observe the occurrence of an unusual type of parallel-fibered bone, with large and randomly shaped osteocyte lacunae (otherwise typical of fibrous bone) and particular microanatomical features in Dallasaurus, which displays, rather than a spongious inner organization, bone mass increase in its humeri and a tubular organization in its femora and ribs. The dominance of an unusual type of parallel-fibered bone suggests growth rates and, by extension, basal metabolic rates intermediate between that of the extant leatherback turtle, Dermochelys, and those suggested for plesiosaur and ichthyosaur reptiles. Moreover, the microanatomical features of the relatively primitive genus Dallasaurus differ from those of more derived mosasaurines, indicating an intermediate stage of adaptation for a marine existence. The more complete image of the various microanatomical trends observed in mosasaurine skeletal elements supports the evolutionary convergence between this lineage of secondarily aquatically adapted squamates and cetaceans in the ecological transition from a coastal to a pelagic lifestyle.


Hormone replacement therapy in systemic lupus erythematosus.
To test whether hormone replacement therapy (HRT) causes an increase in lupus flares. Sixteen postmenopausal patients with systemic lupus erythematosus (SLE) who had been taking HRT for at least 12 months were included in the study. Thirty-two controls were matched to patients for age at start of hormone therapy and calendar year of followup. The incidence of disease flare was defined as any increase in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) over 12 months from baseline in these 2 groups; incidence of flare was compared by McNemar's test or Mantel-Haenszel test. Control patients were older at diagnosis (38.8 vs 30.5 yrs) and at presentation to clinic (41 vs 30 yrs). HRT patients had longer disease duration (17.9 vs 5.6 yrs). SLEDAI at presentation was similar in both groups. There was no statistically significant difference in the rates of flares in both groups. The use of HRT in postmenopausal women with SLE does not appear to increase the rate of lupus flares over a one year followup.


Highlighting award-winning quality initiatives.
Recent award-winning hospitals and health systems share insights into their programs and initiatives that promote quality of care. While these programs address vast and different areas--using ACE inhibitors, expanding community services, providing mental health support, reducing nosocomial pneumonia, and enhancing patient safety--they all have one thing in common: Their work represent weeks, years, and even decades of extraordinary vision, planning, and just plain hard work to successfully provide quality care to patients and communities.


Altered expression of the retinoblastoma (RB) gene in small-cell carcinoma of the lung.
Nine lung small-cell carcinoma (SCC) cell lines and 9 lung non-SCC cell lines were examined for structural changes of the retinoblastoma (RB) gene as well as its expression using a complementary DNA probe. The RB protein product was investigated using an anti-RB antibody which we produced. Although homozygosity or hemizygosity of the RB gene was suggested in 8 of 9 SCCs and one of 2 large cell carcinomas (LCCs) by Southern blot analysis using an RB cDNA probe and polymorphic DNA markers for chromosome 13, no obvious structural changes of the RB gene were detected in these 18 cell lines. However, RB transcripts were either markedly reduced in quantity or abnormal in length in 3 of 9 SCCs. The specific 115 kD protein was not immunoprecipitated by the anti-RB antibody in all 9 SCCs with either normal or abnormal size RB mRNA. Three of 4 adenocarcinomas (AdCs), all 3 squamous cell carcinomas, and one of 2 LCCs expressed normal size RB mRNA, and the 115 kD protein was immunoprecipitated by the anti-RB antibody. The 115 kD protein was also absent in one of 2 LCCs with shortened RB mRNA and in one of 4 AdCs with low level of RB mRNA expression. These results strongly suggest that inactivation of the RB gene might be involved in the development of lung cancers, especially of SCCs.


Exploratory multivariate analysis of hospital admissions data in conjunction with workforce data.
The prevalence of electronic health data has brought us a step closer to understanding of the dynamics of hospital admissions. However, little research has investigated hospital admission data in conjunction with information about the environment where the patient was admitted, such as staffing level and hospital type. This paper studied this crucial but often neglected issue by investigating hospital admission records together with workforce data. Exploratory multivariate analysis methods, such as principal component analysis (PCA) and multiple correspondence analysis (MCA), were applied to study important variables associated with admission and workforce data. The exploratory results obtained shed light on the contribution of these variables to the typology of hospital admissions.


Nanospike electrodes and charge nanoribbons: A new design for nanoscale thin-film transistors.
To scale down thin-film transistor (TFT) channel lengths for accessing higher levels of speed and performance, a redesign of the basic device structure is necessary. With nanospike-shaped electrodes, field-emission effects can be used to assist charge injection from the electrodes in sub-200-nm channel length amorphous oxide and organic TFTs. These designs result in the formation of charge nanoribbons at low gate biases that greatly improve subthreshold and turn-off characteristics. A design paradigm in which the gate electric field can be less than the source-drain field is proposed and demonstrated. By combining small channel lengths and thick gate dielectrics, this approach is also shown to be a promising solution for boosting TFT performance through charge focusing and charge nanoribbon formation in flexible/printed electronics applications.


Behavioral and pharmacologic treatment of delirium.
Delirium is an acute confusional state with a fluctuating course. Since the syndrome of delirium is associated with derangements of cognition, attention and level of consciousness, it can cause behaviors that are difficult to manage. Hallucinations, agitation, insomnia and anxiety are common in the delirious patient. Behavioral and pharmacologic interventions can be used while the underlying etiology of delirium is sought. Nonpharmacologic measures include frequent reassurance, environmental cues to reorient the patient and the judicious use of physical restraints. Haloperidol, which has negligible anticholinergic effects, is the drug most often used to treat the symptoms of delirium. Short-acting benzodiazepines may be useful in patients with delirium caused by alcohol withdrawal, but these agents may cause increased agitation in elderly patients and patients with hepatic dysfunction.


The relationship between the thickness of de-epithelialization and occurrence of sebaceous cysts at the incision site after mastopexy and reduction mammaplasty.
Periareolar sebaceous cysts at the incision site after mastopexy and reduction mammaplasty are very unpleasant complications that affect the surgical result and the degree of patient satisfaction. The author sought to investigate the cause and prevention of such sebaceous cysts. Sixty patients undergoing mastopexy or reduction mammaplasty were randomly divided into 2 groups. Periareolar de-epithelialization was performed to a depth of superficial layer of the dermis in group A and nearly the full thickness of the dermis in group B, and the incidence of sebaceous cysts was compared between these 2 groups. Patients were followed-up for 2 to 4 years. In group A, sebaceous cysts at the incision site were found in 4 patients (13.3%); however, no sebaceous cysts occurred in group B. Increasing the thickness of de-epithelialization appears to decrease the incidence of sebaceous cysts at the incision site.


Mitochondrial dysfunction in cholestatic liver diseases.
Cholestatic liver diseases are characterized by blockade of bile flow from the liver to the intestine, and accumulation of hydrophobic bile acids in the liver and plasma. As a consequence an inflammatory response evolves associated with increased apoptosis, oxidative stress, and eventually fibrosis. Cholestasis is associated with profound metabolic changes, alterations in the mitochondrial function, decreased fatty acid oxidation, and increased glycolisis. Mitochondria play a central role in the development of this liver disease because they mediate death receptor signaling - triggered by inflammatory cytokines or bile acids - and contribute to oxidative damage, metabolic disorder, and onset of fibrosis. During the pathogenesis of biliary cirrhosis mitochondria's need for renewal is hampered by a blunted mitochondrial biogenesis. Lack of stimulation of mitochondrial renewal helps to explain mitochondrial impairment in long-term cholestasis. The marked depletion of mitochondrial DNA and occurrence of mitochondrial DNA deletions are probably relevant contributors to the progression of this severe disease. All these findings certainly support the consideration of long-term cholestasis as a secondary mitochondrial hepatopathy.


National pride and multiculturalism.
The author traces trends in attitudes toward ethnic assimilation and multiculturalism in Australia. "'Hard multiculturalism' was promoted by the left-liberal intelligentsia. It valued separate ethnic cultures and denigrated mainstream Australia. It is now being supplanted by 'soft multiculturalism' which values tolerance, acceptance and inclusion, values that have long been central to mainstream Australia."


A study of innovative patient safety education.
Medical error continues to significantly harm patients, notwithstanding the continued efforts to improve the situation over the past decade. We report a pilot project using high-fidelity simulation to integrate the World Health Organisation (WHO) patient safety curriculum into undergraduate medical education. From the literature on avoidable medical error we developed a series of authentic clinical scenarios using a Clinical Skills Lab (CSL) and simulated patients to produce a high-fidelity simulated ward environment. The clinical challenges embody common day-to-day encounters experienced by newly graduated doctors. After participating, final-year medical students were given time to reflect on the experience, given feedback and completed a quantitative evaluation. Twenty final-year medical students completed the scenarios, and gave written feedback using a Likert scale (ranging from 1, strongly disagree, to 7, strongly agree). The responses showed 18 students agreed or strongly agreed that the session was valuable, all 20 would recommend the session to peers and 18 would be interested in attending further sessions. The students gave more mixed views of faculty feedback: 13 agreed or strongly agreed that this was useful, five were undecided and two were undecided or disagreed. With the caveats of a small sample size, first experience of high-fidelity simulation, the 'halo' effect in the evaluation, and with possible omissions from our evaluation, the students reported predominantly positively on the experience. We believe that the use of high-fidelity simulation in patient safety is a promising, safe and low-cost curricular development in undergraduate medical education. It is transferable worldwide and has the potential to improve patient safety outcomes by reducing medical error.


Impact of pulse duration on localized single-cell nano-electroporation.
We introduce a localized single-cell membrane nano-electroporation with controllable sequential molecular delivery by millisecond to nanosecond electrical pulses. An intense electrical field was generated by a pair of transparent indium tin oxide (ITO)-based nano-electrodes, which was confined to a narrow region of the single-cell membrane surface near the nano-electrode edges (approximately 2 μm × 50 nm area), whereas the remaining area of the membrane was unaffected. Moreover, a 250 nm SiO2 passivation layer on top of the nano-electrode reduced not only the thermal effect on the cell membrane surface, but it also avoided the generation of ions during the experiment, resulting in the reduction of cell toxicity and a significant enhancement of cell viability. Our approach precisely delivers dyes, Quantum Dots (QDs) and plasmids, through a localized region of single HeLa cells by considerably enhanced electrophoresis and diffusion effects with different duration of the pulsing process. The smaller molecules took less time to deliver into a single cell with a single pulse, whereas larger biomolecules took longer time even for multiple numbers of long lasting pulses. The system not only generates sequential well-controlled nano-pores allowing for the rapid recovery of cell membranes, but it also provides spatial, temporal and qualitative dosage control to deliver biomolecules into localized single-cell levels, which can be potentially beneficial for single cell studies and therapeutic applications.


VEGF Pathways in the Lymphatics of Healthy and Diseased Heart.
Cardiac lymphatic system is a rare focus of the modern cardiovascular research. Nevertheless, the growing body of evidence is depicting lymphatic endothelium as an important functional unit in healthy and diseased myocardium. Since the discovery of angiogenic VEGF-A in 1983 and lymphangiogenic VEGF-C in 1997, an increasing amount of knowledge has accumulated on the essential roles of VEGF ligands and receptors in physiological and pathological angiogenesis and lymphangiogenesis. Tissue adaptation to several stimuli such as hypoxia, pathogen invasion, degenerative process and inflammation often involves coordinated changes in both blood and lymphatic vessels. As lymphatic vessels are involved in the initiation and resolution of inflammation and regulation of tissue edema, VEGF family members may have important roles in myocardial lymphatics in healthy and in cardiac disease. We will review the properties of VEGF ligands and receptors concentrating on their lymphatic vessel effects first in normal myocardium and then in cardiac disease.


Race, Ethnicity, Family Socioeconomic Status, and Children's Hippocampus Volume.
The hippocampus has a significant role in memory, learning, and cognition. Although hippocampal size is highly susceptible to family socioeconomic status (SES) and associated stress, very little is known on racial and ethnic group differences in the effects of SES indicators on hippocampus volume among American children. This study explored the multiplicative effects of race, ethnicity, and family SES on hippocampus volume among American children. Using data from the Adolescent Brain Cognitive Development (ABCD), we analyzed the functional Magnetic Resonance Imaging (fMRI) data of 9390 9-10 years old children. The main outcome was hippocampus volume. The predictor was parental education. Subjective family SES was the independent variable. Age, sex, and marital status were the covariates. Racial and ethnic group membership were the moderators. To analyze the data, we used regression models. High subjective family SES was associated with larger hippocampus volume. This effect was significantly larger for Whites than Black families. The effect of subjective family SES on children's hippocampus volume is weaker in Black than White families.


The role of bone morphogenetic proteins in the differentiation of the ventral optic cup.
The ventral region of the chick embryo optic cup undergoes a complex process of differentiation leading to the formation of four different structures: the neural retina, the retinal pigment epithelium (RPE), the optic disk/optic stalk, and the pecten oculi. Signaling molecules such as retinoic acid and sonic hedgehog have been implicated in the regulation of these phenomena. We have now investigated whether the bone morphogenetic proteins (BMPs) also regulate ventral optic cup development. Loss-of-function experiments were carried out in chick embryos in ovo, by intraocular overexpression of noggin, a protein that binds several BMPs and prevents their interactions with their cognate cell surface receptors. At optic vesicle stages of development, this treatment resulted in microphthalmia with concomitant disruption of the developing neural retina, RPE and lens. At optic cup stages, however, noggin overexpression caused colobomas, pecten agenesis, replacement of the ventral RPE by neuroepithelium-like tissue, and ectopic expression of optic stalk markers in the region of the ventral retina and RPE. This was frequently accompanied by abnormal growth of ganglion cell axons, which failed to enter the optic nerve. The data suggest that endogenous BMPs have significant effects on the development of ventral optic cup structures.


Prediction and Estimation of River Velocity Based on GAN and Multifeature Fusion.
The necessity of predicting and estimating river velocity motivates the development of a prediction method based on GAN image enhancement and multifeature fusion. In this method, in order to improve the image quality of river velocity, GAN network is used to enhance the image, so as to improve the integrity of image data set. In order to improve the accuracy of prediction, the image is extracted and fused with multiple features, and the extracted multiple features are taken as the input of CNN, so as to improve the prediction accuracy of convolution neural network. The results show that when the velocity is 0.25 m/s, 0.50 m/s, and 0.75 m/s, the accuracy of improved method can reach 85%, 90%, and 92%, which are higher than SVM, VGG-16, and BPNET algorithms. The above results indicate that the improvement has certain positive value and practical application value.


Corticostriatal circuit dysfunction in Huntington's disease: intersection of glutamate, dopamine and calcium.
Huntington's disease (HD) is a noncurable and progressive autosomal-dominant neurodegenerative disorder that results from a polyglutamine expansion in the amino-terminal region of the huntingtin protein. The generation of rodent HD models has revealed that cellular dysfunction, rather than cell death alone, occurs early in the disease progression, appearing even before overt symptom onset. Much evidence has now established that dysfunction of the corticostriatal circuit is key to HD symptomology. In this article, we summarize the most current findings that implicate glutamate, dopamine and calcium signaling in this system and discuss how they work in concert to disrupt corticostriatal function. In addition, we highlight therapeutic strategies related to altered corticostriatal signaling in HD.


Personalizing and targeting therapy for COPD: the role of molecular and clinical biomarkers.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by persistent airflow limitation. It is the third leading cause of death worldwide, and there are currently no curative strategies for this disease. Many factors contribute to COPD susceptibility, progression and exacerbations. These include cigarette smoking, environmental and occupational pollutants, respiratory infections and comorbidities. As the clinical phenotypes of COPD are so variable, it has been difficult to devise an individualized treatment plan for patients with this complex chronic disease. This review will highlight how potential clinical, inflammatory, genomic and epigenomic biomarkers for COPD could be used to personalize treatment, leading to improved disease management and prevention for our patients.


Secretion of Wnt ligands requires Evi, a conserved transmembrane protein.
Wnt signaling pathways are important for multiple biological processes during development and disease. Wnt proteins are secreted factors that activate target-gene expression in both a short- and long-range manner. Currently, little is known about how Wnts are released from cells and which factors facilitate their secretion. Here, we identify a conserved multipass transmembrane protein, Evenness interrupted (Evi/Wls), through an RNAi survey for transmembrane proteins involved in Drosophila Wingless (Wg) signaling. During development, evi mutants have patterning defects that phenocopy wg loss-of-function alleles and fail to express Wg target genes. evi's function is evolutionarily conserved as depletion of its human homolog disrupts Wnt signaling in human cells. Epistasis experiments and clonal analysis place evi in the Wg-producing cell. Our results show that Wg is retained by evi mutant cells and suggest that evi is the founding member of a gene family specifically required for Wg/Wnt secretion.


Betulin is a potent anti-tumor agent that is enhanced by cholesterol.
Betulinic Acid (BetA) and its derivatives have been extensively studied in the past for their anti-tumor effects, but relatively little is known about its precursor Betulin (BE). We found that BE induces apoptosis utilizing a similar mechanism as BetA and is prevented by cyclosporin A (CsA). BE induces cell death more rapidly as compared to BetA, but to achieve similar amounts of cell death a considerably higher concentration of BE is needed. Interestingly, we observed that cholesterol sensitized cells to BE-induced apoptosis, while there was no effect of cholesterol when combined with BetA. Despite the significantly enhanced cytotoxicity, the mode of cell death was not changed as CsA completely abrogated cell death. These results indicate that BE has potent anti-tumor activity especially in combination with cholesterol.


Orchestrating neuronal networks: sustained after-effects of transcranial alternating current stimulation depend upon brain states.
The interest in transcranial alternating current stimulation (tACS) has significantly increased in the past decade. It has potential to modulate brain oscillations in a frequency specific manner, offering the possibility to demonstrate a causal nature of oscillation behavior relationships. TACS is a strong candidate as a tool for clinical applications, however, to fulfill this potential, certain parameters have yet to be evaluated. First, little is known about long-lasting after-effects of tACS with respect to the modulations of rhythmic brain activity. Second, the power of endogenous brain oscillations might play a crucial role in the efficacy of tACS. We hypothesize that the after-effects of tACS depend on the endogenous power of oscillations. To this end, we modulated the power of endogenous occipital alpha oscillations via tACS. In two experiments, participants either had their eyes open or closed to keep endogenous alpha power either low or high while they were stimulated for 20 min with their individual alpha frequency (IAF) and simultaneously performing a vigilance task. After-effects on IAF power were evaluated over a course of 30 min with a pre stimulation period serving as baseline. After-effects were strongly dependent on IAF power. Enhanced IAF power was observed for at least 30 min after tACS under conditions of low endogenous IAF power, whereas, IAF power could not be further enhanced by tACS under conditions of high IAF power. The current study demonstrates, for the first time, a long lasting effect after tACS on endogenous EEG power in the range of the stimulation frequency. Additionally, we present conclusive evidence that the power of the endogenous oscillations has a critical impact on tACS efficacy. Long lasting after-effects foster the role of tACS as a tool for non-invasive brain stimulation and demonstrate the potential for therapeutic application to reestablish the balance of altered brain oscillations.


Protective effect of propionyl carnitine against peroxidative damage to arterial endothelium membranes.
Endothelial cells may be damaged by oxygen reactive species produced by granulocytes, by transition metal ions or by xanthine oxidase, an enzyme present in great quantity in these cells. Since it has been observed that propionyl carnitine protects the heart from peroxidation, we have investigated the effect of this compound on the formation of thiobarbituric acid reactive oxidation products (TBAR) in endothelial membranes. The peroxidation systems used were a mixture of Fe3+ and Fe2+, hydrogen peroxide and Fe2+, or xanthine oxidase-- xanthine. Propionyl carnitine at millimolar concentrations decreases TBAR formation. The protection is concentration-dependent and is almost absent in the presence of propionate and carnitine. From these results it appears that propionyl carnitine may protect not only myocardium but also vessels from peroxidative damage that occurs during ischaemia and reperfusion.


High-Performance Polyacrylic Acid-Grafted PVDF Nanofiltration Membrane with Good Antifouling Property for the Textile Industry.
In the textile industry, a high-efficiency dye removal and low-retention of salt is demanded for recycling wastewater. In this study, polyvinylidene fluoride (PVDF) ultrafiltration membrane was transformed to a negatively charged loose nanofiltration (NF) membrane through UV-grafting of acrylic acid. At the optimal exposure of PVDF membrane in UV light for 5 min, the membrane had a high dye recovery above 99% (Congo red and Eriochrome® Black T) and a low sodium chloride (NaCl) rejection of less than 15% along with pure water flux of 26 L∙m-2∙h-1∙bar-1. Its antifouling and oleophobicity surface properties were verified using fluorescent- bovine serum albumin (BSA) and underwater mineral oil contact angle, respectively. According to the fluorescent microscopic images, the modified membrane had ten times lower adhesion of protein on the surface than the unmodified membrane. The underwater oil contact angle was raised from 110° to 155°. Moreover, the salt rejection followed this sequence: Na2SO4 > MgSO4 > NaCl > MgCl2, which agreed with the typical negatively charged NF membrane. In addition, the physicochemical characterization of membranes was further investigated to understand and link to the membrane performance, such as surface functional group, surface elements analysis, surface roughness/morphology, and surface hydrophilicity.


A stepwise approach to developing and maintaining an oncology multidisciplinary conference.
In recent years, there has been a shift in cancer treatment sites, from university-based to community settings. Approximately 85% of cancer patients are now diagnosed and treated in community hospitals. This change has been accompanied by an expansion of oncology services and specialists. One method that has increased communication and knowledge among departments providing oncology services, has been the Oncology Multidisciplinary Conference. This paper provides practical guidelines for establishing and maintaining such a group in a community hospital.


Postmenopausal hormone therapy with estradiol and norethisterone acetate and mammographic density: findings from a cross-sectional study among Norwegian women.
Although a number of studies have evaluated the associations between use of postmenopausal hormone therapy (HT) and mammographic density, few have assessed the effects of the medications containing estradiol (E2) plus norethisterone acetate (NETA). In particular, there are few data on the effects of the low-dose E2/NETA regimen. We included data from 724 women, aged 50-70 years, residing in south-east Norway, who participated in a cross-sectional study conducted within the Norwegian Breast Cancer Screening Program. We assessed mammographic density using a previously validated computer-assisted method. After adjusting for age at screening, number of children and body mass index, women who currently used HT had 6.0% higher percent mammographic density than never-users, p < 0.0001. Women who used either low- or high-dose continuous combined E2/NETA regimens had 7.7% (p < 0.0001) and 8.8% (p < 0.0001) higher percent mammographic density than never-users, respectively. Our study suggests that the effect of E2/NETA regimens on mammographic density could be at least as detrimental to the breast tissue as several other estrogen + progestin regimens. Our results suggest that both low- and high-dose E2/NETA influence mammographic density, but there were some indications in our analyses that the effect of low-dose E2/NETA could be slightly lower than that of the older high-dose regimen.


CO(2) Laser with Simultaneous Active and Passive Q-Switching.
Experiments were performed on a CO(2) laser using both saturable absorbing gas and slowly rotating mirror Q-switches. It was found that the saturating absorber essentially controls the pulse width and structure over a wide range of mirror rotation rates. A theoretical calculation is also reported. The CO(2) laser and the absorber were both assumed to be two-level systems.


Myocardial Reperfusion Injury: Insights Gained from Gene-Targeted Mice.
Myocardial ischemia-reperfusion injury involves activation of multiple cell types, including leukocytes and endothelial cells. The pursuant inflammation involves diminished nitric oxide production, influx of neutrophils, and myocardial cell injury. Gene-targeted animals provide important clues about the progression of this inflammatory cascade.


Selective deposition and self-assembly of triblock copolymers into matrix arrays for membrane protein production.
To improve the stability of cell membrane mimics, there has been growing interest in the use of block copolymers. Here, we present an easy approach to create an array of planar polymeric matrices capable of hosting membrane proteins. The array of polymeric matrices was formed by the selective deposition of triblock copolymers onto an array of hydrophilic islands situated within a hydrophobic background. The thickness of these matrices corresponds to the length of a single polymer chain. These polymeric matrices were used to host cell-free expressed membrane proteins, and offers a prototype from which a membrane protein array can be created for diagnostics or drug discovery purposes.


Clinical impact of arterial ammonia levels in ICU patients with different liver diseases.
Increased arterial ammonia levels are associated with high mortality in patients with acute liver failure (ALF). Data on the prognostic impact of arterial ammonia is lacking in hypoxic hepatitis (HH) and scarce in critically ill patients with cirrhosis. The patient cohort comprised 72 patients with HH, 43 patients with ALF, 100 patients with liver cirrhosis and 45 patients without evidence for liver disease. Arterial ammonia concentrations were assessed on a daily basis in all patients and the results were compared among these four patient groups and between 28-day survivors and 28-day non-survivors overall and in each group. Overall 28-day mortality rates in patients with HH, ALF and cirrhosis and in the control group were 54, 30, 49 and 27 %, respectively. Peak arterial ammonia levels differed significantly between transplant-free 28-day survivors and non-survivors in the HH and ALF groups (p < 0.01 for both). Multivariate regression identified peak arterial ammonia concentrations as an independent predictor of 28-day mortality or liver transplantation in patients with HH and ALF, respectively (p < 0.01). There was no association between mortality and arterial ammonia in patients with liver cirrhosis and in the control group. Admission arterial ammonia levels were independently linked to hepatic encephalopathy grades 3/4 in patients with HH (p < 0.01), ALF (p < 0.05) and cirrhosis (p < 0.05), respectively. Elevated arterial ammonia levels indicate a poor prognosis in acute liver injury and are associated with advanced HE in HH, ALF and cirrhosis. Arterial ammonia levels provide additional information in the risk assessment of critically ill patients with liver disease.


An Interim Examination of the US Public Health Response to Ebola.
From the summer of 2014 to the spring of 2016, the United States was involved in the Ebola response on both the national and international levels. The United States received 2 imported cases from West Africa and had 2 locally hospital-acquired cases, which spurred a massive and unprecedented public health response. As the domestic response stabilized and the epidemic in West Africa slowed, the Association of State and Territorial Health Officials (ASTHO) and the National Association of County and City Health Officials (NACCHO), through a cooperative agreement with the Centers for Disease Control and Prevention (CDC), led an in-progress review to assess the national public health response to Ebola. The goal was to identify opportunities to improve the Ebola response and best practices to inform future responses. To inform the review, NACCHO and ASTHO relied on feedback collected from several sources, including a stakeholder meeting held in August 2015, a series of key informant interviews, ASTHO's and NACCHO's internal response assessments, and perspectives shared by state and local health department members and workgroups and national partner organizations. ASTHO and NACCHO engaged experts and practitioners in public health, health care, emergency management, laboratory sciences, environmental health, occupational health, homeland security, communications, and public works from US federal, state, and local governments, the nonprofit community, and private industry. This article summarizes feedback and lessons learned as shared by these sources. Additionally, this article presents recommendations for federal, state, local, and nongovernment partners to improve current and future preparedness and response efforts to infectious disease threats.


The expression of the class 1 glucose transporter isoforms in human embryonic stem cells, and the potential use of GLUT2 as a marker for pancreatic progenitor enrichment.
Even before the first appearance of the developing pancreas, glucose is the major substrate in the growing embryo. The transport of glucose across cell membranes is facilitated by a family of membranal glucose transporters (GLUT). We analyzed changes in expression of class 1 glucose transporters (GLUT1-4) during human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC) differentiation, from undifferentiated cells to 28-day-old embryoid bodies (EBs). We also examined the potential use of GLUT2 as a marker for differentiating pancreatic progenitor cells. Using quantitative real time polymerase chain reaction (qPCR), western blot, and immunofluorescence, we observed enhanced expression of GLUT1 and GLUT2 during differentiation, but only minor change in GLUT3 expression. GLUT4 expression was found to be very low both at the RNA and in the protein levels. Expression of the early pancreatic transcription factor, pancreatic duodenal homeobox gene 1 (PDX1), correlated with GLUT2 expression, suggesting the potential use of GLUT2 as a surface marker for tracking pancreatic precursor cells. After sorting EBs according to their membranal GLUT2 expression, GLUT2 and PDX1 expression were found elevated, as was expression of other endodermal markers such as PAX4, NGN3, CXCR4, and SOX17. This simple method may be used to differentiate embryonic stem cells and to isolate from them, using GLUT2 as a surface marker, an enriched pancreatic progenitor cell population in order to achieve insulin-producing cells. The sorted GLUT2 cells may potentially be used in the future as insulin-producing cells for beta cell therapies.


Occupational therapy in the dialysis unit.
Occupational therapy is defined by the American Occupational Therapy Association as: the art and science of directing man's participation in selected tasks, to restore, reinforce and enhance performance, facilitate learning of those skills and functions essential for adaptation and productivity, diminish or correct pathology and maintain health.


Myofibroblastic inflammatory tumors of the bladder.
Bladder myofibroblastic inflammatory tumors are rare benign proliferative lesions that can simulate both urothelial and connective tissue malign neoplasms, making a preoperative diagnosis nearly impossible. Conservative treatment appears to be curative, even though local recurrences have been reported, and so malignancy should be ruled out above all by means of an accurate follow-up. Two cases are described, 1 of which with the longest follow-up period reported so far (8 years).


Clinical evaluation of the CDI-100 in-line hematocrit/saturation monitor.
This study was undertaken to evaluate the accuracy, reliability, consistency and biases of the CDI-100 saturation monitor when compared with a blood gas analyzer. The advantage of continuous in-line monitoring is that the perfusionist has continuous updates as to the patient's changing physiologic state. During this study, if the sample readout of the CDI-100 was off by greater than 10% from that of the Gem-Premier, the CDI-100 parameter was recalibrated. The accuracy of the CDI-100 was fair (greater than 10% of the samples needed recalibration) with regards to the initial sample comparisons. Recalibration was needed 67% of the time for the hematocrit and 35% for the saturation. The reliability of the CDI-100 was good (no equipment failure). The CDI-100 was consistent. It consistently overestimated both the hematocrit and saturation. This overestimation is the bias of the monitor. We recommend recalibration of the CDI-100 during clinical use to insure greater accuracy.


[History of ether in the 18th century: George-Louis Lesage's system of corpuscules ultramondains].
The article presents an account of Lesage's theory of corpuscules ultramondains and ether. It shows that essential attributes of the antique concept of ether still belong to his speculative physics. In accordance with this concept, Lesage understood the corpuscules ultramondains as subtle celestial matter and carriers of the primordial movements in the universe which were characterised by their proximity to the divine. On the other hand, Lesage was engaged in the contemporary debate concerning the problem of causa gravitatis. His position turns out to be halfway between dynamic corpuscularity and mechanistic physics. With the former he shared the rejection of vortex theories and the adherence to the corpuscular theory of light and the nutshell theory, with the latter the rejection of action at-a-distance and forces inherent to matter. Contrary to the accusation that he plagiarised Fatio de Duillier's theory of gravitation, it is shown that Lesage formulated a gravitational mechanism essentially different to Fatio's. Lesage used the term ether for the theory of chemical affinities. His attempt to reduce them to gravitational force failed. The complexity of chemical phenomena could not be mastered theoretically by reduction to a uniform natural force.


Improved (and Singular) Disinfectant Protocol for Indirectly Assessing Organic Precursor Concentrations of Trihalomethanes and Dihaloacetonitriles.
Measurements of disinfection byproduct (DBP) organic precursor concentrations (OPCs) are crucial to assess and improve DBP control processes. Typically, formation potential tests - specified in Standard Methods (SM) 5710-B/D - are used to measure OPCs. Here, we highlight several limitations of this protocol for dihaloacetonitriles and trihalomethanes and validate a novel Alternative Method (AM). The effects of pH, disinfectant type (free chlorine and monochloramine), and chlor(am)ine residual (CR) were examined on DBP formation in a suite of waters. Using the SM, DHAN decreased 43-47% as the CR increased from 3 to 5 mg L(-1) as Cl2, compromising OPC assessments. In contrast, a high monochloramine dose (250 mg L(-1) as Cl2) at pH 7.0 (the AM) accurately reflected OPCs. The two methods were compared for assessing DBP precursor removal through three granular activated carbon (GAC) columns in series. Breakthrough profiles assessed using the AM only showed DBP precursor sorption occurred in each column that decreased over time (p = 0.0001). Similarly, the AM facilitated ranking of three types of GAC compared in parallel columns, whereas the SM produced ambiguous results. Fluorescence intensity of a humic-like fluorophore (i.e., I345/425) correlated strongly to precursor removal in the GAC columns. The practical implications of the results are discussed.


Massively Multiplexed Electrohydrodynamic Tip Streaming from a Thin Disc.
We report an experimental study on the multiple tip streaming enabled by an externally wetted thin disc in electric fields. The electrohydrodynamic stress acting on the liquid-air interface triggers an interfacial instability that develops into multiple radial liquid ligaments at the rim of the disc. The scaling law suggests that the wave number is inversely proportional to the square of the peak electric field at the rim, which is determined by the combined thickness of the disc and the attached liquid layer. The thin disc edge effectively intensifies the electric field, which in turn leads to spacing between ligaments as short as 30 μm for ethanol, generating over 1000 cone jets for a 1 cm diam thin disc.


Sevelamer Improves Steatohepatitis, Inhibits Liver and Intestinal Farnesoid X Receptor (FXR), and Reverses Innate Immune Dysregulation in a Mouse Model of Non-alcoholic Fatty Liver Disease.
Bile acid sequestrants are synthetic polymers that bind bile acids in the gut and are used to treat dyslipidemia and hyperphosphatemia. Recently, these agents have been reported to lower blood glucose and increase insulin sensitivity by altering bile acid signaling pathways. In this study, we assessed the efficacy of sevelamer in treating mice with non-alcoholic fatty liver disease (NAFLD). We also analyzed how sevelamer alters inflammation and bile acid signaling in NAFLD livers. Mice were fed a low-fat or Western diet for 12 weeks followed by a diet-plus-sevelamer regimen for 2 or 12 weeks. At the end of treatment, disease severity was assessed, hepatic leukocyte populations were examined, and expression of genes involved in farnesoid X receptor (FXR) signaling in the liver and intestine was analyzed. Sevelamer treatment significantly reduced liver steatosis and lobular inflammation. Sevelamer-treated NAFLD livers had notably fewer pro-inflammatory infiltrating macrophages and a significantly greater fraction of alternatively activated Kupffer cells compared with controls. Expression of genes involved in FXR signaling in the liver and intestine was significantly altered in mice with NAFLD as well as in those treated with sevelamer. In a mouse model of NAFLD, sevelamer improved disease and counteracted innate immune cell dysregulation in the liver. This study also revealed a dysregulation of FXR signaling in the liver and intestine of NAFLD mice that was counteracted by sevelamer treatment.


End-to-End Deep Learning Model to Predict and Design Secondary Structure Content of Structural Proteins.
Structural proteins are the basis of many biomaterials and key construction and functional components of all life. Further, it is well-known that the diversity of proteins' function relies on their local structures derived from their primary amino acid sequences. Here, we report a deep learning model to predict the secondary structure content of proteins directly from primary sequences, with high computational efficiency. Understanding the secondary structure content of proteins is crucial to designing proteins with targeted material functions, especially mechanical properties. Using convolutional and recurrent architectures and natural language models, our deep learning model predicts the content of two essential types of secondary structures, the α-helix and the β-sheet. The training data are collected from the Protein Data Bank and contain many existing protein geometries. We find that our model can learn the hidden features as patterns of input sequences that can then be directly related to secondary structure content. The α-helix and β-sheet content predictions show excellent agreement with training data and newly deposited protein structures that were recently identified and that were not included in the original training set. We further demonstrate the features of the model by a search for de novo protein sequences that optimize max/min α-helix/β-sheet content and compare the predictions with folded models of these sequences based on AlphaFold2. Excellent agreement is found, underscoring that our model has predictive potential for rapidly designing proteins with specific secondary structures and could be widely applied to biomedical industries, including protein biomaterial designs and regenerative medicine applications.


Targeted therapies and the treatment of non-clear cell renal cell carcinoma.
Targeted therapies have shown profound effects on the outcome of patients with advanced renal cell carcinoma (RCC). However, the optimal treatment for RCC of non-clear cell histology (nccRCC)-typically excluded from trials of targeted agents-remains uncertain. By carrying out extensive searches of PubMed and ASCO databases, we identified and summarised research into the biological characteristics, clinical behaviour and treatment of different histological subtypes of nccRCC, focusing on targeted therapy. The available data suggest that treatments currently approved for RCC are active in ncc subtypes, although the overall clinical benefit may be less than for clear cell RCC. Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with nccRCC, based on phase III data, while everolimus, sunitinib and sorafenib have all demonstrated some degree of activity in nccRCC in expanded-access trials. No clear picture has emerged of whether individual histological subtypes are particularly responsive to any individual treatment. Further molecular studies into the pathogenesis of RCC histological subtypes will help direct the development of novel, appropriate targeted agents. Clinical trials specifically designed to evaluate the role of targeted agents in nccRCC are ongoing, and data from trials with sunitinib and everolimus will be reported soon.


Accuracy and linearity of positive airway pressure devices: a technical bench testing study.
To analyze the accuracy and linearity of different CPAP devices outside of the manufacturers' own quality control environment. Accuracy (how well readings agree with the gold standard) and linearity were evaluated by comparing programmed pressure to measured CPAP pressure using an instrument established as the gold standard. Comparisons were made centimeter-by-centimeter (linearity) throughout the entire programming spectrum of each device (from 4 to 20 cm H2O). A total of 108 CPAP devices were tested (1836 measurements); mean use of the devices was 956 hours. Twenty-two of them were new. The intra-class correlation coefficient (ICC) decreased from 0.97 at pressures programmed between 4 and 10 cm H2O, to 0.84 at pressures of 16 to 20 cm H2O. Despite this high ICC, the 95% agreement limit oscillated between -1 and 1 cm H2O. This same behavior was observed in relation to hours of use: the ICC for readings taken on devices with < 2,000 hours of use was 0.99, while that of the 50 measurements made on devices with > 6,000 hours was 0.97 (the agreement limit oscillated between -1.3 and 2.5 cm H2O). "Adequate adjustments" were documented in 97% of measurements when the definition was +/- 1 cm H2O of the programmed pressure, but this index of adequate adjustment readings decreased to 85% when the +/- 0.5 cm H2O criterion was applied. In general, the CPAP devices were accurate and linear throughout the spectrum of programmable pressures; however, strategies to assure short- and long-term equipment reliability are required in conditions of routine use.


Streamlining and large ancestral genomes in Archaea inferred with a phylogenetic birth-and-death model.
Homologous genes originate from a common ancestor through vertical inheritance, duplication, or horizontal gene transfer. Entire homolog families spawned by a single ancestral gene can be identified across multiple genomes based on protein sequence similarity. The sequences, however, do not always reveal conclusively the history of large families. To study the evolution of complete gene repertoires, we propose here a mathematical framework that does not rely on resolved gene family histories. We show that so-called phylogenetic profiles, formed by family sizes across multiple genomes, are sufficient to infer principal evolutionary trends. The main novelty in our approach is an efficient algorithm to compute the likelihood of a phylogenetic profile in a model of birth-and-death processes acting on a phylogeny. We examine known gene families in 28 archaeal genomes using a probabilistic model that involves lineage- and family-specific components of gene acquisition, duplication, and loss. The model enables us to consider all possible histories when inferring statistics about archaeal evolution. According to our reconstruction, most lineages are characterized by a net loss of gene families. Major increases in gene repertoire have occurred only a few times. Our reconstruction underlines the importance of persistent streamlining processes in shaping genome composition in Archaea. It also suggests that early archaeal genomes were as complex as typical modern ones, and even show signs, in the case of the methanogenic ancestor, of an extremely large gene repertoire.


Gait training reduces ankle joint stiffness and facilitates heel strike in children with Cerebral Palsy.
Foot drop and toe walking are frequent concerns in children with cerebral palsy (CP). Increased stiffness of the ankle joint muscles may contribute to these problems. Does four weeks of daily home based treadmill training with incline reduce ankle joint stiffness and facilitate heel strike in children with CP? Seventeen children with CP (4-14 years) were recruited. Muscle stiffness and gait ability were measured twice before and twice after training with an interval of one month. Passive and reflex-mediated stiffness were measured by a dynamometer which applied stretches below and above reflex threshold. Gait kinematics were recorded by 3-D video-analysis during treadmill walking. Foot pressure was measured by force-sensitive foot soles during treadmill and over-ground walking. Children with increased passive stiffness showed a significant reduction in stiffness following training (P = 0.01). Toe lift in the swing phase (P = 0.014) and heel impact (P = 0.003) increased significantly following the training during both treadmill and over-ground walking. Daily intensive gait training may influence the elastic properties of ankle joint muscles and facilitate toe lift and heel strike in children with CP. Intensive gait training may be beneficial in preventing contractures and maintain gait ability in children with CP.


The role of auditory beats induced by frequency modulation and polyperiodicity in the perception of spectrally embedded complex target sounds.
The contribution of auditory beats to the perception of target sounds differing from an interfering background by their frequency modulation (FM) pattern or by a difference in fundamental frequency (F0) was investigated. On each trial, test sounds composed of a single, second-order formant were embedded in harmonic backgrounds and presented in successive intervals. The center frequencies of these "normal" formants differed across intervals. Subjects were to decide which interval contained the test formant with a center frequency matching that of an isolated target formant presented before each test stimulus. Matching thresholds were measured in terms of the width of modulation for FM stimuli or the mistuning of the F0's of unmodulated test formants relative to that of the background. Beats may have allowed the identification of the spectral region of the target in both experiments. To reduce interactions between test and background components, matching thresholds were measured for "flat" formants composed of two or three equal-amplitude components embedded in a harmonic background in which components corresponding to those of test formants were absent. These measures were repeated with the addition of a pink noise floor. Matching was still possible in all cases, though at higher thresholds than for normal formants. Computer simulations suggested that the modulation depth of envelope fluctuations within auditory channels played a significant role in the matching of target sounds when their components were mixed in the same frequency region with those of an interfering sound, but not when the target and background components were separated by as much as 250 Hz, the F0 of the stimulus.


Beamforming with a circular array of microphones mounted on a rigid sphere (L).
Beamforming with uniform circular microphone arrays can be used for localizing sound sources over 360°. Typically, the array microphones are suspended in free space or they are mounted on a solid cylinder. However, the cylinder is often considered to be infinitely long because the scattering problem has no exact solution for a finite cylinder. Alternatively one can use a solid sphere. This investigation compares the performance of a circular array mounded on a rigid sphere with that of such an array in free space and mounted on an infinite cylinder, using computer simulations. The examined techniques are delay-and-sum and circular harmonics beamforming, and the results are validated experimentally.


Impact of Ivabradine on Inflammatory Markers in Chronic Heart Failure.
Background. Inflammation plays a crucial role in the progression of chronic heart failure (CHF). Ivabradine is known to reduce the morbidity and mortality of patients with CHF under certain conditions. Beyond the reduction of heart rate, only limited knowledge exists about potential anti-inflammatory effects of ivabradine that might contribute to its benefit in CHF. Thus, the present study aimed to investigate the effect of ivabradine on systemic inflammation. Methods. In the present study, 33 patients with CHF due to dilated, ischemic, and hypertensive cardiomyopathy were treated with ivabradine according to the guidelines of the European Society of Cardiology (ESC). A number of circulating dendritic cells as well as inflammatory mediators were investigated using FACS analysis and ELISA, respectively, before and during ivabradine therapy. Results. Treatment with ivabradine resulted in a significant improvement of CHF symptoms as well as an increase in left ventricular ejection fraction. Moreover, ivabradine treatment led to a significant reduction of TNF-alpha (TNF-α) serum levels and a reconstitution of circulating dendritic cells which are known to be reduced in patients with CHF. Conclusion. We show that treatment with ivabradine in patients with CHF resulted in an improvement of HF symptoms and ejection fraction as well as a normalization of inflammatory mediators.


Training effect of a virtual reality haptics-enabled dynamic hip screw simulator.
Virtual reality (VR) simulation offers a safe, controlled, and effective environment to complement training but requires extensive validation before it can be implemented within the curriculum. The main objective was to assess whether VR dynamic hip screw (DHS) simulation has a training effect to improve objective performance metrics. 52 surgical trainees who were naïve to DHS procedures were randomized to 2 groups: the training group, which had 5 attempts, and the control group, which had only one attempt. After 1 week, both cohorts repeated the same number of attempts. Objective performance metrics included total procedural time (sec), fluoroscopy time (sec), number of radiographs (n), tip-apex distance (TAD; mm), attempts at guide-wire insertion (n), and probability of cut-out (%). Mean scores (with SD) and learning curves were calculated. Significance was set as p < 0.05. The training group was 68% quicker than the control group, used 75% less fluoroscopy, took 66% fewer radiographs, had 82% less retries at guide-wire insertion, achieved a reduced TAD (by 41%), had lower probability of cut-out (by 85%), and obtained an increased global score (by 63%). All these results were statistically significant (p < 0.001). The participants agreed that the simulator provided a realistic learning environment, they stated that they had enjoyed using the simulator, and they recognized the need for the simulator in formal training. We found a significant training effect on the VR DHS simulator in improving objective performance metrics of naïve surgical trainees. Patient safety, an important priority, was not compromised.


Genome-Wide Profiling of the Toxic Effect of Bortezomib on Human Esophageal Carcinoma Epithelial Cells.
Bortezomib has been widely used to treat multiple myeloma and other hematological malignancies. However, not much is known about its effect on solid tumors. The aim of this study was to study the effect of Bortezomib on human esophageal cancer cell lines and investigate the potential target pathways. Two human esophageal cancer cell lines, TE-1 and KYSE-150, were used in this study. Cell viability, cell cycle distribution, and apoptosis after Bortezomib treatment was detected by Cell Counting Kit-8, flow cytometry, and Annexin V/propidium iodide staining, respectively. The genes targeted by Bortezomib were analyzed at the messenger RNA level by microarray chips and quantitative real-time polymerase chain reaction. The proliferation of human esophageal cancer cell lines was inhibited by Bortezomib in a dose- and time-dependent manner. Bortezomib treatment led to G2/M arrest and apoptosis. Microarray chips revealed multiple signaling pathways targeted by Bortezomib, including proteasome, endoplasmic reticulum, Wnt-, and calcium-mediated pathway. The expression patterns of 4 representative genes UBD, CUL3, HDAC6, and GADD45A were verified by quantitative real-time polymerase chain reaction and showed consistency with the microarray assay. Bortezomib could suppress cell viability, cause G2/M arrest, and induce apoptosis in human esophageal cancer cells, with possible targets including UBD, CUL3, HDAC6, and GADD45A.


[The long-term results of decompression and anterior lumbar interbody fusion for the treatment of degenerative lumbar spondylolisthesis].
In this paper we reviewed 31 patients who had been treated surgically for lumbar degenerative spondylolisthesis. They were operated between 1990-1996. The decompression and anterior lumbar interbody fusion with use of autologous bone graft,was performed in all of them. The duration of follow-up ranged from 12 to 6 years. The outcome was assessed using rating system of Prolo and VAPS. The disc high, degree of slippage, segmental lordosis, before surgery, after 6 weeks and at the time of final follow-up were measured on the radiographs. In all cases spinal fusion were achieved. A significant decrease in radicular pain and low back pain was seen but the relation between clinical and radiological outcomes was not observed.


Adherence to the Planetary Health Diet Index and Obesity Indicators in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).
The EAT-Lancet Commission has proposed a model diet to improve the health of human beings and that of the planet. Recently, we proposed the Planetary Health Diet Index (PHDI) to assess adherence of the population to this model diet. In this study, we aimed to evaluate adherence to the PHDI and obesity outcomes using baseline data from 14,515 participants in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). The dietary data were assessed using a 114-item FFQ. Body mass index (BMI) and waist circumference (WC) were both used continuously and categorized. Linear and multinomial regression models adjusted for potential confounding factors were performed to assess the relationship between adherence to PHDI and outcomes. An inverse association was observed between adherence to PHDI and obesity indicators. Individuals with high adherence to the PHDI had lower BMI (β-0.50 95% CI-0.73:-0.27) and WC (β-1.70 95% CI-2.28:-1.12) values. They were also 24% less likely to be overweight (OR 0.76 95% CI 0.67:0.85) or obese (OR 0.76 95% CI 0.65:0.88), and they were 14% and 27% less likely to have increased WC (OR 0.86 95% CI 0.75:0.98) or substantially increased WC (OR 0.73 95% CI 0.64:0.83) than those with lower adherence. Our results showed that higher adherence to the PHDI may decrease obesity indicators.


Attenuation of interleukin 2 signal in the spleen cells of complex ganglioside-lacking mice.
T cell development and function in complex ganglioside-lacking (GM2/GD2 synthase gene-disrupted) mice were analyzed. GM1, asialo-GM1, and GD1b were representative gangliosides expressed on T cells of the wild type mice and completely deleted on those of the mutant mice. The sizes and cell numbers of the mutant mice spleen and thymus were significantly reduced. Spleen cells from the mutant mice showed clearly reduced proliferation compared with the wild type when stimulated by interleukin 2 (IL-2) but not when treated with concanavalin A or anti-CD3 cross-linking. Expression levels of IL-2 receptor alpha, beta, and gamma were almost equivalent, and up-regulation of alpha chain after T cell activation was also similar between the mutant and wild type mice. Activation of JAK1, JAK3, and SAT5 after IL-2 treatment was reduced, and c-fos expression was delayed and reduced in the mutant spleen cells, suggesting that the IL-2 signal was attenuated in the mutant mice probably due to the modulation of IL-2 receptors by the lack of complex gangliosides.


ICU Length of Stay and Factors Associated with Longer Stay of Major Trauma Patients with Multiple Rib Fractures: A Retrospective Observational Study.
Chest injury with multiple rib fractures is the most common injury among major trauma patients in New South Wales (23%) and is associated with a high rate of mortality and morbidity. The aim of this study was to determine the intensive care unit (ICU) length of stay (LOS) among major trauma patients with multiple rib fractures and to identify factors associated with a prolonged ICU LOS. Single-centre, retrospective observational cohort study of adult patients with 3 or more traumatic rib fractures, who were admitted to ICU between June 2014 and June 2019. A comparison was made between patients who stayed in ICU for less than 7 days and those that stay for 7 or more days. Among 215 patients who were enrolled, 150 (69.7%) were male, the median Injury Severity Score (ISS) was 24 (interquartile range (IQR): 17-32). The median ICU LOS was 4 (IQR: 2-7) days and the average ICU LOS was 6.5 (SD 8.5; 95% CI 5.3-7.6) days. The median number of rib fractures was 6 (IQR: 5-9) and 76 (35.3%) patients had a flail chest. Patients who stayed longer than 7 days in ICU had higher ISS, higher APACHE-II score, greater number of rib fractures, higher rate of lung contusions, and required more respiratory support of any type. ISS, number of rib fractures, lung contusion, and flail chest were associated with prolonged ICU LOS in patients with traumatic multiple rib fractures.


Predominant VNTR family of strains of Mycobacterium tuberculosis isolated from South Asian patients.
Despite the low incidence of tuberculosis in the UK, some minority ethnic groups, particularly those originating from South Asia, experience very high incidence rates. Comparison of the variable number tandem repeat (VNTR) profiles of strains of Mycobacterium tuberculosis circulating in an immigrant community in the UK with those found in the country of ethnic origin. Isolates of M. tuberculosis were collected from samples obtained from patients attending clinics in Leeds and Bradford, UK and Rawalpindi, Pakistan. Strains were compared using VNTR analysis and mixed-linker PCR. Comparison of VNTR profiles found that one profile (42235) represented 37% of patient isolates from Rawalpindi and 23% of patient isolates in Leeds and Bradford, where it was associated exclusively with patients with South Asian names. A second profile (02235) represented 15% of patient isolates in Leeds and Bradford, and was also exclusively associated with the South Asian community. These profiles could be subdivided by mixed-linker PCR analysis. The VNTR profile 42235 may represent a family of strains commonly found in communities associated with South Asia.


DNA damage-inducible loci in Salmonella typhimurium.
lac operon fusions to DNA damage-inducible (din) loci were generated in Salmonella typhimurium LT2. Many of these din fusions were efficiently repressed by cloned Escherichia coli LexA, while others were not; all required RecA for induction. Several din fusions exhibited strong inducibility and will be useful in developing an SOS induction assay in S. typhimurium to detect genotoxins.


Influence of ferrous sulfate on the solubility, partition coefficient, and stability of mycophenolic acid and the ester mycophenolate mofetil.
Studies were performed to (1) evaluate whether the presence of iron affected the physicochemical properties of mycophenolate mofetil (MMF) and mycophenolic acid (MPA), and (2) determine whether alteration of these properties was indicative of formation of an MMF-iron complex. The solubility, stability (chemical reactivity), and partitioning properties of MMF and MPA were evaluated over a pH range of 2-7 in the presence and absence of ferrous sulfate. In addition, the solubility and partitioning properties of MMF were assessed after the MMF drug product, CellCept capsules, was combined with an iron tablet (Fero-Gradumet, ferrous sulfate, tablets). The results of studies showed that: The solubility of MMF in the presence of ferrous sulfate was generally unaffected over a pH range of 2-7; a small increase in solubility was observed in pH 5.2 buffer solution. The solubility of MPA decreased in pH 5.2 and 7.0 buffer solutions. Both MMF and MPA were more stable in the presence of ferrous sulfate at pH 2.0; ferrous sulfate had no effect on the stability of MMF and MPA at pH 7.0. Overall, the partitioning of MMF and MPA was unaffected by the addition of ferrous sulfate. The solubility and partitioning of MMF from CellCept capsules combined with Fero-Gradumet (ferrous sulfate) tablets showed a twofold increase in aqueous solubility of MMF as well as increased concentration of MMF in both the n-octanol and aqueous phases, leading to a decrease in the octanol/water partition coefficient due to a reduction in pH of the aqueous phase. Based on these results, it was concluded that the physicochemical properties of MMF and MPA were generally not affected by the presence of ferrous sulfate. Further, the presence of ferrous sulfate did not suggest the formation of an MMF-iron complex.


Fluoro-deoxy-glucose positron emission tomography/computed tomography in lymphoma: A pictorial essay.
F-18 fluoro-deoxy-glucose (FDG) positron emission tomography/computed tomography (PET/CT) has emerged as a powerful imaging modality in the field of oncology. F-18 FDG PET/CT is now an established tool in the management of lymphoma. This has been shown to be useful in staging, detection of bone marrow involvement (BMI), early response assessment and end of therapy response assessment in lymphoma. Interpretation of F-18 FDG PET/CT in lymphoma is carried out by various qualitative response assessment criteria. London criteria are used for interpretation of interim PET/CT and International Harmonization Project (IHP) criteria are used to interpret PET/CT done after the end of chemotherapy. Quantitative analysis is also found to be useful in assessment of response early after two cycles of chemotherapy in patients with diffuse large B cell lymphoma (DLBCL). This pictorial essay provides few images describing the FDG avidity of lymphoma, patterns of bone marrow uptake and their relevance in predicting BMI, role of staging PET/CT, quantitative analysis in response assessment, example images of response according to London criteria and IHP criteria. Few pitfalls in imaging of lymphoma with PET/CT are also discussed in the images legend.


Superparamagnetic state by linear and non-linear AC magnetic susceptibility in Mn0.5Zn0.5Fe2O4 ferrites nanoparticles.
The Mn0.5Zn0.5Fe2O4 nanoparticles has been synthesized using citrate-gel-precursor method. The direct mixing of nitrates and acetates yields homogeneous nanoparticles. Phase formation and crystal structure of the synthesized powder were examined through the X-ray diffraction (XRD). Fourier transform infrared (FTIR) spectra of the sample confirm the spinel structure. The average particle size was determined by transmission electron microscopy (TEM) and field emission scanning electron microscopy (FESEM). The average particle size is found to be about 13 nm. Superparamagnetic-like nature of the nanoparticles of Mn0.5Zn0.5Fe2O4 has been revealed through various dc and linear and non-linear ac magnetization measurements. However, the nanoparticles do not behave like ideal non-interacting superparamagnets. The magnetic particle size is found to be about 8 nm with saturation magnetization about 18.1 emu/g. The blocking temperature (T(B)) of the nanoparticle assembly is found to be about 150 K as observed from dc and ac magnetization measurements. The frequency dependence of the blocking temperature (T(B)) is found to follow Vogel-Fulcher law. The associated characteristic time tau0 is found to be 10(-5) s. This value is different from that generally found for non-interacting superparamagnetic (SPM) systems (tau0 = 10(-9)-10(-10) s).


A Phase-1 Study Comparing Pharmacokinetic and Safety Profiles of Three Different Dose Intervals of Aripiprazole Lauroxil.
Aripiprazole lauroxil (AL) is an FDA-approved treatment for schizophrenia. AL is a non-ester prodrug of aripiprazole that results in extended systemic release of aripiprazole after intramuscular (IM) administration. This Phase-1 study evaluated the pharmacokinetics (PK) and safety of a new AL dose (1064 mg)* for 2-month dose intervals. The study also evaluated 4- and 6-week dose intervals of AL at the 441 mg and 882 mg doses, respectively. A total of 139 patients diagnosed with schizophrenia and stabilized on a first-line antipsychotic (other than aripiprazole) were randomized to one of 3 dose/dose-interval groups: a 4-week interval of AL 441 mg (n = 35), a 6-week interval of AL 882 mg (n = 34), and an 8-week interval of AL 1064 mg IM injection (n = 70). After randomization, AL assignment was open label and administered as gluteal injections over 24 weeks. The total number of injections over this time period was related to the interval: 7 injections for the 441 mg group, 5 for the 882 mg group, and 4 for the 1064 mg group. PK and safety assessments occurred every 2 weeks and extended for an additional 20 weeks after the last injection. Patients continued their prior antipsychotic throughout, such that the safety (but not the PK) findings also reflect a second antipsychotic co-prescribed with AL. PK findings: administration of AL 1064 mg every 8 weeks and AL 882 mg every 6 weeks provided continuous exposure to aripiprazole. Compared with the AL 441 mg every 4 weeks group, the longer dose-interval groups had consistently higher plasma concentrations for the entirety of the 6- and 8-week dose intervals for the 882 mg and 1064 mg dose groups. Safety findings: the overall safety profile of the group randomized to the 8 week/1064 mg combination was comparable to the 6 week/882 mg and 4 week/441 mg groups. The most common adverse event (AE) for all groups was injection-site reaction (pain). There was no apparent dose-AE signal for extrapyramidal symptoms, akathisia, sedation, or weight gain. In particular, there was no other safety signal identified with the longest interval/highest-dose AL group of 8 weeks/1064 mg. AL allows for a range of dose/dose-interval combinations. The PK results from this study show that a dosing interval of every 8 weeks for the 1064 mg dose resulted in aripiprazole concentrations within the established therapeutic window for AL. There was no safety signal directing any particular concern to any of the three doses/dose intervals studied. All patients continued their primary antipsychotics without any apparent tolerability issue arising from the addition of the AL injections. The results of this study show that 1064 mg AL may be suitable for a 2-month dose interval. The three doses/dose intervals studied have the potential to help clinicians and patients expand their choice of AL treatment to best meet the needs of the individual patient.


Determination of the free radical scavenging activity of dihydropyran-2,4-diones.
The antioxidant activities of four synthetic dihydropyran-2,4-diones have been established through the determination of their abilities to inhibit free radicals using DPPH(*) as the stable radical. Whilst all of the compounds exhibited high inhibition percentages, the most active member of the group was 6-phenyl-dihydropyran-2,4-dione. The antioxidant activity of the dihydropyran-2,4-diones is reported here for the first time and extends our knowledge of the range of valuable biological activities associated with this group of compounds.


Upregulation of microRNA-23a regulates proliferation and apoptosis by targeting APAF-1 in laryngeal carcinoma.
MicroRNA-23a (miR-23a) is a potential biomarker for laryngeal cancer. Apoptotic protease activating factor 1 (APAF-1) was recently demonstrated to be a target of miR-23a. However, whether miR-23a exerts its effects via APAF-1 in laryngeal cancer, remains unknown. In the present study, miR-23a expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). APAF-1 mRNA and protein expression levels were assayed by RT-qPCR and western blotting, respectively. Binding of miR-23a to APAF-1 was monitored by a luciferase reporter assay. Gain-of-function and loss-of-function studies were performed in order to investigate the roles of miR-23a and APAF-1 in Hep2 cell proliferation and apoptosis. miR-23a and APAF-1 were found to be significantly upregulated and downregulated, respectively, in laryngeal cancer tissues, and there was a significant negative correlation between APAF-1 and miR-23a expression. The results of the luciferase reporter assay demonstrated that miR-23a bound directly to the APAF-1 mRNA 3'-untranslated region. Ectopic expression of miR-23a and knockdown of APAF-1 significantly promoted cell proliferation and colony formation, and inhibited early apoptosis in Hep2 cells. In conclusion, miR-23a acts as an oncogenic regulator in laryngeal carcinoma by directly targeting APAF-1, and may be a useful biomarker in the diagnosis and treatment of laryngeal carcinoma.


Autobiographical memory characteristics in depression vulnerability: formerly depressed individuals recall less vivid positive memories.
The differential activation hypothesis (DAH; Teasdale, 1988) proposes that individuals who are vulnerable to depression can be distinguished from non-vulnerable individuals by the degree to which negative thoughts and maladaptive cognitive processes are activated during sad mood. While retrieval of negative autobiographical memories is noted as one such process, the model does not articulate a role for deficits in recalling positive memories. Two studies were conducted to compare the autobiographical memory characteristics of never-depressed and formerly depressed individuals following a sad mood induction. In Study 1, features of negative memories of never-depressed and formerly depressed individuals did not differ, either in neutral or sad mood. For positive memories, groups did not differ in neutral mood, but following a sad mood induction, formerly depressed individuals rated their positive memories as less vivid than their never-depressed counterparts. Study 2 examined positive autobiographical memory features more comprehensively and replicated the finding that in a sad mood formerly depressed individuals recalled less vivid positive memories than never-depressed controls. These findings suggest that the phenomenological features of positive memories could represent an important factor in depressive vulnerability, and, more broadly, that depression may be associated with a deficit in the processing of positive material.