Medical students' perspectives on a multicultural curriculum.
The Liaison Committee on Medical Education requires medical schools to deliver curriculum that prepares graduates to care for a culturally diverse patient population. This study explores student perceptions of 1 multicultural curriculum and their preparedness for dealing with: racism, stereotypes, community partnership and disparities. Focus groups were conducted with 22 preclinical and clinical students. Participants were asked semistructured and open-ended questions. Using a conceptual approach to thematic content analysis of transcripts, the data were reviewed by the study's authors for common themes. The authors identified the following: 1) Students asserted that topics of multiculturalism, disparities and racism should be incorporated both throughout the curriculum and in discrete packages; these topics would be most effective if highlighted during their clinical training. 2) Students preferred learning about topics such as racism and bias from "real" patients. 3) At times, written cases may be counterproductive by reinforcing stereotypes. 4) Finally, students note that without recurrent assessment, many students do not perceive topics on multicultural issues as vital to their education. Given these recurring themes, we have reviewed our assessment strategies for the multicultural curriculum and are implementing a longitudinal assessment of our multicultural curriculum. Our findings should inform our school and others as to the need for further faculty development and clerkship materials in the area of cultural competency.


Case-control study of lung cancer risk from residential radon exposure in Worcester county, Massachusetts.
A study of lung cancer risk from residential radon exposure and its radioactive progeny was performed with 200 cases (58% male, 42% female) and 397 controls matched on age and sex, all from the same health maintenance organization. Emphasis was placed on accurate and extensive year-long dosimetry with etch-track detectors in conjunction with careful questioning about historic patterns of in-home mobility. Conditional logistic regression was used to model the outcome of cancer on radon exposure, while controlling for years of residency, smoking, education, income, and years of job exposure to known or potential carcinogens. Smoking was accounted for by nine categories: never smokers, four categories of current smokers, and four categories of former smokers. Radon exposure was divided into six categories (model 1) with break points at 25, 50, 75, 150, and 250 Bq m, the lowest being the reference. Surprisingly, the adjusted odds ratios (AORs) were, in order, 1.00, 0.53, 0.31, 0.47, 0.22, and 2.50 with the third category significantly below 1.0 (p < 0.05), and the second, fourth, and fifth categories approaching statistical significance (p < 0.1). An alternate analysis (model 2) using natural cubic splines allowed calculating AORs as a continuous function of radon exposure. That analysis produces AORs that are substantially less than 1.0 with borderline statistical significance (0.048 < or = p < or = 0.05) between approximately 85 and 123 Bq m. College-educated subjects in comparison to high-school dropouts have a significant reduction in cancer risk after controlling for smoking, years of residency, and job exposures with AOR = 0.30 (95% CI: 0.13, 0.69), p = 0.005 (model 1).


An investigation into the low temperature thermal behaviour of vitamin E preparation USP using differential scanning calorimetry and low frequency dielectric analysis.
The thermal and dielectric responses of Vitamin E Preparation USP have been examined to further understand the melting and solidification of this material. A TA Instruments 2920 Differential Scanning Calorimeter was used to examine the thermal response of the sample at a range of scanning speeds. Isothermal dielectric studies were performed using a Novocontrol Dielectric Spectrometer over a range of temperatures down to -70 degrees C and a frequency range of 10(6)-10(-2) Hz. The differential scanning calorimetry (DSC) studies showed an anomalous response whereby at slow heating rates (2 degrees C min(-1)) a small exotherm followed immediately by an endotherm was observed. This response was considerably diminished in magnitude at higher rates (5 degrees C min(-1)) and was not observed at the fastest heating rate of 10 degrees C min(-1). No thermal events were seen on cooling the sample to -60 degrees C. It was suggested that the material formed a glass on cooling, with a predicted transition temperature of approximately -100 degrees C. Further studies using a liquid nitrogen cooling system indicated that the system did indeed exhibit a glass transition, albeit at a higher temperature than predicted (ca -63 degrees C). Low frequency dielectric analysis showed a clear relaxation peak in the loss component, from which the relaxation time could be calculated using the Havriliak-Negami model. The relationship between the relaxation time and the temperature was studied and was found to follow the Vogel-Tammann-Fulcher (VTF) modification of the Arrhenius equation. It is therefore concluded that Vitamin E Preparation USP is a glass-forming material that exhibits kinetically-hindered recrystallisation and melting behaviour. The study has also indicated that DSC and low frequency dielectric analysis may be powerful complementary tools in the study of the low temperature behaviour of pharmaceuticals.


Hajj: infectious disease surveillance and control.
Religious festivals attract a large number of pilgrims from worldwide and are a potential risk for the transmission of infectious diseases between pilgrims, and to the indigenous population. The gathering of a large number of pilgrims could compromise the health system of the host country. The threat to global health security posed by infectious diseases with epidemic potential shows the importance of advanced planning of public health surveillance and response at these religious events. Saudi Arabia has extensive experience of providing health care at mass gatherings acquired through decades of managing millions of pilgrims at the Hajj. In this report, we describe the extensive public health planning, surveillance systems used to monitor public health risks, and health services provided and accessed during Hajj 2012 and Hajj 2013 that together attracted more than 5 million pilgrims from 184 countries. We also describe the recent establishment of the Global Center for Mass Gathering Medicine, a Saudi Government partnership with the WHO Collaborating Centre for Mass Gatherings Medicine, Gulf Co-operation Council states, UK universities, and public health institutions globally.


Functional Role of Mitochondrial DNA in Cancer Progression.
Mitochondrial DNA (mtDNA) has been identified as a significant genetic biomarker in disease, cancer and evolution. Mitochondria function as modulators for regulating cellular metabolism. In the clinic, mtDNA variations (mutations/single nucleotide polymorphisms) and dysregulation of mitochondria-encoded genes are associated with survival outcomes among cancer patients. On the other hand, nuclear-encoded genes have been found to regulate mitochondria-encoded gene expression, in turn regulating mitochondrial homeostasis. These observations suggest that the crosstalk between the nuclear genome and mitochondrial genome is important for cellular function. Therefore, this review summarizes the significant mechanisms and functional roles of mtDNA variations (DNA level) and mtDNA-encoded genes (RNA and protein levels) in cancers and discusses new mechanisms of crosstalk between mtDNA and the nuclear genome.


Vibration perception thresholds in workers with long term exposure to lead.
To evaluate the impact of long term occupational exposure to lead on function of the peripheral nervous system as reflected by vibration perception threshold (VPT), measured with a portable vibrameter. 217 Workers in a lead battery factory were required to have an annual blood lead measurement during each of the 5 years preceding this study. All were invited to take the VPT test. A total of 206 workers were studied. The associations were analysed between VPTs and current blood lead concentration, mean concentration of blood lead over the past 5 years, maximum blood lead concentration during the past 5 years, index of cumulative blood lead (ICL), time weighted index of cumulative blood lead (TWICL), and percentage of lifespan spent at work in the plant, as well as the other potential confounders. Ordinary multiple regressions, generalised additive models, and hockey stick regression analyses were used to explore the potential existence of a threshold effect of blood lead variables on VPT. VPT at a frequency of 220 Hz ranged from 6 to 100 (10(-2) g, or 0.098 m/s(2)) with a mean (SD) of 19.8 (14.2) for the feet and from 4 to 43 with a mean (SD) of 10.2 (6.1) for the hands. The five variables of exposure to lead were all significantly correlated with VPT of the feet but not the hands. In multiple linear regression analyses, the mean of the blood lead concentrations and the TWICL were significantly associated with VPT of the feet. The relation between VPT of the feet and mean blood lead was shown to be a J shaped curve with a generalised additive model and local smoothing technique. In the hockey stick regression, evidence was found of a threshold effect at a mean blood lead concentration of 31 microgram/dl. Above this threshold it was estimated that each increase of 1 microgram/dl mean blood lead over 5 years would increase VPT of the feet by 0.29 (10(-2) g) or 0.028 m/s(2) (at a frequency of 220 Hz) with other potential confounders held constant. This study suggests that measurement of vibration sensory threshold is a relatively effective tool for detecting lead neuropathy in field studies, and that lead might cause sensory neuropathy with an effect threshold corresponding to a 5 year mean blood lead concentration of 31 microgram/dl.


Modulation of long-range neural synchrony reflects temporal limitations of visual attention in humans.
Because of attentional limitations, the human visual system can process for awareness and response only a fraction of the input received. Lesion and functional imaging studies have identified frontal, temporal, and parietal areas as playing a major role in the attentional control of visual processing, but very little is known about how these areas interact to form a dynamic attentional network. We hypothesized that the network communicates by means of neural phase synchronization, and we used magnetoencephalography to study transient long-range interarea phase coupling in a well studied attentionally taxing dual-target task (attentional blink). Our results reveal that communication within the fronto-parieto-temporal attentional network proceeds via transient long-range phase synchronization in the beta band. Changes in synchronization reflect changes in the attentional demands of the task and are directly related to behavioral performance. Thus, we show how attentional limitations arise from the way in which the subsystems of the attentional network interact.


[Possible commonality of origin of the RNA polymerase genes of plus-RNA-containing viruses of bacteria, plants and animals].
The data given testify that picornavirus RNA-dependent RNA-polymerase, RNA-polymerase encoded by the genome of MS2 phage and the certain polypeptides involved in the replication of RNA genomes of alphaviruses, tobamoviruses and tricornaviruses include the homologous stretches of the amino acids. The common sequences are located in the COOH-terminal regions of the viral proteins. These sequences have been found to be conserved also in RNA-replicase MS2 phage. The similarity of the primary structure between the RNA-polymerase phages and proteins of eucaryotic plus-RNA-containing viruses testifies in favour of the hypothesis on possible ancestral relationship of virus RNA-polymerases genes. These data point out that it is possible to localize an indispensable functional domain conserved upon evolutionary divergence of an ancestral RNA-polymerase gene. Such conservative region is recently found in the composition of RNA-dependent DNA-polymerases animals and plants virus. An attention is drawn to the region of protein similarity between conservative domains of viral RNA-dependent DNA-polymerases and RNA-polymerases.


Substrate-based inhibitors of the (S)-adenosyl-L-methionine:delta24(25)- to delta24(28)-sterol methyl transferase from Saccharomyces cerevisiae.
A series of 31 side-chain-modified analogs of cholesterol, zymosterol, lanosterol, and cycloartenol and the steroidal alkaloids solasodine and solanidine were studied as inhibitors of (S)-adenosyl-L-methionine:delta24(25)-sterol methyl transferase (SMT) enzyme activity from Saccharomyces cerevisiae. Two classes of sterol methylation inhibitors were tested: substrate analogs, including mechanism-based inhibitors, and transition state analogs. Several novel sterol methylation inhibitors that contained an aza, aziridine, or ammonium group in the sterol side chain were prepared and tested for the first time. The degree and kinetic pattern of methylation inhibition were found to be influenced by the position and nature of the variant functional group introduced into the side chain. The most potent inhibitors of SMT enzyme activity were transition state analog inhibitors (Ki values of 5 to 10 nM) that mimicked the structure and conformation of the natural substrate presumed to form in the ternary complex generated in the transition state. Steroidal alkaloids were potent competitive inhibitors with Ki values ranging from 2 to 30 microM, which is about the Kmapp of zymosterol, ca. 27 microM. An isosteric analog of the natural substrate, zymosterol, in which the 26/27-gem-dimethyl groups were joined to form a cyclopropylidene function is shown to be a potent irreversible mechanism-based inactivator of SMT enzyme activity that exhibits competitive-type inhibition, Ki 48 microM with a K(inact) of 1.52 min(-1). Mechanistic implications of these results provide new insights into the topology of the ternary complex involving sterol-AdoMet-enzyme.


Retinoic acid-induced stimulation of sodium iodide symporter expression and cytotoxicity of radioiodine in prostate cancer cells.
We reported recently the induction of androgen-dependent iodide uptake activity in the human prostatic adenocarcinoma cell line LNCaP using a prostate-specific antigen (PSA) promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. In the current study, we examined the regulation of PSA promoter-directed NIS expression and therapeutic effectiveness of (131)I in LNCaP cells by all-trans-retinoic acid (atRA). For this purpose, NIS mRNA and protein expression levels in the NIS-transfected LNCaP cell line NP-1 were examined by Northern and Western blot analysis following incubation with atRA (10 (-9) to 10(-6) M) in the presence of 10(-9) M mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of (131)I was examined by in vitro clonogenic assay. Following incubation with atRA, NIS mRNA levels in NP-1 cells were stimulated 3-fold in a concentration-dependent manner, whereas NIS protein levels increased 2.3-fold and iodide accumulation was stimulated 1.45-fold. This stimulatory effect of atRA, which has been shown to be retinoic acid receptor mediated, was completely blocked by the pure androgen receptor antagonist casodex (10(-6) M), indicating that it is androgen receptor dependent. The selective killing effect of (131)I in NP-1 cells was 50% in NP-1 cells incubated with 10(-9) M mib. This was increased to 90% in NP-1 cells treated with atRA (10(-7) M) plus 10(-9) M mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of (131)I in prostate cancer cells stably expressing NIS under the control of the PSA promoter. Therefore atRA may be used to enhance the therapeutic response to radioiodine in prostate cancer cells following PSA promoter-directed NIS gene delivery.


Child Abuse as an Example of Coexistence of Emotional and Physical Trauma Among Children: An Academic Overview With Altmetric Perspective.
Child abuse combines emotional, physical, sexual, and neglect aspects of violence, thus diversifying the trauma for a child. Publications about child abuse had been discussed in academia for long years and evaluated by bibliometric analysis, frequently. This study aims to evaluate the most discussed/disseminated scientific publications about child abuse in electronic media such as social media accounts, blogs, podcasts, and media news sites using a new analysis method called altmetric analysis. The data were obtained from the Altmetric Explorer database using the phrase "child abuse," in 2021. After being ranked by altmetric attention score (AAS), descriptive statistics for all publications as well as detailed analyses for the first-100 publications were performed. Variables evaluated were AAS, dimensions-badge value, distribution of web sources, demographic/geographic-breakdown type distributions, main subject categories, and mesh terms. Kruskal Wallis test was used for AAS and dimensions-badge value comparisons while Spearman correlations and regression analysis were also performed. Analyses were performed by SPSS 23.0 (IBM SPSS, Inc., Chicago, IL, USA) and p<0.05 was considered statistically significant. Publications about child abuse were shared extensively on social media, mostly on Twitter. In terms of the main subject, sexual abuse was the trending topic, followed by physical abuse and maltreatment. Psychology, studies in human society, health sciences, and law/legal issues were the four main science categories about the subject. The United States was the major disseminator of publications while Child Abuse and Neglect was the most productive journal. There was a weak but significant (p<0.05) positive correlation between AAS and dimensions-badge values. Child abuse is a multidimensional subject in social media. As the number of publications increases, the possibility of articles to be shared on different social media platforms also increases. The majority of the top-100 publications are the ones emphasizing the importance of child abuse in terms of the prevalence, individual/social burden, and negative consequences.


Explicitly sexing health security: analysing the downstream effects of Panama's sex-segregated COVID-19 disease control policy.
In response to COVID-19, Panama implemented a sex-segregated lockdown policy whereby women were allowed to access essential services on Monday, Wednesday and Friday and men on Tuesday, Thursday and Saturday. The logic was to reduce disease transmission by controlling population circulation at any one time. We sought to understand the impact of this policy approach on Panamanian society. To do so, we undertook key informant interviews with representatives from groups of society that have been significantly affected by this policy across Panamanian society. Framework analysis was undertaken on interview transcripts to identify key trends, which were latterly triangulated with academic, media and grey literature. Firstly, we engage with intersectional analyses to show that those most affected were marginalised groups including trans population, disabled groups, indigenous groups and migrants who faced discrimination as a consequence of this policy. Secondly, we highlight practical tensions that individuals faced relating to access to resources (financial, health-related and beyond), and third we interrogate the methods used to enforce this policy, and the role of the police and exemption passes. We conclude that this policy was regressive in that it affected those most vulnerable in Panamanian society, entrenching existing inequalities. Before implementing sex-segregated policies in future health crises, governments must seek advice of gender and equality advisors and ensure impact assessments are undertaken to understand the burden such policies may pose across society.


The development of a helpline for chronic obstructive pulmonary disease (COPD).
The goal of the helpline is to assist individuals with chronic obstructive pulmonary disease (COPD) better manage their disease through improved understanding of COPD, its symptoms and treatment. The purpose of this project was to develop and validate a protocol for a COPD helpline. Ten key informants with expertise in helpline development or COPD were interviewed. Fifty individuals with COPD participated in content validation of the protocol. An initial protocol for the helpline aimed to provide: (1) information and education regarding COPD and its management via the telephone and with written materials; (2) guidance regarding course of management; (3) resource links to other support services and programs locally, provincially, and/or nationally; and (4) caring support and reassurance to those with COPD and their families. The majority of the calls from individuals with COPD sought medical information (74%) and required 36.6 +/- 14.5 min (range: 15-85) to complete. Many different topics were discussed, with medication and exercise being the most common. The availability of the call center was identified as one means of replacing information sought from other health care providers, mainly physicians and pulmonary rehabilitation staff. A protocol of a helpline for COPD has been developed based on the literature, theoretical knowledge, and input from key informants and individuals with COPD.


Identifying the ichthyoplankton of a coral reef using DNA barcodes.
Marine fishes exhibit spectacular phenotypic changes during their ontogeny, and the identification of their early stages is challenging due to the paucity of diagnostic morphological characters at the species level. Meanwhile, the importance of early life stages in dispersal and connectivity has recently experienced an increasing interest in conservation programmes for coral reef fishes. This study aims at assessing the effectiveness of DNA barcoding for the automated identification of coral reef fish larvae through large-scale ecosystemic sampling. Fish larvae were mainly collected using bongo nets and light traps around Moorea between September 2008 and August 2010 in 10 sites distributed in open waters. Fish larvae ranged from 2 to 100 mm of total length, with the most abundant individuals being <5 mm. Among the 505 individuals DNA barcoded, 373 larvae (i.e. 75%) were identified to the species level. A total of 106 species were detected, among which 11 corresponded to pelagic and bathypelagic species, while 95 corresponded to species observed at the adult stage on neighbouring reefs. This study highlights the benefits and pitfalls of using standardized molecular systems for species identification and illustrates the new possibilities enabled by DNA barcoding for future work on coral reef fish larval ecology.


Striatal dopamine release in a schizophrenia mouse model measured by electrochemical amperometry in vivo.
Schizophrenia is a severely devastating mental disorder, the pathological process of which is proposed to be associated with the dysfunction of dopaminergic transmission. Our previous results have demonstrated slower kinetics of transmitter release (glutamate release in hippocampus and norepinephrine release in adrenal slice) in a schizophrenia model, dysbindin null-sandy mice. However, whether dopaminergic transmission in the nigrostriatal pathway contributes to the pathology of dysbindin-/- mice remains unknown. Here, we have provided a step-by-step protocol to be applied in the in vivo amperometric recording of dopamine (DA) release from the mouse striatum evoked by an action potential (AP) pattern. With this protocol, AP pattern-dependent DA release was recorded from dysbindin-/- mice striatum in vivo. On combining amperometric recording in slices and electrophysiology, we found that in dysbindin-/- mice, (1) presynaptically, AP-pattern dependent dopamine overflow and uptake were intact in vivo; (2) the recycling of the dopamine vesicle pool remained unchanged. (3) Postsynaptically, the excitability of medium spiny neuron (MSN) was also normal, as revealed by patch-clamp recordings in striatal slices. Taken together, in contrast to reduced norepinephrine release in adrenal chromaffin cells, the dopaminergic transmission remains unchanged in the nigrostriatal pathway in dysbindin-/- mice, providing a new insight into the functions of the schizophrenia susceptibility gene dysbindin.


The BDNF Val66Met polymorphism is associated with the functional connectivity dynamics of pain modulatory systems in primary dysmenorrhea.
Primary dysmenorrhea (PDM), menstrual pain without an organic cause, is a prevailing problem in women of reproductive age. We previously reported alterations of structure and functional connectivity (FC) in the periaqueductal gray (PAG) of PDM subjects. Given that the brain derived neurotrophic factor (BDNF) acts as a pain modulator within the PAG and the BDNF Val66Met polymorphism contributes towards susceptibility to PDM, the present study of imaging genetics set out to investigate the influence of, firstly, the BDNF Val66Met single nucleotide polymorphism and, secondly, the genotype-pain interplays on the descending pain modulatory systems in the context of PAG-seeded FC patterning. Fifty-six subjects with PDM and 60 controls participated in the current study of resting-state functional magnetic resonance imaging (fMRI) during the menstruation and peri-ovulatory phases; in parallel, blood samples were taken for genotyping. Our findings indicate that the BDNF Val66Met polymorphism is associated with the diverse functional expressions of the descending pain modulatory systems. Furthermore, PAG FC patterns in pain-free controls are altered in women with PDM in a genotype-specific manner. Such resilient brain dynamics may underpin the individual differences and shed light on the vulnerability for chronic pain disorders of PDM subjects.


Infection of human enterocyte-like cells with rotavirus enhances invasiveness of Yersinia enterocolitica and Y. pseudotuberculosis.
Mixed infection with rotavirus and either Yersinia enterocolitica or Y. pseudotuberculosis was analysed in Caco-2 cells, an enterocyte-like cell line highly susceptible to these pathogens. Results showed an increase of bacterial adhesion and internalisation in rotavirus-infected cells. Increased internalisation was also seen with Escherichia coli strain HB101 (pRI203), harbouring the inv gene from Y. pseudotuberculosis, which is involved in the invasion process of host cells. In contrast, the superinfection with bacteria of Caco-2 cells pre-infected with rotavirus resulted in decreased viral antigen synthesis. Transmission electron microscopy confirmed the dual infection of enterocytes. These data suggest that rotavirus infection enhances the early interaction between host cell surfaces and enteroinvasive Yersinia spp.


Direct observation of coordinated assembly of individual native centromeric nucleosomes.
Eukaryotic chromosome segregation requires the kinetochore, a megadalton-sized machine that forms on specialized centromeric chromatin containing CENP-A, a histone H3 variant. CENP-A deposition requires a chaperone protein HJURP that targets it to the centromere, but it has remained unclear whether HJURP has additional functions beyond CENP-A targeting and why high AT DNA content, which disfavors nucleosome assembly, is widely conserved at centromeres. To overcome the difficulties of studying nucleosome formation in vivo, we developed a microscopy assay that enables direct observation of de novo centromeric nucleosome recruitment and maintenance with single molecule resolution. Using this assay, we discover that CENP-A can arrive at centromeres without its dedicated centromere-specific chaperone HJURP, but stable incorporation depends on HJURP and additional DNA-binding proteins of the inner kinetochore. We also show that homopolymer AT runs in the yeast centromeres are essential for efficient CENP-A deposition. Together, our findings reveal requirements for stable nucleosome formation and provide a foundation for further studies of the assembly and dynamics of native kinetochore complexes.


Induction of the sexual stage of Pestalotiopsis microspora, a taxol-producing fungus.
Pestalotiopsis microspora, isolate NE-32, is an endophyte of the Himalayan yew (Taxus wallichiana) that produces taxol, an important chemotherapeutic drug used in the treatment of breast and ovarian cancers. Conditions were determined to induce the perfect stage (teleomorph) of this organism in the laboratory as a critical first step to study inheritance of taxol biosynthetic genes. The perfect stage of Pestalotiopsis microspora NE-32 forms in a period of 3-6 weeks on water agarose with dried yew needles at 16-20 degrees C with 12 h of light per day. Morphological analysis of the teleomorph and sequencing of the 18S rDNA indicates that Pestalosphaeria hansenii is the perfect stage of Pestalotiopsis microspora. Only certain plants (e.g. yews, some pines, pecan, oat and some barley cultivars) allow the production of perithecia. Exhaustive methylene chloride extraction of yew (Taxus cuspidata) needles removes their capacity to induce production of perithecia. The methylene chloride extract is able to induce formation of perithecia by strain NE-32 in a bioassay system utilizing the sterilized sheaths of the Cholla cactus (Opuntia bigelovii) spine, indicating that a chemical compound(s) in yew stimulates the formation of the perfect stage. This hydrophobic plant compound(s) has been designated the perithecial-stimulating factor (PSF). The data suggest that plant products may play a role in regulating the biology of endophytic microbes.


Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes.
The ATP-sensitive potassium (KATP) channel couples membrane excitability to cellular metabolism and is a critical mediator in the process of glucose-stimulated insulin secretion. Increasing numbers of KATP channel polymorphisms are being described and linked to altered insulin secretion indicating that genes encoding this ion channel could be susceptibility markers for type-2 diabetes. Genetic variation of KATP channels may result in altered beta-cell electrical activity, glucose homeostasis, and increased susceptibility to type-2 diabetes. Of particular interest is the Kir6.2 E23K polymorphism, which is linked to increased susceptibility to type-2 diabetes in Caucasian populations and may also be associated with weight gain and obesity, both of which are major diabetes risk factors. This association highlights the potential contribution of both genetic and environmental factors to the development and progression of type-2 diabetes. In addition, the common occurrence of the E23K polymorphism in Caucasian populations may have conferred an evolutionary advantage to our ancestors. This review will summarize the current status of the association of KATP channel polymorphisms with type-2 diabetes, focusing on the possible mechanisms by which these polymorphisms alter glucose homeostasis and offering insights into possible evolutionary pressures that may have contributed to the high prevalence of KATP channel polymorphisms in the Caucasian population.


Thyroid hormone action: a binding contract.
Thyroid hormones are critical for differentiation, growth, and metabolism. A new study investigating the biological role of the TH receptor TR-beta has demonstrated that DNA binding is critical for most of its functions, but also suggests that novel mechanisms independent of DNA binding may contribute to regulation of auditory function by TR-beta.


Effects of cordycepin on HepG2 and EA.hy926 cells: Potential antiproliferative, antimetastatic and anti-angiogenic effects on hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a hypervascular tumor and accumulating evidence suggests that angiogenesis plays an important role in HCC development. Cordycepin, also known as 3'-deoxyadenosine, is a derivative of adenosine, and numerous cellular enzymes cannot differentiate the two. The aim of the present study was to determine whether cordycepin regulates proliferation, migration and angiogenesis in a human umbilical vein endothelial cell line (EA.hy926) and in a hepatocellular carcinoma cell line (HepG2). MTT was used to assess cell proliferation. Apoptosis was analyzed by flow cytometry (propidium iodide staining). Transwell and wound healing assays were used to analyze the migration and invasion of HepG2 and EA.hy926 cells. Angiogenesis in EA.hy926 cells was assessed using a tube formation assay. Cordycepin strongly suppressed HepG2 and EA.hy926 cell proliferation in a dose- and time-dependent manner. Cordycepin induced EA.hy926 cell apoptosis in a dose-dependent manner (2,000 μg/ml: 50.20±1.55% vs. 0 μg/ml: 2.62±0.19%; P<0.01). Cordycepin inhibited EA.hy926 cell migration (percentage of wound healing area, 2,000 μg/ml: 3.45±0.29% vs. 0 μg/ml: 85.48±0.84%; P<0.05), as well as tube formation (total length of tubular structure, 1,000 μg/ml: 107±39 μm vs. 0 μg/ml: 936±56 μm; P<0.05). Cordycepin also efficiently inhibited HepG2 cell invasion and migration. High-performance liquid chromatography analysis of the cytosol from EA.hy926 cells showed that cordycepin was stable for 3 h. In conclusion, cordycepin not only inhibited human HepG2 cell proliferation and invasion, but also induced apoptosis and inhibited migration and angiogenesis in vascular endothelial cells, suggesting that cordycepin may be used as a novel anti-angiogenic therapy in HCC.


Roles for pituitary adenylate cyclase-activating peptide (PACAP) expression and signaling in the bed nucleus of the stria terminalis (BNST) in mediating the behavioral consequences of chronic stress.
Anxiety disorders are frequently long-lasting and debilitating for more than 40 million American adults. Although stressor exposure plays an important role in the etiology of some anxiety disorders, the mechanisms by which exposure to stressful stimuli alters central circuits that mediate anxiety-like emotional behavior are still unknown. Substantial evidence has implicated regions of the central extended amygdala, including the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala as critical structures mediating fear- and anxiety-like behavior in both humans and animals. These areas organize coordinated fear- and anxiety-like behavioral responses as well as peripheral stress responding to threats via direct and indirect projections to the paraventricular nucleus of the hypothalamus and brainstem regions (Walker et al. Eur J Pharmacol 463:199-216, 2003, Prog Neuropsychopharmacol Biol Psychiatry 33(8):1291-1308, 2009; Ulrich-Lai and Herman Nat Rev Neurosci 10:397-409, 2009). In particular, the BNST has been argued to mediate these central and peripheral responses when the perceived threat is of long duration (Waddell et al. Behav Neurosci 120:324-336, 2006) and/or when the anxiety-like response is sustained (Walker and Davis Brain Struct Funct 213:29-42, 2008); hence, the BNST may mediate pathological anxiety-like states that result from exposure to chronic stress. Indeed, chronic stress paradigms result in enhanced BNST neuroplasticity that has been associated with pathological anxiety-like states (Vyas et al. Brain Res 965:290-294, 2003; Pego et al. Eur J Neurosci 27:1503-1516, 2008). Here we review evidence that suggests that pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing hormone (CRH) work together to modulate BNST function and increase anxiety-like behavior. Moreover, we have shown that BNST PACAP as well as its cognate PAC1 receptor is substantially upregulated following chronic stress, particularly in the BNST oval nucleus where PACAP-containing neurons closely interact with CRH-containing neurons (Kozicz et al. Brain Res 767:109-119, 1997; Hammack et al. Psychoneuroendocrinology 34:833-843, 2009). We describe how interactions between PACAP and CRH in the BNST may mediate stress-associated behaviors, including anorexia and anxiety-like behavior. These studies have the potential to define specific mechanisms underlying anxiety disorders, and may provide important therapeutic strategies for stress and anxiety management.


[Ultrastructure of the cells of the neural crest].
Ultrastructure of the neural crest cells (NCC) has been studied in 9-day-old white rat embryos. Mechanisms, determining the amount of the NCC that get out of the neuroepithelium of the nervous tube have been discussed. By means of ruthenium red components of the extracellular matrix are demonstrated in the area where the NCC get out and in the ventromedial pathway of migration. Certain peculiarities of ruthenium red fixation by the cells are presented.


Antibacterial copper-nickel bilayers and multilayer coatings by pulsed laser deposition on titanium.
Biofouling, especially microfouling, is a major concern with the use of titanium (Ti) in the marine environment as a condenser material in cooling water systems. Earlier, copper-nickel (Cu/Ni) alloys were extensively used in marine environments due to their high corrosion and biofouling resistance. However, the choice of condenser material for the new fast breeder reactor in Kalpakkam is Ti to avoid steam side corrosion problems, which may pose a threat to steam generator parts having sodium as the secondary coolant. This study evaluates the surface modification of Ti using nano films of copper (Cu) and nickel (Ni) to utilize the antibacterial property of copper ions in reducing microfouling. The surface modification of Ti was carried out by the deposition of a Cu/Ni bilayer and (Cu/Ni)(10) multilayer films using a pulsed laser deposition technique. Various surface characterization studies revealed that the deposited Cu/Ni films were thin and nanocrystalline in nature. The antibacterial properties were evaluated using total viable count and epifluorescence microscopic techniques. The results showed an apparent decrease in bacterial attachment on multilayered and bilayered Cu/Ni thin films on Ti surfaces. Comparative studies between the two types of films showed a bigger reduction in numbers of microorganisms on the multilayers.


[Heterogeneity of the population of pseudotuberculosis microbe cultures].
Use of the method of oblique illumination of the colonies permitted to detect four variants of pseudotuberculosis microbe differing by the character of fluorescence, and also by virulence, toxicity and immunogenicity. Strains isolated from sick persons, carriers and rodents were characterized by polychromatic character of fluorescence of the colonies, whereas strains isolated from the external environment were monochromatic. Since colonies with a different fluorescence had different biological properties it can be supposed that the properties of each strain as a whole were determined by its quantitative and qualitative composition as of a heterogeneous population.


Retinoblastoma: care and support of the pediatric patient and family.
This paper presents the holistic approach to the care of the pediatric patient with strabismus. It discusses preoperative management, contemporary surgical procedures including postoperative suture adjustments, complications and the care and management of the patient and family on the pediatric unit. It reviews discharge instructions including pain management, postoperative safety and the follow-up appointment with the surgeon. Methods of determining the level of knowledge of the child's primary caregiver are also a major focus.


Antibody response to human immunodeficiency virus after primary infection.
The antibody response to human immunodeficiency virus (HIV) after primary infection was monitored in eight homosexual men with the acute mononucleosis-like illness associated with seroconversion. Multiple sera from each subject, taken at frequent intervals after onset of acute illness, were tested for antibody to HIV by IgM and IgG immunofluorescent assays (IFAs), four commercial enzyme-linked immunosorbent assays (ELISAs), and Western immunoblot (WB). Antibody to HIV was detected first by IgM IFA (mean +/- SD, 5 +/- 3 days), followed by IgG IFA (11 +/- 3 days); the IgM antibody titer peaked at 24 +/- 17 days and disappeared by 81 +/- 27 days, whereas the IgG antibody titer peaked at 133 +/- 63 days and has not disappeared in any subject. Antibody to HIV was first detected by ELISA from 31 +/- 14 to 58 +/- 32 days, depending on the assay kit used. Antibody to p24 and gp41 was first detected by WB at 24 +/- 10 days, followed by antibody to p55 (40 +/- 20 days), p68 (57 +/- 19 days), and p34 (71 +/- 22 days).


Acceptability of Mobile Health Interventions to Increase Diabetic Risk Factor Awareness Among the Commuter Population in Johannesburg: Descriptive Cross-Sectional Study.
Developing countries are experiencing a shift from infectious diseases such as HIV and tuberculosis to noncommunicable diseases (NCDs) such as diabetes. Diabetes accounts for more disability-adjusted life years than any other NCD in South Africa, and research has identified a number of preventable risk factors; however, there is not enough evidence from lower resource settings as to how best to disseminate this information to the population. Today, 90% of the world's population lives in mobile phone coverage areas, and this provides a unique opportunity to reach large populations with health information. This study aimed to investigate how potential mobile health (mHealth) platforms should be paired with diabetes risk factor education so that at-risk communities are empowered with information to prevent and manage diabetes. A Likert-style survey was distributed to commuters in the City of Johannesburg in July 2018 that explored participants' background characteristics as well as their knowledge and awareness surrounding diabetic risk factors (such as exercise, smoking, and hypertension) and their comfort level with various information delivery methods (such as WhatsApp, short message service, and email). The grouped variables from diabetic risk factors and information delivery methods were described with mean Likert scores and then investigated for relationships with Spearman Rho correlation coefficients. Background characteristics revealed that the self-reported prevalence of diabetes was twice as high in this studied commuter population than the national average. WhatsApp was the most favorable mHealth information delivery method and had a moderate correlation coefficient with diet and nutrition (0.338; P<.001) as well as a weaker correlation with physical activity (0.243; P<.001). Although not as robust as the WhatsApp correlations, each of the other information delivery methods also showed weaker, yet statistically significant, relationships with one or more of the risk factors. The elevated self-reported diabetes prevalence reinforces the need for diabetes risk factor education in the studied commuter population of Johannesburg. The most feasible mHealth intervention for diabetic risk factor education should focus on WhatsApp messaging while also offering content across other mHealth and traditional platforms to remove barriers to access and enhance the user experience. The content should emphasize diet and nutrition as well as physical activity while also incorporating information on secondary risk factors.


Blood Pressure Variability in Fabry Disease Patients.
Fabry disease is a rare metabolic, multisystemic, and X-linked lysosomal storage disorder. The involvement of the autonomic nervous system is well defined; however, data on the variability of the blood pressure (BP) and heart rate in Fabry disease are largely missing. In this study, we aimed to examine the circadian variations of BP and heart rate variability in Fabry disease patients. We recruited 31 consecutive adult (age >18 years) Fabry disease patients (16 males and 15 females) who were regularly followed up in our outpatient clinic between July 2019 and March 2020. We performed ambulatory blood pressure monitoring and echocardiography in all patients. We used standard deviation (SD), coefficient of variation (CV), and average real variability as the measures of variability. We constructed 2 control groups for propensity score matching using age, sex, and eGFR parameters in the first group and adding antihypertensive drug use to the above parameters in the second group. All BP measurements were significantly lower in the FD group compared to that of the control groups, except the nighttime systolic BP. Regarding nondipping and reverse dipping statuses, FD patients and controls were similar. We found that none of the BP variability measures were higher in FD patients. Regarding heart rate variability data, both the nighttime SD and CV were significantly lower in FD patients compared to those of the controls. A decrease in heart rate variability, rather than an increase in BP variability, might be an early marker of autonomic involvement in FD.


Designing a compact high performance brain PET scanner-simulation study.
The desire to understand normal and disordered human brain function of upright, moving persons in natural environments motivates the development of the ambulatory micro-dose brain PET imager (AMPET). An ideal system would be light weight but with high sensitivity and spatial resolution, although these requirements are often in conflict with each other. One potential approach to meet the design goals is a compact brain-only imaging device with a head-sized aperture. However, a compact geometry increases parallax error in peripheral lines of response, which increases bias and variance in region of interest (ROI) quantification. Therefore, we performed simulation studies to search for the optimal system configuration and to evaluate the potential improvement in quantification performance over existing scanners. We used the Cramér-Rao variance bound to compare the performance for ROI quantification using different scanner geometries. The results show that while a smaller ring diameter can increase photon detection sensitivity and hence reduce the variance at the center of the field of view, it can also result in higher variance in peripheral regions when the length of detector crystal is 15 mm or more. This variance can be substantially reduced by adding depth-of-interaction (DOI) measurement capability to the detector modules. Our simulation study also shows that the relative performance depends on the size of the ROI, and a large ROI favors a compact geometry even without DOI information. Based on these results, we propose a compact 'helmet' design using detectors with DOI capability. Monte Carlo simulations show the helmet design can achieve four-fold higher sensitivity and resolve smaller features than existing cylindrical brain PET scanners. The simulations also suggest that improving TOF timing resolution from 400 ps to 200 ps also results in noticeable improvement in image quality, indicating better timing resolution is desirable for brain imaging.


Epigallocatechin-3-Gallate Promotes the in vitro Maturation and Embryo Development Following IVF of Porcine Oocytes.
Epigallocatechin-3-gallate (EGCG) is a major ingredient of catechin polyphenols and exerts protective effects because of its strong antioxidant properties. As far as we know, there is still a lack of systematic research on the effects of EGCG on the in vitro maturation (IVM) and in vitro fertilization (IVF) of porcine oocytes. The present study aimed to determine the effects of EGCG on the IVM and IVF of porcine oocytes. Porcine oocytes were treated with different concentrations of EGCG (5, 10 and 20 µM), and the cumulus cell expansion, oocyte maturation rate, reactive oxygen species (ROS), glutathione (GSH) and malondialdehyde (MDA) levels, total antioxidant capacity were determined. The mRNA expression levels of oxidative stress- and apoptosis-associated genes were determined by quantitative real-time PCR. The cleavage rate and blastocyst rate of oocytes after 10 μM EGCG treatment during IVM and IVF were also evaluated. EGCG at 5, 10 and 20 μM significantly promoted cumulus cell expansion, and EGCG at 10 μM increased the oocyte maturation rate. EGCG (10 μM) treatment reduced the ROS and MDA levels, while increased the antioxidant capacity and GSH concentrations in the mature oocytes. The qRT-PCR results showed that EGCG treatment up-regulated the mRNA expression of catalase, glutathione peroxidase and superoxide dismutase in the mature oocytes. In addition, EGCG treatment also decreased the mRNA expression levels of Bax and caspase-3 and increased the Bcl-2 mRNA expression level in the mature oocytes. In addition, the cleavage rate and blastocyst rate of oocytes treated with 10 μM EGCG during IVM and IVF were significantly higher than those of the control group. Our results suggest that EGCG promotes the in vitro maturation and embryo development following IVF of porcine oocytes. The protective effects of EGCG on the oocytes may be associated with its antioxidant and anti-apoptosis properties.


Effects of remifentanil anesthesia on cardiac electrophysiologic properties in children undergoing catheter ablation of supraventricular tachycardia.
Remifentanil is commonly used during anesthesia in pediatric electrophysiologic studies (EPS). The purpose of this study is to determine the effects of remifentanil on the cardiac electrophysiologic properties of children undergoing ablation of supraventricular tachycardia (SVT). A prospective study was performed in patients undergoing EPS before ablation of SVT. Each patient received two different anesthetic protocols: protocol 1 = propofol (200 mcg/kg/min) and protocol 2 = propofol (120 mcg/kg/min) plus remifentanil (0.3 mcg/kg/min). EPS data were measured during the steady state of each protocol. Paired Student t test was performed for analysis of continuous data. All p values <0.05 were considered statistically significant. Fifteen patients were enrolled between April 2005 and January 2006. The mean age was 13.3 ± 2.9 years (range 6.7 to 17.7). Seven patients had atrioventricular (AV) nodal re-entry tachycardia; 5 patients had Wolff-Parkinson-White syndrome; 2 patients had a concealed accessory pathway; and 1 patient was not inducible. Of the 14 patients who underwent ablation, 13 (93%) achieved successful. The baseline sinus cycle length extended from 884 ± 141 ms during protocol 1 to 980 ± 165 ms during protocol 2 (p = 0.01), and the Wenckebach cycle length lengthened from 377 ± 96 ms to 406 ± 109 ms (p = 0.01). No other variables measured (atrial-His (AH) and His-ventricular (HV) interval, atrioventricular node (AVN), and atrial, ventricular, and accessory pathway effective refractory periods) changed significantly between the two different protocols. In pediatric patients undergoing EPS before ablation of SVT, remifentanil appears to slow both sinus and AV nodal function. These effects should be taken into consideration when performing EPS.


Growth arrest DNA damage gene expression in naevi.
Thirty-one naevus cell naevi, 30 dysplastic naevi and 12 fibromatous naevi were stained for the presence of p53 and Growth Arrest DNA Damage genes. All naevus cell naevi and fibromatous naevi were highly positive for GADD genes and negative for p53. Dysplastic naevi had significantly lower GADD34 and GADD153 expression as well as higher p53 expression in relation to the other naevi groups. The absence or decrease of GADD genes expression in naevus may indicate a potential malignant transformation.


Dependence of endoplasmic reticulum-associated degradation on the peptide binding domain and concentration of BiP.
ER-associated degradation (ERAD) removes defective and mis-folded proteins from the eukaryotic secretory pathway, but mutations in the ER lumenal Hsp70, BiP/Kar2p, compromise ERAD efficiency in yeast. Because attenuation of ERAD activates the UPR, we screened for kar2 mutants in which the unfolded protein response (UPR) was induced in order to better define how BiP facilitates ERAD. Among the kar2 mutants isolated we identified the ERAD-specific kar2-1 allele (Brodsky et al. J. Biol. Chem. 274, 3453-3460). The kar2-1 mutation resides in the peptide-binding domain of BiP and decreases BiP's affinity for a peptide substrate. Peptide-stimulated ATPase activity was also reduced, suggesting that the interdomain coupling in Kar2-1p is partially compromised. In contrast, Hsp40 cochaperone-activation of Kar2-1p's ATPase activity was unaffected. Consistent with UPR induction in kar2-1 yeast, an ERAD substrate aggregated in microsomes prepared from this strain but not from wild-type yeast. Overexpression of wild-type BiP increased substrate solubility in microsomes obtained from the mutant, but the ERAD defect was exacerbated, suggesting that simply retaining ERAD substrates in a soluble, retro-translocation-competent conformation is insufficient to support polypeptide transit to the cytoplasm.


Effect of Propolis on Neurological Recovery After Experimental Spinal Cord Injury.
To examine the effect of propolis on the healing process in terms of both electrophysiological and ultrastructural parameters in a rat model of experimental spinal cord injury. Thirty rats were divided into control, spinal cord trauma, and treated trauma groups with 10 rats per group. The rats were sacrificed after 10 days. Before sacrifice, all rats were neurologically assessed by electrophysiological monitoring, and immediately after sacrifice, the spinal cord was examined ultrastructurally by transmission electron microscopy (TEM). According to the electrophysiological examination, the treatment group was statistically significantly different from the trauma group. However, no statistically significant difference was found between the control and treatment groups. In terms of the TEM examination, the treatment group was significantly different from the trauma group. In this study, propolis was administered just before the induction of trauma, and the findings suggest that the use of propolis has a positive effect on the healing process. This implies that in order to prevent postoperative deficits, this treatment may be preferably applied before spinal cord surgery for trauma.


Ethnicity, ethics, and the deaf-world.
This article is concerned with ethical aspects of the relations between language minorities using signed languages (called the Deaf-World) and the larger societies that engulf them. The article aims to show that such minorities have the properties of ethnic groups, and that an unsuitable construction of the Deaf-World as a disability group has led to programs of the majority that discourage Deaf children from acquiring the language and culture of the Deaf-World and that aim to reduce the number of Deaf births-programs that are unethical from an ethnic group perspective. Four reasons not to construe the Deaf-World as a disability group are advanced: Deaf people themselves do not believe they have a disability; the disability construction brings with it needless medical and surgical risks for the Deaf child; it also endangers the future of the Deaf-World; finally, the disability construction brings bad solutions to real problems because it is predicated on a misunderstanding.


Downregulation of LncRNA-MEG3 promotes HTR8/SVneo cells apoptosis and attenuates its migration by repressing Notch1 signal in preeclampsia.
A successful pregnancy crucially depends on well-regulated extravillous trophoblast migration and invasion. Maternally expressed gene 3 (MEG3) is a long noncoding RNA that plays an important role in regulating trophoblast cells cell function. As previously reported, the expression of MEG3 was reduced in preeclampsia, and downregulation of MEG3 could suppress trophoblast cells migration and promote its apoptosis. However, the downstream regulatory mechanism of MEG3 remains unknown. As reported, MEG3 could inhibit cell proliferation in endometrial carcinoma by regulating Notch signaling. Our previous studies have demonstrated that Notch1 is downregulated in preeclampsia and that inhibiting the expression of Notch1 could promote trophoblast cell apoptosis. Therefore, this study was designed to investigate the role of MEG3 and its the relationship with Notch1 in trophoblasts. In this study, the mRNA expression levels of both MEG3 and Notch1 were decreased in preeclampsia placenta (n = 15) compared to the normal samples (n = 15). Exogenous upregulation and downregulation of MEG3 in HTR8/SVneo cells were performed to investigate the role of MEG3 in cell biological behavior and its effects on Notch1 expression. The results showed that MEG3 enhancement promoted trophoblast cell migration and invasion and inhibited cell apoptosis. Downregulation of MEG3 elicited the opposite results. Associated factors, such as matrix metalloproteinases 2 (MMP2), BAX, and Bcl-2, were examined at the mRNA and protein levels. Our study demonstrated that MEG3 could regulate Notch1 expression to modulate trophoblast cell migration, invasion, and apoptosis, which may represent the molecular mechanism of poor placentation during preeclampsia.


Role of excretion in manganese homeostasis and neurotoxicity: a historical perspective.
The essential metal manganese (Mn) induces incurable neurotoxicity at elevated levels that manifests as parkinsonism in adults and fine motor and executive function deficits in children. Studies on Mn neurotoxicity have largely focused on the role and mechanisms of disease induced by elevated Mn exposure from occupational or environmental sources. In contrast, the critical role of excretion in regulating Mn homeostasis and neurotoxicity has received less attention although 1) studies on Mn excretion date back to the 1920s; 2) elegant radiotracer Mn excretion assays in the 1940s to 1960s established the routes of Mn excretion; and 3) studies on patients with liver cirrhosis in the 1990s to 2000s identified an association between decreased Mn excretion and the risk of developing Mn-induced parkinsonism in the absence of elevated Mn exposure. Notably, the last few years have seen renewed interest in Mn excretion largely driven by the discovery that hereditary Mn neurotoxicity due to mutations in SLC30A10 or SLC39A14 is caused, at least in part, by deficits in Mn excretion. Quite remarkably, some of the recent results on SLC30A10 and SLC39A14 provide explanations for observations made ∼40-50 years ago. The goal of the current review is to integrate the historic studies on Mn excretion with more contemporary recent work and provide a comprehensive state-of-the-art overview of Mn excretion and its role in regulating Mn homeostasis and neurotoxicity. A related goal is to discuss the significance of some of the foundational studies on Mn excretion so that these highly consequential earlier studies remain influential in the field.


Seizure control after stimulation of the vagus nerve: clinical outcome measures.
Currently, decreases in seizure frequency are the accepted efficacy outcome measure of therapeutic interventions in the management of patients with epilepsy. In a longitudinal randomized controlled trial of 10 subjects with intractable complex partial seizures who received left vagal nerve stimulation (VNS) to control seizures, it was found that the total number of consecutive seizure-free days is a significant efficacy outcome measure. Unlike measures in which percentage decreases in seizure frequency are calculated, measures of consecutive seizure days indicate improvement in the amount of time for which patients may function at a higher level in activities of daily living. Fourteen day blocks of consecutive seizure-free days and 14 day blocks of consecutive days in which subjects had seizures were tabulated. A Pearson correlation coefficient showed that prior to VNS subjects had few, if any, seizure free blocks of time and after VNS they had more blocks of time seizure free r = -1.00 and r = -0.99. The blocks of seizure-free days increased tenfold (mean 0.85 to mean 8.00) from 1991-1995 while mean seizure frequency in those blocks in which subjects had seizures only decreased from (mean 20.14 to mean 17.59) for the same time period. Correlations between total number of seizures after 24 months of VNS and after 50 months of VNS were r = 0.85 showing a consistency in the effect of VNS. Monitoring the number of consecutive seizure-free days is a significant clinical outcome measure of VNS.


Dispersion analysis of perpendicular modes in anisotropic crystals and layers.
Until today dispersion analysis could not be successfully applied to evaluate oscillator parameters of modes that have their transition moments perpendicular to the surface of an anisotropic crystal or a layered medium. The main reason for this failure is that while such modes generate maxima in the external reflection spectra, which are obtained with polarized light parallel to the plane of incidence under nonzero angles of incidence, the positions of these maxima do not allow us to unambiguously trace back the oscillator positions. In contrast, total internal reflection of parallel polarized light generates minima at spectral positions close to the oscillator frequency. Starting from this observation, we found that a combined evaluation of external and total internal reflection spectra by dispersion analysis allows us to gain the oscillator parameters of perpendicular modes unambiguously.


Binding of hnRNP H and U2AF65 to respective G-codes and a poly-uridine tract collaborate in the N50-5'ss selection of the REST N exon in H69 cells.
The splicing of the N exon in the pre-mRNA coding for the RE1-silencing transcription factor (REST) results in a truncated protein that modifies the expression pattern of some of its target genes. A weak 3'ss, three alternative 5'ss (N4-, N50-, and N62-5'ss) and a variety of putative target sites for splicing regulatory proteins are found around the N exon; two GGGG codes (G2-G3) and a poly-Uridine tract (N-PU) are found in front of the N50-5'ss. In this work we analyzed some of the regulatory factors and elements involved in the preferred selection of the N50-5'ss (N50 activation) in the small cell lung cancer cell line H69. Wild type and mutant N exon/β-globin minigenes recapitulated N50 exon splicing in H69 cells, and showed that the N-PU and the G2-G3 elements are required for N50 exon splicing. Biochemical and knockdown experiments identified these elements as U2AF65 and hnRNP H targets, respectively, and that they are also required for N50 exon activation. Compared to normal MRC5 cells, and in keeping with N50 exon activation, U2AF65, hnRNP H and other splicing factors were highly expressed in H69 cells. CLIP experiments revealed that hnRNP H RNA-binding occurs first and is a prerequisite for U2AF65 RNA binding, and EMSA and CLIP experiments suggest that U2AF65-RNA recognition displaces hnRNP H and helps to recruit other splicing factors (at least U1 70K) to the N50-5'ss. Our results evidenced novel hnRNP H and U2AF65 functions: respectively, U2AF65-recruiting to a 5'ss in humans and the hnRNP H-displacing function from two juxtaposed GGGG codes.


Critical effects of intense sun exposure on the expression of epiluminescence microscopy features of acquired melanocytic nevi.
Current knowledge of the histologic counterparts of epiluminescence microscopy (ELM) features in pigmented skin lesions is limited. As a particular aspect of this problem, the transient effects of intense sun exposure on the morphological characteristics of melanocytic nevi may influence the expression of ELM features as well as the demonstration of stable and consistent histologic correlates. Forty melanocytic nevi from 11 subjects living in Northern Italy were examined by digital ELM before and after 5 to 13 days of sun exposure at latitudes of 5 degrees north to 3 degrees south. A number of multifaceted changes were observed. In particular, 3 lesions showed the expression of some structures compatible with radial streaming, pseudopods, and gray-blue areas. These features are considered to have often severe histologic correlates. In a third image, obtained 5 to 6 weeks later, they showed partial or total regression. Another case showed a massive regression of the pigment network as a result of a progressive inflammatory reaction with marked asymmetry in the distribution of pigmentation. Digital ELM has the potential to detect subtle changes in the structure of nevi after intense sun exposure. The transient observation of certain ELM features often associated with severe histologic substrates casts doubts on the ability of ELM to characterize sun-exposed nevi by a single examination.


A negative effector of blue light-induced and gravitropic bending in Arabidopsis.
Although sessile, plants are able to grow toward or away from an environmental stimulus. Important examples are stem or leaf orientation of higher plants in response to the direction of the incident light. The responsible photoreceptors belong to the phototropin photoreceptor family. Although the mode of phototropin action is quite well understood, much less is known of how the light signal is transformed into a bending response. Several lines of evidence indicate that a lateral auxin gradient is responsible for asymmetric cell elongation along the light gradient within the stem. However, some of the molecular key players leading to this asymmetric auxin distribution are, as yet, unidentified. Previously, it was shown that phototropin gets autophosphorylated upon illumination and binds to a scaffold protein termed NPH3 (for nonphototropic hypocotyl 3). Using a yeast three-hybrid approach with phototropin and NPH3 as a bait complex, we isolated a protein, termed EHB1 (for enhanced bending 1), with a so far unknown function, which binds to this binary complex. This novel interacting factor negatively affects hypocotyl bending under blue light conditions in Arabidopsis (Arabidopsis thaliana) and thus seems to be an important component regulating phototropism. Interestingly, it could be shown that the gravitropic response was also affected. Thus, it cannot be ruled out that this protein might also have a more general role in auxin-mediated bending toward an environmental stimulus.


Differentiation of a teratocarcinoma line: preferential development of cholinergic neurons.
A line of embryonal carcinoma cells, PCC7-S, established in vitro from a spontaneous testicular teratocarcinoma, has been studied. Upon removing the cells from a low density monolayer culture system and permitting the cells to form aggregates in suspension, we observed a change of several physical and biochemical parameters: (a) reduction in average cell volume, (b) blockage and accumulation of cells in G1, (c) rise in secreted protease activity, (d) rise in acetylcholinesterase and choline acetyltransferase activities, and (e) disappearance of embryonic antigen F9. Although PCC7 aggregates did not undergo substantial morphological changes while suspended, when aggregates 4 or more days old were allowed to attach to plastic tissue culture dishes, substantial neurite outgrowth occurred over the next 1-3 d. This process was markedly enhanced by the addition to the growth medium of carboxymethylcellulose and inhibitors of DNA synthesis. Transmission electron microscopy disclosed a neurite ultrastructure consistent with that of neuronal processes. A veratridine-stimulated, tetrodotoxin-blocked sodium influx of 100 nmol/min per mg protein was also observed in these differentiated surface cultures. This cell line is discussed in terms of its utility for the study of early events leading to a commitment to cellular differentiation, as well as for the investigation of terminal differentiation to cholinergic neurons.


Extracellular Matrix Production by Mesenchymal Stromal Cells in Hydrogels Facilitates Cell Spreading and Is Inhibited by FGF-2.
In native tissues, the interaction between cells and the surrounding extracellular matrix (ECM) is reciprocal, as cells not only receive signals from the ECM but also actively remodel it through secretion of cell-derived ECM. However, very little is known about the reciprocal interaction between cells and their secreted ECM within synthetic biomaterials that mimic the ECM for use in engineering of tissues for regenerative medicine or as tissue models. Here, poly(ethylene glycol) (PEG) hydrogels with fully defined biomaterial properties are used to investigate the emerging role of cell-derived ECM on culture outcomes. It is shown that human mesenchymal stromal cells (MSCs) secrete ECM proteins into the pericellular space early after encapsulation and that, even in the absence of material-presented cell adhesion motifs, cell-derived fibronectin enables cell spreading. Then, it is investigated how different culture conditions influence MSC ECM expression in hydrogels. Most strikingly, it is found by RNA sequencing that the fibroblast growth factor 2 (FGF-2) changes ECM gene expression and, in particular, decreases the expression of structural ECM components including fibrillar collagens. In summary, this work shows that cell-derived ECM is a guiding cue in 3D hydrogels and that FGF-2 is a potentially important ECM regulator within bioengineered cell and tissue systems.


Screening of alginate lyase-excreting microorganisms from the surface of brown algae.
Alginate lyase is a biocatalyst that degrades alginate to produce oligosaccharides, which have many bioactive functions and could be used as renewable biofuels. Here we report a simple and sensitive plate assay for screening alginate lyase-excreting microorganisms from brown algae. Brown algae Laminaria japonica, Sargassum horneri and Sargassum siliquatrum were cultured in sterile water. Bacteria growing on the surface of seaweeds were identified and their capacity of excreting alginate lyase was analyzed. A total of 196 strains were recovered from the three different algae samples and 12 different bacterial strains were identified capable of excreting alginate lyases. Sequence analysis of the 16S rRNA gene revealed that these alginate lyase-excreting strains belong to eight genera: Paenibacillus (4/12), Bacillus (2/12), Leclercia (1/12), Isoptericola (1/12), Planomicrobium (1/12), Pseudomonas (1/12), Lysinibacillus (1/12) and Sphingomonas (1/12). Further analysis showed that the LJ-3 strain (Bacillus halosaccharovorans) had the highest enzyme activity. To our best knowledge, this is the first report regarding alginate lyase-excreting strains in Paenibacillus, Planomicrobium and Leclercia. We believe that our method used in this study is relatively easy and reliable for large-scale screening of alginate lyase-excreting microorganisms.


COVID-19's impact on worker stress in human service organizations: The mediating role of inclusion.
Human service organizations faced extraordinary challenges due to COVID-19. Despite the increasing interest and research in this new scenario, there has been limited discussion about the impact of COVID-19 on workers, the challenges they faced, and the resulting stress. This study aimed to analyze the impact of COVID-19 on work-related stress and the mediating role of inclusion among workers in human service organizations in Chile during the pandemic. The research design was quantitative and involved a sample of 173 workers from civil society organizations who were contacted during the pandemic. The study confirmed that individuals most affected by the pandemic experienced higher levels of work-related stress, and that inclusion played a negative mediating role in this relationship. This article highlights the importance of relationships, decision-making processes, and access to information in reducing stress in post-COVID scenarios for organizations that traditionally handle crises.


Alarm pheromone processing in the ant brain: an evolutionary perspective.
Social insects exhibit sophisticated communication by means of pheromones, one example of which is the use of alarm pheromones to alert nestmates for colony defense. We review recent advances in the understanding of the processing of alarm pheromone information in the ant brain. We found that information about formic acid and n-undecane, alarm pheromone components, is processed in a set of specific glomeruli in the antennal lobe of the ant Camponotus obscuripes. Alarm pheromone information is then transmitted, via projection neurons (PNs), to the lateral horn and the calyces of the mushroom body of the protocerebrum. In the lateral horn, we found a specific area where terminal boutons of alarm pheromone-sensitive PNs are more densely distributed than in the rest of the lateral horn. Some neurons in the protocerebrum responded specifically to formic acid or n-undecane and they may participate in the control of behavioral responses to each pheromone component. Other neurons, especially those originating from the mushroom body lobe, responded also to non-pheromonal odors and may play roles in integration of pheromonal and non-pheromonal signals. We found that a class of neurons receive inputs in the lateral horn and the mushroom body lobe and terminate in a variety of premotor areas. These neurons may participate in the control of aggressive behavior, which is sensitized by alarm pheromones and is triggered by non-pheromonal sensory stimuli associated with a potential enemy. We propose that the alarm pheromone processing system has evolved by differentiation of a part of general odor processing system.


Immune mechanisms in atherosclerosis and potential for an atherosclerosis vaccine.
A large body of evidence implicates the immune system in the pathogenesis and modulation of atherosclerosis. Dendritic cells and lymphocytes are among the many components of the immune system that are involved in modulating atherogenesis. This review focuses on the current knowledge of the complex role of the dendritic cells and lymphocytes in atherogenesis and the potential for immune-modulation therapies for atherosclerosis.


Experimental folate deficiency in human subjects: what is the influence of vitamin C status on time taken to develop megaloblastic anaemia?
In 1962 Victor Herbert developed megaloblastic anaemia four months after commencing a severely folate-deficient diet whereas, in his self-experiment 50 years later, this author took 19 months to fully deplete his liver folate store. This author proposed that his own larger initial liver folate store, due to his vegetarian diet and consumption of fortified foods, was the cause of the time difference. This author now proposes that Herbert was also likely to have been deficient in vitamin C, thus shortening the time taken to develop folate deficiency. Several human experiments have confirmed the role of vitamin C in protecting reduced forms of folate from oxidation. Although there has historically been no consensus on the required intake of vitamin C, and official recommendations set a level below that required to ensure plasma saturation, recent research supports an intake that would ensure saturation. There have been no longitudinal experiments on human subjects since the introduction of voluntary or mandatory folic acid fortification of food, and the few published models differ significantly in their estimates of human liver folate storage capacity. Because of the importance of folate in one-carbon metabolism, the potential influence of vitamin C intake on the time taken to deplete the liver folate store should be experimentally investigated.


Determinants of woody encroachment and cover in African savannas.
Savanna ecosystems are an integral part of the African landscape and sustain the livelihoods of millions of people. Woody encroachment in savannas is a widespread phenomenon but its causes are widely debated. We review the extensive literature on woody encroachment to help improve understanding of the possible causes and to highlight where and how future scientific efforts to fully understand these causes should be focused. Rainfall is the most important determinant of maximum woody cover across Africa, but fire and herbivory interact to reduce woody cover below the maximum at many locations. We postulate that woody encroachment is most likely driven by CO2 enrichment and propose a two-system conceptual framework, whereby mechanisms of woody encroachment differ depending on whether the savanna is a wet or dry system. In dry savannas, the increased water-use efficiency in plants relaxes precipitation-driven constraints and increases woody growth. In wet savannas, the increase of carbon allocation to tree roots results in faster recovery rates after disturbance and a greater likelihood of reaching sexual maturity. Our proposed framework can be tested using a mixture of experimental and earth observational techniques. At a local level, changes in precipitation, burning regimes or herbivory could be driving woody encroachment, but are unlikely to be the explanation of this continent-wide phenomenon.


Change in hepatitis C virus genotype in injecting drug users.
Six major genotypes of the hepatitis C virus (HCV) have been described; it is assumed to be uncommon for genotypes to change in chronically infected individuals. Venous blood samples obtained from Vietnamese-Australian injecting drug users who participated in successive studies conducted in Melbourne, Australia, were genotyped using the Bayer line probe assay and genotype confirmed by sequencing whenever possible. Three changes of HCV genotype were observed, and one infection in an individual not exposed previously. The rate of change of genotype was 3 in 11.4 person-years (py), or 26.4 per 100 py (95% CI: 8.5, 81.6). Traditionally-calculated HCV incidence was 1 in 4.3 py, or 23.3 per 100 py (95% CI: 3.3, 165.1). These data imply that HCV genotype change in injecting drug users occurs at least as frequently as infections in naive individuals, and that traditionally-calculated HCV incidence rates represent a minority of actual HCV transmission among practicing injecting drug users.


Evolution of accelerometer methods for physical activity research.
The technology and application of current accelerometer-based devices in physical activity (PA) research allow the capture and storage or transmission of large volumes of raw acceleration signal data. These rich data not only provide opportunities to improve PA characterisation, but also bring logistical and analytic challenges. We discuss how researchers and developers from multiple disciplines are responding to the analytic challenges and how advances in data storage, transmission and big data computing will minimise logistical challenges. These new approaches also bring the need for several paradigm shifts for PA researchers, including a shift from count-based approaches and regression calibrations for PA energy expenditure (PAEE) estimation to activity characterisation and EE estimation based on features extracted from raw acceleration signals. Furthermore, a collaborative approach towards analytic methods is proposed to facilitate PA research, which requires a shift away from multiple independent calibration studies. Finally, we make the case for a distinction between PA represented by accelerometer-based devices and PA assessed by self-report.


Enterovirus pathogenesis requires the host methyltransferase SETD3.
Enteroviruses (EVs) comprise a large genus of positive-sense, single-stranded RNA viruses whose members cause a number of important and widespread human diseases, including poliomyelitis, myocarditis, acute flaccid myelitis and the common cold. How EVs co-opt cellular functions to promote replication and spread is incompletely understood. Here, using genome-scale CRISPR screens, we identify the actin histidine methyltransferase SET domain containing 3 (SETD3) as critically important for viral infection by a broad panel of EVs, including rhinoviruses and non-polio EVs increasingly linked to severe neurological disease such as acute flaccid myelitis (EV-D68) and viral encephalitis (EV-A71). We show that cytosolic SETD3, independent of its methylation activity, is required for the RNA replication step in the viral life cycle. Using quantitative affinity purification-mass spectrometry, we show that SETD3 specifically interacts with the viral 2A protease of multiple enteroviral species, and we map the residues in 2A that mediate this interaction. 2A mutants that retain protease activity but are unable to interact with SETD3 are severely compromised in RNA replication. These data suggest a role of the viral 2A protein in RNA replication beyond facilitating proteolytic cleavage. Finally, we show that SETD3 is essential for in vivo replication and pathogenesis in multiple mouse models for EV infection, including CV-A10, EV-A71 and EV-D68. Our results reveal a crucial role of a host protein in viral pathogenesis, and suggest targeting SETD3 as a potential mechanism for controlling viral infections.


Classical nucleation theory of homogeneous freezing of water: thermodynamic and kinetic parameters.
The probability of homogeneous ice nucleation under a set of ambient conditions can be described by nucleation rates using the theoretical framework of Classical Nucleation Theory (CNT). This framework consists of kinetic and thermodynamic parameters, of which three are not well-defined (namely the interfacial tension between ice and water, the activation energy and the prefactor), so that any CNT-based parameterization of homogeneous ice formation is less well-constrained than desired for modeling applications. Different approaches to estimate the thermodynamic and kinetic parameters of CNT are reviewed in this paper and the sensitivity of the calculated nucleation rate to the choice of parameters is investigated. We show that nucleation rates are very sensitive to this choice. The sensitivity is governed by one parameter - the interfacial tension between ice and water, which determines the energetic barrier of the nucleation process. The calculated nucleation rate can differ by more than 25 orders of magnitude depending on the choice of parameterization for this parameter. The second most important parameter is the activation energy of the nucleation process. It can lead to a variation of 16 orders of magnitude. By estimating the nucleation rate from a collection of droplet freezing experiments from the literature, the dependence of these two parameters on temperature is narrowed down. It can be seen that the temperature behavior of these two parameters assumed in the literature does not match with the predicted nucleation rates from the fit in most cases. Moreover a comparison of all possible combinations of theoretical parameterizations of the dominant two free parameters shows that one combination fits the fitted nucleation rates best, which is a description of the interfacial tension coming from a molecular model [Reinhardt and Doye, J. Chem. Phys., 2013, 139, 096102] in combination with the activation energy derived from self-diffusion measurements [Zobrist et al., J. Phys. Chem. C, 2007, 111, 2149]. However, some fundamental understanding of the processes is still missing. Further research in future might help to tackle this problem. The most important questions, which need to be answered to constrain CNT, are raised in this study.


Metabolic syndrome: soybean foods and serum lipids.
Metabolic syndrome is a cluster of coronary heart disease (CHD) risk factors of which central obesity, insulin resistance, increased triglycerides/decreased HDL cholesterol, and hypertension are major cardiovascular risk factors. The educational objectives of this review are to describe hypocholesteromic effects from soybean foods. Early Italian observations indicated that isolated soy protein lowered total cholesterol, especially the LDL component, in humans with elevated serum lipids. Whole soybeans, with their major phytoestrogen inflavones (genistein, daidzein, and glycetin) intact, are known to decrease both total and LDL cholesterol. Major early reviews, meta-analyses, and clinical trials in hyperlipidemic humans indicate a predictable range of decreases in serum lipids: total cholesterol (10-19%), LDL cholesterol (14-20%), and triglycerides (8-14%). Recent, large, randomized trials in postmenopausal women indicated that a soy protein component induces significant increases in HDL cholesterol. Therapy for metabolic syndrome must first be patient education, especially for predominant U.S. minority groups (Afro-, Latino-, and Native Americans). The four major preventive health educational facts necessary to reduce CHD/metabolic syndrome must now recognize that whole soybeans are abundant sources of: 1) vegetable protein, 2) high soluble fiber content, 3) virtual absence of saturated fat, though high in polyunsaturated fats, and 4) major phytoestrogens.


Immune response to Yersinia outer proteins and other Yersinia pestis antigens after experimental plague infection in mice.
There is limited information concerning the nature and extent of the immune response to the virulence determinants of Yersinia pestis during the course of plague infection. In this study, we evaluated the humoral immune response of mice that survived lethal Y. pestis aerosol challenge after antibiotic treatment. Such a model may replicate the clinical situation in humans and indicate which virulence determinants are expressed in vivo. Immunoglobulin G enzyme-linked immunosorbent assay and immunoblotting were performed by using purified, recombinant antigens including F1, V antigen, YpkA, YopH, YopM, YopB, YopD, YopN, YopE, YopK, plasminogen activator protease (Pla), and pH 6 antigen as well as purified lipopolysaccharide. The major antigens recognized by murine convalescent sera were F1, V antigen, YopH, YopM, YopD, and Pla. Early treatment with antibiotics tended to reduce the immune response and differences between antibiotic treatment regimens were noted. These results may indicate that only some virulence factors are expressed and/or immunogenic during infection. This information may prove useful for selecting potential vaccine candidates and for developing improved serologic diagnostic assays.


DRIFTS studies on the photosensitized transformation of gallic acid by iron(III) chloride as a model for HULIS in atmospheric aerosols.
Little is known about the interfacial photochemistry of transition metal cations and chromophores relevant to atmospheric aerosols. We report herein water uptake and in situ surface-sensitive spectroscopic studies on the photosensitized transformation of solid gallic acid (GA), externally mixed with FeCl(3) as a photosensitizer, under dry and humid conditions of <1% and 30% relative humidity (RH), respectively. GA is a hydrolysis product of tannic acid, a model macromolecule for humic-like substances (HULIS) in aerosols and aged polyaromatic hydrocarbons (PAH). Water uptake on GA and GA/FeCl(3) mixture films was quantified using a quartz crystal microbalance (QCM) as a function of %RH (<1-60%). Results indicate continuous multilayer formation of adsorbed water with no phase transitions, with a monolayer of adsorbed water forming around 30 and 12%RH, respectively. Photochemical studies were conducted using diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). Spectra were collected as a function of irradiation time (4 h), mass fraction of FeCl(3) (0.5-3%) using irradiance of simulated solar light equivalent to 120 Wm(-2) at 555 nm. Difference absorbance spectra show changes to GA functional groups suggesting the formation of organochlorine compounds in the condensed phase with their signature v(C=C) at 1601 cm(-1), and release of CO(2). Potential halogenation pathways of GA in the presence of Fe(3+) are discussed based on well-known aqueous phase chemistry. These pathways along with our results also suggest the release of volatile organochlorine compounds and Cl(2) gas. Apparent first order rate constants, k(s), of the photosensitized reactions were derived from kinetic curves of the most intense positive and negative spectral features at 1601 and 1381 cm(-1), respectively. Values of k(s) at 120 Wm(-2) are found to be higher than those reported from UV photo-Fenton reactions of GA in bulk aqueous phases containing H(2)O(2), Fe(2+) or Fe(3+). The implication of our studies on the aging of multicomponent aerosols containing organic matter, transition metals and halide ions due to heterogeneous photochemistry is discussed.


[Persisting and late onset psychotic disorder due to consumption of ecstasy (MDMA)].
Let us present a case of recurrent paranoid psychotic episodes in a patient with a history of abuse of <<ecstasy>> (MDMA: 3, 4-methylenedioxymethamphetamine), that persisted after a long withdrawal time, that, in our opinion, after an exhaustive differential diagnosis, may be attributed to that consumption. The carachteristics of this case are formally and naturally equivalent to those referred to in other papers about paranoid psychosis after abuse of MDMA, in which the sudden appearance, and the symptomatolgy of an intense feeling of threat and physical violence outstands, accompanied by abnormal corporal perceptions. In the case hereby presented, the withdrawal time is longer than that described in other publications. Even though in some authors' opinion this should be considered as comorbility or dual diagnosis, in our opinion enough facts exist suggesting that this is not a case of functional mental disorder but an organic disorder secondary to the neurotoxic effect of MDMA.


Cardiac computed tomography, changing the way we look at the heart.
Cardiac computed tomography angiography (CCTA) produces excellent anatomic information of the coronary arteries and other cardiac structures. A high negative predictive value (99%) for the exclusion of coronary lesions establishes CCTA as a highly effective noninvasive alternative to invasive coronary angiography. It is, however, less accurate for determining degrees of lesion severity, and intermediate grade lesions require either physiologic stress testing or invasive coronary angiography. CCTA allows visualization of the vessel wall so plaque can be classified as soft, calcified, or mixed on the basis of Hounsfield units. Precise quantification of the plaque burden is readily performed with coronary artery calcium scoring (CACS). This measurement of plaque burden is one of the most predictive of future cardiac events and mortality available. CCTA also serves as an excellent tool prior to surgical and percutaneous cardiac procedures. CT scanning continues to evolve as an imaging modality for all stages of the treatment of cardiac disease: CACS for risk assessment for asymptomatic patients, CCTA to evaluate patients with symptoms, and cardiac CT to plan cardiac procedures.


Quality of life in older patients with systolic and diastolic heart failure.
To get insight into the quality of life of a clinical practice sample of patients with heart failure that are admitted to the hospital. Secondly to determine differences between patients with systolic and diastolic dysfunction and finally to describe factors relating to quality of life. Three dimensions of quality of life (functional capabilities, symptoms and psychosocial adjustment to illness) were assessed during interviews of 186 patients with chronic heart failure. In addition, data on demographic, clinical and self-care characteristics were collected and patients completed a 6-min walk. On average patients walked 172 m in 6 min and reported functioning in daily life at a mean level of 4.5 MET. Patients experienced four different symptoms of heart failure. Most of them described dyspnea, fatigue, sleep disturbance and ankle oedema. Problems with psychosocial adaptation occurred mostly in social and vocational domains. Overall well-being of patients was rated as 6.4 on a 10-point scale. In regard to quality of life, the only differences between patients with systolic and diastolic heart failure was the occurrence of ankle oedema and health-care orientation. The variance in components of quality of life were partly explained by demographics and clinical characteristics. All three dimensions of quality of life were related to ability for self-care. Patients with heart failure seen in clinical practice are often not comparable to patients described in major clinical trials or patients that are admitted for transplant evaluation. Their functional capabilities are more compromised, but they may have fewer problems with psychosocial adjustment. Patients with normal systolic dysfunction also report a low quality of life. It could be important to enhance self-care abilities of patients to improve psychosocial adaptation to illness.


Lipopolysaccharide core defects in Salmonella typhimurium mutants which are resistant to Felix O phage but retain smooth character.
FOR mutants of Salmonella typhimurium are resistant to Felix O phage, whose receptor includes the N-acetylglucosamine branch of the lipopolysaccharide (LPS) core, but smooth in cultural properties, antigenic character and phage sensitivity pattern (MacPhee et al., 1975). The rfa(FOR) genes determining the FOR character of nine mutants were transduced into a smooth cysE pyrE recipient: the nine FOR transductants (and a tenth FOR mutant) were then made rfb (i.e. unable to make O chains) by transduction or Hfr crosses. The rfb FOR strains were sensitive to FO phage but nearly all of them showed a somewhat reduced efficiency of plating and diminished rate of adsorption of the phage. This observation and the Ra (complete core) serological activity of their LPS (tested by haemagglutination inhibition) indicate the presence of some, but less than the normal number of, completed core chains in FOR rfb LPS. On the basis of the sensitivities of the FOR transductants and their rfb derivatives to various 'rough-specific' phages, their increased sensitivities to some antibiotics and to deoxycholate and the serological activity of the rfb FOR LPS in various incomplete core systems, the mutants were divided into three groups: (i) five mutants with probable defects in previously undetected rfa gene(s) concerned with formation of both the galactose I and the galactose II units of the LPS core; (ii) two mutants with defects inferred to affect the structure of the inner part of the core and also interfere with addition of the N-acetylglucosamine branch; (iii) three mutants in which no type of incomplete core could be detected, probably affected in formation of the inner part of the core chain. The mutation of one mutant of the last class, unlike those of the other nine mutants tested, lay outside the cysE-pyrE segment, in the 90 to 116 min region of the linkage map.


Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.
Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939. Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1-23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2-18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7-9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1-11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87-1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group. Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. F Hoffmann-La Roche.