Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures.
Structured RNA regulatory motifs exist from the prebiotic stages of the RNA world to the more complex eukaryotic systems. In cases where a functional RNA structure is within the coding sequence a selective pressure drives a parallel co-evolution of the RNA structure and the encoded peptide domain. The p53-MDM2 axis, describing the interactions between the p53 tumor suppressor and the MDM2 E3 ubiquitin ligase, serves as particularly useful model revealing how secondary RNA structures have co-evolved along with corresponding interacting protein motifs, thus having an impact on protein - RNA and protein - protein interactions; and how such structures developed signal-dependent regulation in mammalian systems. The p53(BOX-I) RNA sequence binds the C-terminus of MDM2 and controls p53 synthesis while the encoded peptide domain binds MDM2 and controls p53 degradation. The BOX-I peptide domain is also located within p53 transcription activation domain. The folding of the p53 mRNA structure has evolved from temperature-regulated in pre-vertebrates to an ATM kinase signal-dependent pathway in mammalian cells. The protein - protein interaction evolved in vertebrates and became regulated by the same signaling pathway. At the same time the protein - RNA and protein - protein interactions evolved, the p53 trans-activation domain progressed to become integrated into a range of cellular pathways. We discuss how a single synonymous mutation in the BOX-1, the p53(L22 L), observed in a chronic lymphocyte leukaemia patient, prevents the activation of p53 following DNA damage. The concepts analysed and discussed in this review may serve as a conceptual mechanistic paradigm of the co-evolution and function of molecules having roles in cellular regulation, or the aetiology of genetic diseases and how synonymous mutations can affect the encoded protein.


Tips and tricks for the extravesical robotic-assisted laparoscopic ureteral reimplantation for pediatric vesicoureteral reflux.
Over the past few years, robotic-assisted laparoscopic ureteral reimplantation (RALUR) has gained popularity as an acceptable alternative for the traditional open approach if surgery is elected for children with vesicoureteral reflux (VUR). We present our technique including the tips and tricks for both male and female patients, including a stepwise approach for ureteral identification in female patients depending on the level of technical difficulty. Our series include 30 patients who represent a spectrum in which we presented the different tips and tricks included in this video.


The glycolytic pathway to coronary heart disease: a hypothesis.
Coronary heart disease (CHD) is pathogenetically linked to numerous metabolic disturbances. These are inextricably interrelated, constituting identifiable clusters or syndromes of cardiovascular risk. Prominent among these is the insulin resistance syndrome, whose components, including hyperuricemia, have all been linked to CHD pathogenesis. Many mechanisms have been put forward to account for the emergence of this syndrome, but none offer a satisfactory explanation for the involvement of hyperuricemia. Possible explanations relate to the observation of glycolytic disturbances in insulin-resistant and hyperuricemic states. This might be expected from the fact that uric acid production is linked to glycolysis and that glycolysis is controlled by insulin. Phosphoribosylpyrophosphate (PPRP) is an important metabolite in this respect. Its availability depends on ribose-5-phosphate (R-5-P), the production of which is governed by glycolytic flux. Diversion of glycolytic intermediates toward R-5-P, PPRP, and uric acid will follow if there is diminished activity of glyceraldehyde-3-phosphate dehydrogenase (GA3PDH), which is regulated by insulin. Serum triglyceride concentrations may also increase, as might be expected from accumulation of glycerol-3-phosphate. Thus, intrinsic defects in GA3PDH and a loss of its responsiveness to insulin, by causing accumulation of glycolytic intermediates, may explain the association between insulin resistance, hyperuricemia, and hypertriglyceridemia. This scenario raises the possibility that disturbances of a single glycolytic enzyme may be pivotal in the modulation of metabolic risk factors for CHD.


Adaptation of the BKB-SIN test for use as a pediatric aided outcome measure.
There is a need for objective pediatric hearing aid outcome measurement and thus a need for the evaluation of outcome measures. We explored a commercially available pediatric sentence-in-noise measure adapted for use as an aided outcome measure. The purposes of the current study were (1) to administer an adapted BKB-SIN (Bamford-Kowal-Bench Speech-in-Noise test) to adults and children who have normal hearing and children who use hearing aids and (2) to evaluate the utility of this adapted BKB-SIN as an aided, within-subjects outcome measure for amplification strategies. We used a mixed within and between groups design to evaluate speech recognition in noise for the three groups of participants. The children who use hearing aids were tested under the omnidirectional, directional, and digital noise reduction (DNR) conditions. Results from each group were compared to each other, and we compared results of each aided condition for the children who use hearing aids to evaluate the test utility as an aided outcome measure. The study sample consisted of 14 adults with normal hearing (aged 22-28 yr) and 15 children with normal hearing (aged 6-18 yr), recruited through word of mouth, and 14 children who use hearing aids (aged 9-16 yr) recruited from local audiology clinics. List pairs of the BKB-SIN test were presented at 50 dB HL as follows: four list pairs to each participant with normal hearing, four list pairs in the omnidirectional condition, and two list pairs in the directional and DNR conditions. Children who use hearing aids were fitted bilaterally with laboratory devices and completed the BKB-SIN test aided. Data were plotted as mean percent of key words correct at each signal-to-noise ratio (SNR). Further, we conducted an analysis of variance for group differences and within-groups for the three aided conditions. Adult participants outperformed children with normal hearing, who outperformed the children who use hearing aids. SNR-50 (signal-to-noise ratio at which listener can obtain a speech recognition score of 50% correct) scores demonstrated reliability of the adapted test implementation. The BKB-SIN test measured significant differences in performance for omnidirectional versus directional microphone conditions but not between omnidirectional and DNR conditions. We conclude that the adapted implementation of the BKB-SIN test can be administered reliably and feasibly. Further study is warranted to develop norms for the adapted implementation as well as to determine if an adapted implementation can be sensitive to age effects. Until such norms are developed, clinicians should refrain from comparing results from the adapted test to the test manual norms and should instead use the adapted implementation as a within-subject measure.


Fruit and vegetable consumption and cancer mortality in the Caerphilly Study.
We investigated whether the consumption of fruit and vegetables lowered cancer mortality in a cohort of 2112 Welsh men ages 45-69 years (The Caerphilly Study), which was followed-up for 13.8 years. At baseline (between 1979 and 1983), participants completed a 56-item food frequency questionnaire from which the consumption of fruit and vegetables was calculated. Relative risks (RR) were estimated with Cox proportional hazard analysis, with death from various types of cancer as a dependent variable, and fruit, vegetables, vitamin C, beta-carotene, dietary fiber, and potential confounders as independent variables. Mean consumption of vegetables and fruit at baseline was 118 g/day and 83 g/day, respectively. During follow-up 114 men died from cancer, including 51 men who died from respiratory tract cancer and 45 men who died from digestive tract cancer. Fruit consumption and the intake of dietary fiber were inversely related to respiratory tract cancer, but after adjustment for potential confounders including age, smoking, and social class, the association with fruit consumption became nonsignificant. Vegetable and fruit consumption was, independently from other risk factors, inversely related to mortality from cancer of the digestive tract (P for trend = 0.021), mainly due to an inverse association with fruit consumption (RR for the highest quartile versus the lowest was 0.3; 95% CI, 0.1-0.8). Vitamin C, beta-carotene, and dietary fiber were not significantly associated with cancers of the digestive tract. Vegetable and fruit consumption was also inversely related to all-cause cancer mortality, and the strongest association was observed for fruit consumption (RR in the highest versus lowest quartile was 0.5; 95% CI, 0.3-1.0). Consumption of vegetables and particularly the consumption of fruit could considerably lower the risk of dying from cancer in middle-aged men.


Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world.
Several lines of evidence suggest that patterns of genetic variability in the human angiotensinogen gene (AGT) contribute to phenotypic variability in human hypertension. The A(-6) promoter variant of AGT is associated with higher plasma angiotensinogen levels and increased risk of essential hypertension. The geographic distribution of the A(-6) variant leads to the intriguing hypothesis that the G(-6) promoter variant has been selectively advantageous outside Africa. To test these hypotheses, we investigated the roles of population history and natural selection in shaping patterns of genetic diversity in AGT, by sequencing the entire AGT gene (14400 bp) in 736 chromosomes from Africa, Asia, and Europe. We found that the A(-6) variant is present at higher frequency in African populations than in non-African populations. Neutrality tests found no evidence of a departure from selective neutrality, when whole AGT sequences were compared. However, tests restricted to sites in the vicinity of the A(-6)G polymorphism found evidence of a selective sweep. Sliding-window analyses showed that evidence of the sweep is restricted to sites in tight linkage disequilibrium (LD) with the A(-6)G polymorphism. Further, haplotypes carrying the G(-6) variant showed elevated levels of LD, suggesting that they have risen recently to high frequency. Departures from neutral expectation in some but not all regions of AGT indicate that patterns of diversity in the gene cannot be accounted for solely by population history, which would affect all regions equally. Taken together, patterns of genetic diversity in AGT suggest that natural selection has generally favored the G(-6) variant over the A(-6) variant in non-African populations. However, important localized effects may also be present.


Molecular mechanism of panaxydol on promoting axonal growth in PC12 cells.
Nerve growth factor (NGF) promotes axonal growth in PC12 cells primarily by regulating the RTK-RAS-MEK-ERK pathway. Panaxydol, a polyacetylene isolated from Panax notoginseng, can mimic the effects of NGF. Panaxydol promotes neurite outgrowth in PC12 cells, but its molecular mechanism remains unclear. Indeed, although alkynol compounds such as panaxydol can increase intracellular cyclic adenosine 3',5'-monophosphate (cAMP) levels and the ERK inhibitor U0126 inhibits alkynol-induced axonal growth, how pathways downstream of cAMP activate ERK have not been investigated. This study observed the molecular mechanism of panaxydol-, NGF- and forskolin-induced PC12 cell axon growth using specific signaling pathway inhibitors. The results demonstrated that although the RTK inhibitor SU5416 obviously inhibited the growth-promoting effect of NGF, it could not inhibit the promoting effect of panaxydol on axonal growth of PC12 cells. The adenylate cyclase inhibitor SQ22536 and cAMP-dependent protein kinase inhibitor RpcAMPS could suppress the promoting effect of forskolin and panaxydol on axonal growth. The ERK inhibitor U0126 inhibited axonal growth induced by all three factors. However, the PKA inhibitor H89 inhibited the promoting effect of forskolin on axonal growth but could not suppress the promoting effect of panaxydol. A western blot assay was used to determine the effects of stimulating factors and inhibitors on ERK phosphorylation levels. The results revealed that NGF activates the ERK pathway through tyrosine receptors to induce axonal growth of PC12 cells. In contrast, panaxydol and forskolin increased cellular cAMP levels and were inhibited by adenylyl cyclase inhibitors. The protein kinase A inhibitor H89 completely inhibited forskolin-induced axonal outgrowth and ERK phosphorylation, but could not inhibit panaxydol-induced axonal growth and ERK phosphorylation. These results indicated that panaxydol promoted axonal growth of PC12 cells through different pathways downstream of cAMP. Considering that exchange protein directly activated by cAMP 1 (Epac1) plays an important role in mediating cAMP signaling pathways, RNA interference experiments targeting the Epac1 gene were employed. The results verified that Epac1 could mediate the axonal growth signaling pathway induced by panaxydol. These findings suggest that compared with NGF and forskolin, panaxydol elicits axonal growth through the cAMP-Epac1-Rap1-MEK-ERK-CREB pathway, which is independent of PKA.


Computational prediction of RNA structural motifs involved in posttranscriptional regulatory processes.
Messenger RNA molecules are tightly regulated, mostly through interactions with proteins and other RNAs, but the mechanisms that confer the specificity of such interactions are poorly understood. It is clear, however, that this specificity is determined by both the nucleotide sequence and secondary structure of the mRNA. Here, we develop RNApromo, an efficient computational tool for identifying structural elements within mRNAs that are involved in specifying posttranscriptional regulations. By analyzing experimental data on mRNA decay rates, we identify common structural elements in fast-decaying and slow-decaying mRNAs and link them with binding preferences of several RNA binding proteins. We also predict structural elements in sets of mRNAs with common subcellular localization in mouse neurons and fly embryos. Finally, by analyzing pre-microRNA stem-loops, we identify structural differences between pre-microRNAs of animals and plants, which provide insights into the mechanism of microRNA biogenesis. Together, our results reveal unexplored layers of posttranscriptional regulations in groups of RNAs and are therefore an important step toward a better understanding of the regulatory information conveyed within RNA molecules. Our new RNA motif discovery tool is available online.


Virological failure at one year in triple-class experienced patients switching to raltegravir-based regimens is not predicted by baseline factors.
We evaluated rates and determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens from a national observational study over 48 weeks, defined by any one of the following: (1) no HIV-RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) detectable viral load after obtaining undetectable levels; and (3) leaving the study before 48 weeks. Among 101 eligible patients, 26 (25.7%; 95% CI 17.2-34.2) had virological failure. No significant differences between patients with and without virological failure were observed for gender, age, route of transmission, baseline CD4/HIV-RNA, CDC group, hepatitis B or C co-infections, resistance (based on the last genotype available), type and number of concomitant drug classes, concomitant use of darunavir, atazanavir, etravirine, enfuvirtide or maraviroc, and health-related quality-of-life measures. A high rate of treatment response was observed. The analyses did not identify any baseline factor associated with failure, including resistance status. Even if we cannot exclude the presence of pre-existing minority resistant variants not captured by genotypic tests, the lack of baseline predictors of failure suggests the need to monitor patients closely during follow up for other factors, such as potential drug interactions and reduced levels of adherence, which may favour virological failure.


[Preparation with air abrasion].
Air abrasive technology has re-emerged in dentistry. The history, characteristics and clinical application of this approach are reviewed, including advantages and limitations for the removal of enamel, dentin and decay. Air-abrasive technology may be especially suited for use in bonded restorations as well as for repair of all types of restorations. The factors affecting adequate bond strength are discussed.


Character Strengths in the Life Domains of Work, Education, Leisure, and Relationships and Their Associations With Flourishing.
A growing body of research demonstrates the relevance of character strengths for flourishing in general, but also for important outcomes across different life domains (e.g., work performance and relationship satisfaction). Studies have also shown that there are differences in the extent to which character strengths are applied, that is, perceived as relevant and shown in behavior in a given context, between work and private life, but they have not considered other life domains. This study aims to close this gap by examining the life domains of work, education, leisure, close personal relationships, and romantic relationships. The present study investigates whether (a) strengths-related behavior across different life domains explains additional variance in flourishing beyond the trait level of each respective character strength and studies (b) differences in the relevance of character strengths and strengths-related behavior across different life domains, and examines (c) their relationships with flourishing. A sample of 203 German-speaking adults (78.8% females; mean age = 29.4 years) completed self-reports assessing flourishing and character strengths. They also indicated which of the five life domains were personally relevant to them (i.e., on average 4.23 life domains) and reported the character strengths' perceived relevance and the frequency of displaying strengths-related behavior for each of these life domains separately. The results demonstrate that (a) strengths-related behavior averaged across all relevant life domains explained unique variance in flourishing above the trait-level of character strengths in some cases (e.g., creativity, kindness, and fairness), (b) different life domains were characterized by specific profiles of character strength-regarding both their relevance and strength-related behavior. Moreover, (c) character strengths and strengths-related behavior in different life domains both showed substantial correlations with flourishing. In some cases, these associations were domain-specific (e.g., displaying love of learning in the context of education was related to higher levels of flourishing). In conclusion, we suggest that examining strengths-related behavior across different life domains represents a worthwhile addition to research on character strengths.


Biomarkers of food intake and metabolite differences between plasma and red blood cell matrices; a human metabolomic profile approach.
Untargeted metabolomic analyses of plasma and red blood cells (RBCs) can provide complementary information on biomarkers of food consumption. To assess blood collection differences in biomarkers, fasting blood was drawn from 10 healthy individuals using sodium citrate and lithium heparin as anticoagulants. Plasma and RBCs were separated into aqueous and lipid fractions to be analyzed using 1D and 2D (1)H NMR spectroscopy. Fatty acids were analyzed using gas chromatography-mass spectrometry (GC-MS). Polyphenols were extracted from plasma and RBCs by micro-elution solid-phase extraction and analyzed by ultra performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). (1)H NMR demonstrated higher aqueous metabolites such as glucose in plasma compared to RBCs, while RBCs contained higher ADP-ATP, creatine and acetone than plasma. Lipoproteins and their subclasses were higher in plasma than in RBCs. Percentages of saturated fatty acids (SFA) 16 : 0, 17 : 0, 20 : 0, 24 : 0 and polyunsaturated fatty acids (PUFA) 22 : 6 n-3 (docosahexaenoic acid) and 20 : 4 n-6 (arachidonic acid) were higher in RBCs than in plasma (p < 0.05), while SFA 14 : 0, monounsaturated fatty acids (MUFA) 14 : 1 n-5, 16 : 1 n-7, 17 : 1 n-7 and 18 : 1 n-9 and PUFA 18 : 3 n-3, 18 : 2 n-6, 18 : 3 n-6 and 20 : 3 n-6 were higher in plasma than in RBCs (p < 0.05). Polyphenols differed in plasma from those of RBCs. Biomarker concentrations were lower in sodium citrate compared to lithium heparin plasma. In conclusion, metabolomic profiles generated by NMR spectroscopy, GC-MS and UPLC-MS/MS analyses of RBCs versus plasma show complementary information on several specific molecular biomarkers that could be applied in nutritional assessment.


Strategies for perceiving facial expressions in adults with autism spectrum disorder.
Rutherford and McIntosh (J Autism Dev Disord 37:187–196, 2007) demonstrated that individuals with autism spectrum disorder (ASD) are more tolerant than controls of exaggerated schematic facial expressions, suggesting that they may use an alternative strategy when processing emotional expressions. The current study was designed to test this finding using photographs of real people. In addition, two control tasks were added to eliminate alternative explanations. We replicated the findings of Rutherford and McIntosh (J Autism Dev Disord 37:187–196, 2007) and also demonstrated that adults with ASD do not show this tolerance when evaluating how realistic the expressions are. These results suggest adults with ASD employ a rule-based strategy to a greater extent than typical adults when processing facial expressions but not when processing other aspects of faces.


[Variability of cultures of Pullularia pullulans with different ploidy levels].
As the level of ploidy rises in Pullularia pullulans, this causes an increase in the frequency of spontaneous and UV-induced auxotrophic mutants as well as mutants with a modified respiration activity while the frequency of morphological mutants decreases. The latter can arise as a result of recessive and dominant mutations. A higher frequency of morphological mutants in the haploid may be result of recessive mutations. It is likely that the frequency of dominant mutations increases in cultures with a higher level of ploidy since, as the difference between the frequency of UV-induced mutants and the frequency of spontaneous morphological mutants increases.


Ex vivo penetration of low-level laser light through equine skin and flexor tendons.
OBJECTIVE To measure penetration efficiencies of low-level laser light energy through equine skin and to determine the fraction of laser energy absorbed by equine digital flexor tendons (superficial [SDFT] and deep [DDFT]). SAMPLE Samples of skin, SDFTs, and DDFTs from 1 metacarpal area of each of 19 equine cadavers. PROCEDURES A therapeutic laser with wavelength capabilities of 800 and 970 nm was used. The percentage of energy penetration for each wavelength was determined through skin before and after clipping and then shaving of hair, through shaved skin over SDFTs, and through shaved skin, SDFTs, and DDFTs (positioned in anatomically correct orientation). Influence of hair color; skin preparation, color, and thickness; and wavelength on energy penetration were assessed. RESULTS For haired skin, energy penetration was greatest for light-colored hair and least for dark-colored hair. Clipping or shaving of skin improved energy penetration. Light-colored skin allowed greatest energy penetration, followed by medium-colored skin and dark-colored skin. Greatest penetration of light-colored skin occurred with the 800-nm wavelength, whereas greatest penetration of medium- and dark-colored skin occurred with the 970-nm wavelength. As skin thickness increased, energy penetration of samples decreased. Only 1% to 20% and 0.1% to 4% of energy were absorbed by SDFTs and DDFTs, respectively, depending on skin color, skin thickness, and applied wavelength. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that most laser energy directed through equine skin was absorbed or scattered by the skin. To achieve delivery of energy doses known to positively affect cells in vitro to equine SDFTs and DDFTs, skin preparation, color, and thickness and applied wavelength must be considered.


Improving detection and genetic counseling in carriers of spinal muscular atrophy with two copies of the SMN1 gene.
Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in the survival motor neuron1 gene (SMN1). Global carrier frequency is around 1 in 50 and carrier detection is crucial to define couples at risk to have SMA offspring. Most SMA carriers have one SMN1 copy and are currently detected using quantitative methods. A few, however, have two SMN1 genes in cis (2/0 carriers), complicating carrier diagnosis in SMA. We analyzed our experience in detecting 2/0 carriers from a cohort of 1562 individuals, including SMA parents, SMA relatives, and unrelated individuals of the general population. Interestingly, in three couples who had an SMA child, both the parents had two SMN1 copies. Families of this type have not been previously reported. Our results emphasize the importance of performing a detailed carrier study in SMA parents with two SMN1 copies. Expanding the analysis to other key family members might confirm potential 2/0 carriers. Finally, when a partner of a known carrier presents two SMN1 copies, the study of both parents will provide a more accurate diagnosis, thus optimizing genetic counseling.


Dissociable role of the basolateral complex of the amygdala in the acquisition and extinction of conditioned fear following reproductive experience in female rats.
In female rats and humans, reproductive experience (i.e., pregnancy) alters the behavioral, hormonal and molecular substrates of fear extinction. Here, we assessed whether the role of a central neural substrate of fear extinction, the basolateral amygdala (BLA), also changes following reproductive experience. Nulliparous (virgin) and primiparous (one prior pregnancy) female rats received infusions of the GABAA agonist, muscimol, to temporarily inactivate the BLA prior to fear conditioning or extinction training. In follow up experiments, the BLA was also inactivated immediately after extinction training. BLA inactivation impaired the acquisition and expression of conditioned fear in both nulliparous and primiparous rats. In nulliparous rats, BLA inactivation prior to or immediately after extinction training impaired extinction retention. In contrast, in primiparous rats, BLA inactivation prior to or immediately after extinction training did not impair extinction retention, despite suppressing freezing during extinction training. These results suggest that, consistent with past findings in males, the BLA is a central component of the neural circuitry of fear acquisition and its extinction in virgin female rats. However, after pregnancy, female rats no longer depend on the BLA to extinguish fear, despite requiring the BLA to acquire conditioned fear. Given that fear extinction forms the basis of exposure therapy for anxiety disorders in humans, the present findings may have clinical implications. To improve the efficacy of exposure therapy for anxiety disorders, we may need to target different mechanisms in females dependent on their reproductive history.


A viral microRNA cluster strongly potentiates the transforming properties of a human herpesvirus.
Epstein-Barr virus (EBV), an oncogenic human herpesvirus, induces cell proliferation after infection of resting B lymphocytes, its reservoir in vivo. The viral latent proteins are necessary for permanent B cell growth, but it is unknown whether they are sufficient. EBV was recently found to encode microRNAs (miRNAs) that are expressed in infected B cells and in some EBV-associated lymphomas. EBV miRNAs are grouped into two clusters located either adjacent to the BHRF1 gene or in introns contained within the viral BART transcripts. To understand the role of the BHRF1 miRNA cluster, we have constructed a virus mutant that lacks all its three members (Δ123) and a revertant virus. Here we show that the B cell transforming capacity of the Δ123 EBV mutant is reduced by more than 20-fold, relative to wild type or revertant viruses. B cells exposed to the knock-out virus displayed slower growth, and exhibited a two-fold reduction in the percentage of cells entering the cell cycle S phase. Furthermore, they displayed higher latent gene expression levels and latent protein production than their wild type counterparts. Therefore, the BHRF1 miRNAs accelerate B cell expansion at lower latent gene expression levels. Thus, this miRNA cluster simultaneously enhances expansion of the virus reservoir and reduces the viral antigenic load, two features that have the potential to facilitate persistence of the virus in the infected host. Thus, the EBV BHRF1 miRNAs may represent new therapeutic targets for the treatment of some EBV-associated lymphomas.


Topological superconductivity and unconventional pairing in oxide interfaces.
Pinpointing the microscopic mechanism for superconductivity has proven to be one of the most outstanding challenges in the physics of correlated quantum matter. Thus far, the most direct evidence for an electronic pairing mechanism is the observation of a new symmetry of the order parameter, as done in the cuprate high-temperature superconductors. Alternatively, global, topological invariants allow for a sharp discrimination between states of matter that cannot be transformed into each other adiabatically. Here we propose an unconventional pairing state for the electron fluid in two-dimensional oxide interfaces and establish a direct link to the emergence of non-trivial topological invariants. Topological signatures, in particular Majorana edge states, can then be used to detect the microscopic origin of superconductivity. In addition, we show that also the density wave states that compete with superconductivity sensitively depend on the nature of the pairing interaction.


A Case of Functional Metastatic Follicular Thyroid Carcinoma that Presented with Hip Fracture and Hypercalcemia.
Thyroid follicular cancers are one of the thyroid gland cancers. This cancer can lead to metastases to various areas of the body. We describe a patient with thyroid follicular carcinoma who after total thyroidectomy had severe hypercalcemia, increased creatinine, and thyrotoxicosis due to extensive bone metastases. The patient was a 52-year-old man who had femoral neck fracture as the first manifestation of thyroid cancer. He was hospitalized for some time after orthopedic measures because of thyrotoxicosis and deep-venous thrombosis. The study found that the origin of metastatic lesions was thyroid follicular cancer, leading to extensive bone metastases. After administering of methimazole and control of thyrotoxicosis, he was subjected to total thyroidectomy. Methimazole was discontinued immediately after surgery. One month after surgery, ultrasound confirmed that the thyroid was completely removed. However, T3 (triiodothyronine) remained high; besides the patient had hypercalcemia and increased creatinine due to dehydration. The patient was retreated with methimazole due to thyrotoxicosis, and for hypercalcemia fluid therapy, intravenous zoledronic acid was prescribed. These measures led to the normalization of creatinine and glomerular filtration rate. The purpose of introducing this case report was that these symptoms are a rare manifestation of functional metastases of follicular thyroid carcinoma after total thyroidectomy. Bone metastases of follicular thyroid carcinoma may be functional and are lytic that can lead to hypercalcemia and its complications.


Effect of rhGH and rhIGF-I treatment on protein utilization in elderly women.
To assess the effect of recombinant human growth hormone (rhGH) and recombinant human insulin-like growth factor I (rhIGF-I) on protein utilization, 14 women, age 66-82 yr, were invited to participate in studies of nitrogen balance (n = 14), whole body protein turnover (n = 14), and muscle protein synthesis (n = 8). They were studied both 1 wk before and during the last week of a 1-mo regimen, to which they had been randomly assigned, of either 0.025 mg rhGH/kg once daily or rhIGF-I at 0.015 (low), 0.03 (mid), or 0.06 (high) mg/kg twice daily. Nitrogen balance increased significantly after 1 wk of treatment in all groups (P < 0.05). After 1 mo, the magnitude of this effect had diminished by 50% in the rhGH group but remained elevated throughout the treatment period with all doses of rhIGF-I. Both protein synthesis and breakdown, measured by a primed constant infusion of [15N]glycine, were significantly increased with rhGH (9% and 8%, respectively), low-dose rhIGF-I (4.5% and 4%), and high-dose rhIGF-I (18% and 17%). Net synthesis was significantly increased with rhGH (48%) and high- and mid-dose rhIGF-I (27% and 196%, respectively). Muscle protein synthesis as measured by incorporation of [1-13C]leucine increased significantly with rhGH (50%) and the mid (67%) and high (57%) doses of rhIGF-I. These data show that whole body and muscle protein synthesis are responsive to growth factor stimulation in elderly women.


Racial/Ethnic Composition and Violence: Size-of-Place Variations in Percent Black and Percent Latino Effects on Violence Rates.
According to racial invariance positions and mainstream sociological perspectives on race and crime, race differences in structural conditions should account for most if not all of the racial composition (or percent black) effect on aggregate-level violence rates. However, prior research (mostly conducted prior to 1990) generally provides mixed or contrary evidence for this position, showing instead that greater concentrations of blacks are linked to increased violence even after accounting for racial differences in socioeconomic conditions. The current study uses recent data and a novel unit of analysis to go beyond extant research in two ways. First, we include percent Latino in our examination of the extent to which both racial and ethnic composition effects on violent crime rates are mediated by racial/ethnic disparities in socioeconomic disadvantage. Second, we test whether racial/ethnic composition effects are conditioned by size of place, through the use census places as a uniquely varying unit of analysis. We find that both black and Latino composition effects are partly explained by controlling for structural conditions (especially structural disadvantage), but this characterizes smaller places much more than the largest, most urbanized places.


Activated CaMKII couples GluN2B and casein kinase 2 to control synaptic NMDA receptors.
Synaptic activity triggers a profound reorganization of the molecular composition of excitatory synapses. For example, NMDA receptors are removed from synapses in an activity- and calcium-dependent manner, via casein kinase 2 (CK2) phosphorylation of the PDZ ligand of the GluN2B subunit (S1480). However, how synaptic activity drives this process remains unclear because CK2 is a constitutively active kinase, which is not directly regulated by calcium. We show here that activated CaMKII couples GluN2B and CK2 to form a trimolecular complex and increases CK2-mediated phosphorylation of GluN2B S1480. In addition, a GluN2B mutant, which contains an insert to mimic the GluN2A sequence and cannot bind to CaMKII, displays reduced S1480 phosphorylation and increased surface expression. We find that although disrupting GluN2B/CaMKII binding reduces synapse number, it increases synaptic-GluN2B content. Therefore, the GluN2B/CaMKII association controls synapse density and PSD composition in an activity-dependent manner, including recruitment of CK2 for the removal of GluN2B from synapses.


[Effect of new adenine derivative on emotional status of rats under conditions of "voluntary alcoholization" model].
In continuation of the study of pharmacological properties of the new drug VMA-99-82 (9-[2-(4-isopropylphenoxy)ethyl]adenine), the influence of this drug on the psycho-emotional status of rats was evaluated using a voluntary alcoholization model. It is established that VMA-99-82 administered at doses of 10 and 50 mg/kg produces a positive effect on impaired cognitive functions in alcoholized rats and eliminated the depression caused by the consumption of excess ethanol.


Serotonin transporter gene polymorphism and personality traits in primary alcohol dependence.
We tested the hypothesis of an association between the serotonin transporter (5-HTT) gene regulatory region polymorphism and the Temperament and Character Inventory (TCI) personality dimension of Harm Avoidance. For the study, 124 subjects seeking inpatient treatment for primary alcohol dependence were grouped by their 5-HTT genotype and assessed with the TCI. Genotypes differed statistically significantly in Harm Avoidance but not in any other personality trait. This gives support to the hypothesis that the TCI temperament Harm Avoidance is associated with serotonergic neurotransmission in primary alcohol dependence.


The Transcriptome of Brassica napus L. Roots under Waterlogging at the Seedling Stage.
Although rapeseed (Brassica napus L.) is known to be affected by waterlogging, the genetic basis of waterlogging tolerance by rapeseed is largely unknown. In this study, the transcriptome under 0 h and 12 h of waterlogging was assayed in the roots of ZS9, a tolerant variety, using digital gene expression (DGE). A total of 4432 differentially expressed genes were identified, indicating that the response to waterlogging in rapeseed is complicated. The assignments of the annotated genes based on GO (Gene Ontology) revealed there were more genes induced under waterlogging in "oxidation reduction", "secondary metabolism", "transcription regulation", and "translation regulation"; suggesting these four pathways are enhanced under waterlogging. Analysis of the 200 most highly expressed genes illustrated that 144 under normal conditions were down-regulated by waterlogging, while up to 191 under waterlogging were those induced in response to stress. The expression of genes involved under waterlogging is mediated by multiple levels of transcriptional, post-transcriptional, translational and post-translational regulation, including phosphorylation and protein degradation; in particular, protein degradation might be involved in the negative regulation in response to this stress. Our results provide new insight into the response to waterlogging and will help to identify important candidate genes.


Granulocytapheresis in the treatment of patients with rheumatoid arthritis.
The G-1 column is an extracorporeal type granulocytapheresis device packed with 220 g cellulose acetate beads to which granulocytes and monocytes specifically adhere. A total of 59 rheumatoid arthritis patients with elevated granulocyte counts from 4 hospitals in Japan received 2 apheresis sessions of 1 h duration/week for a total of 8 times over a period of 4 weeks. About 55% of the leukocytes which entered the G-1 column were adsorbed onto the beads: 95% were granulocytes, 3.5% monocytes, and 0.4% lymphocytes. Clinical and efficacy assessments showed improvements in swollen joints (p < 0.01), tender joints (p < 0.001), the active joint score (p < 0.001), duration of morning stiffness (p < 0.01), and grip strength (p < 0.001). In good responders, the improvements were observed for up to 12 weeks following the last apheresis. Exacerbation was noted in 2 patients. It is suggested that the efficacy of the G-1 column is attributable to the removal or suppression of hyperactive leukocytes and inflammatory cytokines, inducing a kind of immunomodulation.


Medical Parole and Aging Prisoners: A Qualitative Study.
The population of geriatric prisoners in the United States will reach unprecedented levels in the coming decades. Geriatric prisoners are at increased risk for deteriorating health and experience the onset of disease earlier than the aging population at large. Medical parole is an underutilized program that allows aging prisoners to transition to community-based health care. This article presents original key informant interview data and analysis of the perceptions of medical parole. Three dominant themes emerged: (1) drugs and nonviolent crimes; (2) politics, costs, and consequences; and (3) quality of health care and sense of security in prison. Participants rejected the possibility that medical care provided is below the clinical standard or is the cause of geriatric prisoners' deteriorating health and consistently implied that medical care at this prison is better than most Americans receive. Participants perceived their careers more as contributions to public health than criminal justice.


Peripheral facial palsy in patients with tick-borne encephalitis.
Although tick-borne encephalitis (TBE) has been recognized in Europe for more than 70 years and has been the topic of numerous reports, information on the involvement of facial nerves in the course of the disease is limited. Our study conducted at a single medical centre revealed that facial nerve involvement in the course of TBE in Central Europe is (i) infrequent--it was found in only 11 of 1218 (0.9%) consecutive adult patients diagnosed with TBE; (ii) manifests with unilateral or rarely bilateral peripheral facial palsy (PFP) (nine and two patients, respectively); (iii) appears late in the course of acute illness--in our patients 10-20 days after the onset of the meningoencephalitic phase of TBE, and often after defervescence (in 8/11 patients; 6-13 days after normalization of body temperature); (iv) develops more often in patients with more severe illness, i.e. more frequently in those with encephalitic than in those with meningitic clinical presentation, and more commonly in patients with monophasic than biphasic illness; and (v) has a favourable outcome--our patients had a clinically complete recovery from PFP within 7-90 (median 30) days after its onset. Moreover, the finding of Borrelia infection in 3/11 (27.3%) patients (diagnosis of confirmed Lyme neuroborreliosis was established in 1/11 patients and two patients fulfilled criteria for possible Lyme neuroborreliosis) suggests that in countries where TBE and Lyme borreliosis are endemic, concomitant infection with Borrelia burgdorferi sensu lato should be considered and searched for in patients who develop PFP in the course of TBE.


A pilot whole systems clinical trial of traditional Chinese medicine and naturopathic medicine for the treatment of temporomandibular disorders.
To assess the feasibility and acceptability of studying whole systems of Traditional Chinese Medicine (TCM) and Naturopathic medicine (NM) in the treatment of temporomandibular disorders (TMD), and to determine whether there is indication to support further research. A pilot study using a randomized controlled clinical trial design of whole system TCM and NM versus state-of-the-art specialty care (SC). Kaiser Permanente Northwest (KPNW), and practitioner offices in Portland, Oregon. One hundred and sixty (160) women 25-55 years of age attending a KPNW TMD specialty clinic. Whole system TCM and NM, and KPNW TMD clinic SC; the intervention protocols were designed to model the individually tailored type of community care offered in alternative medicine practices in Portland and in the KPNW TMD clinic, using protocols that enhanced similarities among practitioners within each system and permitted full descriptions of the treatments provided. TMD was ascertained using the Research Diagnostic Criteria/TMD; outcomes were self-reported worst and average facial pain and interference with activities (scaled 0-10 where 10 is worst). Of 948 consecutive eligible patients, 160 were randomized to one of three arms; 128 provided endpoint data. TCM and NM demonstrated significantly greater in-treatment reductions for worst facial pain compared to SC (adjusted regression analysis; higher negative values indicate greater improvement, = -1.11 +/- 0.43, p = 0.010 and -1.02 +/- 0.45, p = 0.025 for TCM and NM, respectively, compared to SC) and at 3 months post-treatment (-1.07 +/- 0.51, p = 0.037 and -1.27 +/- 0.54, p = 0.019 for TCM and NM versus SC, respectively). Additionally, TCM provided significantly greater decreases in average pain than SC; NM provided significantly greater decreases than SC or TCM in TMD-related psychosocial interference. These alternative medicine approaches each resulted in significantly greater reduction of pain and psychosocial interference than SC. Further research on the potential benefits of traditional whole systems of medicine for TMD appears warranted.


Activity and architecture of pyroglutamate-modified amyloid-β (AβpE3-42) pores.
Among the family of Aβ peptides, pyroglutamate-modified Aβ (AβpE) peptides are particularly associated with cytotoxicity in Alzheimer's disease (AD). They represent the dominant fraction of Aβ oligomers in the brains of AD patients, but their accumulation in the brains of elderly individuals with normal cognition is significantly lower. Accumulation of AβpE plaques precedes the formation of plaques of full-length Aβ (Aβ1-40/42). Most of these properties appear to be associated with the higher hydrophobicity of AβpE as well as an increased resistance to enzymatic degradation. However, the important question of whether AβpE peptides induce pore activity in lipid membranes and their potential toxicity compared with other Aβ pores is still open. Here we examine the activity of AβpE pores in anionic membranes using planar bilayer electrical recording and provide their structures using molecular dynamics simulations. We find that AβpE pores spontaneously induce ionic current across the membrane and have some similar properties to the other previously studied pores of the Aβ family. However, there are also some significant differences. The onset of AβpE3-42 pore activity is generally delayed compared with Aβ1-42 pores. However, once formed, AβpE3-42 pores produce increased ion permeability of the membrane, as indicated by a greater occurrence of higher conductance electrical events. Structurally, the lactam ring of AβpE peptides induces a change in the conformation of the N-terminal strands of the AβpE3-42 pores. While the N-termini of wild-type Aβ1-42 peptides normally reside in the bulk water region, the N-termini of AβpE3-42 peptides tend to reside in the hydrophobic lipid core. These studies provide a first step to an understanding of the enhanced toxicity attributed to AβpE peptides.


A video method for the evaluation of antidepressant clinical and behavioural actions.
Measuring efficacy and behavioural actions of new antidepressants (ADs) is greatly enhanced by having videotaped records of assessment interviews. This study describes a revised version of the Video Interview Behaviour Evaluation Scales (VIBES), shortened to make it more applicable to clinical trials. The method focuses on physically expressive, motor and social behavioural aspects of the depressive disorder. The Brief version permits juxtaposing of baseline and outcome interviews during the same viewing session thereby reducing the role of memory in the rater's observations. The method provides measures of behavioural components and four new severity dimensions, Social withdrawal-motor retardation, Anxiety-agitation, Hostility, Depressive mood-cognitive impairment. Viewing a patient's series of baseline, during treatment, and outcome interviews can be conducted in about 1 h. This study compared the VIBES with the Hamilton Depression Rating Scale (HAMD) in (1) assessing the efficacy of the selectively targeted ADs, desipramine and paroxetine, and placebo in depressed in-patients and (2) determining onset and nature of the drugs' early behavioural actions. The findings showed (1) components of the method to be reliable; (2) the VIBES to be more sensitive than the HAMD in measuring efficacy; (3) the methods to be equally sensitive in detecting early clinical actions of the two drugs; (4) the VIBES more informative in identifying discrete behavioural aspects of the disorder that are impacted by the drugs; and (5) that in differentiating the drugs' behavioural actions, desipramine was indicated to initially 'stimulate', i.e. effect motor activity and depressed mood, and paroxetine to reduce global severity and anxiety. The study shows the VIBES to be capable of uncovering behavioural mechanisms underlying AD's capacity to resolve depressive disorder.


Pathogenesis and prevention of stroke in spontaneously hypertensive rats.
1. A colony of stroke-prone spontaneously hypertensive rats has been developed by selective breeding. 2. These animals developed severe hypertension early in life, the magnitude of the hypertension being closely related to the incidence of stroke. 3. No evidence was obtained of any humoral factor responsible for strokes. 4. Local factors predisposing to stroke were a scanty arterial supply with characteristic recurrent branching of long and large arteries, together with increased vascular permeability, angio-necrosis, and formation of microaneurysms. 5. Strokes could be prevented by adequate antihypertensive therapy from an early age.


Parasites and cancers: parasite antigens as possible targets for cancer immunotherapy.
An adverse relationship between some parasite infections and cancer in the human population has been reported by different research groups. Anticancer activity of some parasites such as Trypanosoma cruzi, Toxoplasma gondii, Toxocara canis, Acantamoeba castellani and Plasmodium yoelii has been shown in experimental animals. Moreover, it has been shown that cancer-associated mucin-type O-glycan compositions are made by parasites, therefore cancers and parasites have common antigens. In this report anticancer activities of some parasites have been reviewed and the possible mechanisms of these actions have also been discussed.


[A study on motility of sphincter of Oddi in postcholecystectomy syndrome].
Endoscopic manometry of sphincter of Oddi (SO) and serum levels of gastrin, glucagon, and somatostatin were measured in patients with postcholecystectomy syndrome (n = 12), asymptomatic cholecystectomy patients (n = 6), and controlled subjects (n = 14). Pentagastrin-stimulated gastric acid secretion test was also performed in part of patients who had symptoms or no symptoms after the removal of gallbladder. The results showed that the patients of symptomatic group had hypertonic dyskinesia of SO as shown by deep and wide waves superimposed on high basal pressure plateau of SO. The symptomatic group also had a higher serum level of gastrin and a greater BAO than those of other two groups. No difference of serum levels of glucagon and somatostatin was found among these three groups. The hypertonic dyskinesia of SO and hypergastrinemia are possibly important factors in the pathogenesis of postcholecystectomy syndrome.


A scalable analytical approach from bacterial genomes to epidemiology.
Recent years have seen a remarkable increase in the practicality of sequencing whole genomes from large numbers of bacterial isolates. The availability of this data has huge potential to deliver new insights into the evolution and epidemiology of bacterial pathogens, but the scalability of the analytical methodology has been lagging behind that of the sequencing technology. Here we present a step-by-step approach for such large-scale genomic epidemiology analyses, from bacterial genomes to epidemiological interpretations. A central component of this approach is the dated phylogeny, which is a phylogenetic tree with branch lengths measured in units of time. The construction of dated phylogenies from bacterial genomic data needs to account for the disruptive effect of recombination on phylogenetic relationships, and we describe how this can be achieved. Dated phylogenies can then be used to perform fine-scale or large-scale epidemiological analyses, depending on the proportion of cases for which genomes are available. A key feature of this approach is computational scalability and in particular the ability to process hundreds or thousands of genomes within a matter of hours. This is a clear advantage of the step-by-step approach described here. We discuss other advantages and disadvantages of the approach, as well as potential improvements and avenues for future research. This article is part of a discussion meeting issue 'Genomic population structures of microbial pathogens'.


Gene delivery potential of biofunctional carbonate apatite nanoparticles in lungs.
Existing nonviral gene delivery systems to lungs are inefficient and associated with dose limiting toxicity in mammalian cells. Therefore, carbonate apatite (CO3Ap) nanoparticles were examined as an alternative strategy for effective gene delivery to the lungs. This study aimed to (1) assess the gene delivery efficiency of CO3Ap in vitro and in mouse lungs, (2) evaluate the cytotoxicity effect of CO3Ap/pDNA in vitro, and (3) characterize the CO3Ap/pDNA complex formulations. A significantly high level of reporter gene expression was detected from the lung cell line transfected with CO3Ap/pDNA complex prepared in both serum and serum-free medium. Cytotoxicity analysis revealed that the percentage of the viable cells treated with CO3Ap to be almost similar to the untreated cells. Characterization analyses showed that the CO3Ap/pDNA complexes are in a nanometer range with aggregated spherical structures and tended to be more negatively charged. In the lung of mice, highest level of transgene expression was observed when CO3Ap (8 μL) was complexed with 40 μg of pDNA at day 1 after administration. Although massive reduction of gene expression was seen beyond day 1 post administration, the level of expression remained significant throughout the study period.


Recovery of nerve conduction following microvascular decompression for trigeminal neuralgia.
To assess the function of trigeminal nerve before and after microvascular decompression for trigeminal neuralgia. To date there is no direct evidence that microvascular decompression of the trigeminal root restores normal conduction in the nerve. The authors examined 10 patients with trigeminal neuralgia in whom preoperative MRI and MR angiography demonstrated neurovascular contact. During microvascular decompression, the trigeminal nerve was monitored by recording early scalp trigeminal evoked potentials immediately before, during, and after decompression. Direct recordings from the root entry zone were also performed. In all patients preoperative scalp evoked potentials showed impaired conduction of the trigeminal root. Microvascular decompression was associated with immediate recovery of conduction in seven patients, demonstrated by both scalp evoked potentials and direct root recordings. All 10 patients were pain free postoperatively. Improvement in trigeminal neuralgia following microvascular decompression is often associated with normalization of neurophysiologic data, suggesting recovery of nerve function. Rapid electrophysiologic recovery and pain relief following microvascular decompression argue that neither phenomenon is linked to remyelination. It is possible that the trigeminal evoked potentials might predict an effective microvascular decompression.


An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence.
Here we describe a previously unknown form of inherited immunodeficiency revealed by an N-ethyl-N-nitrosourea-induced mutation called elektra. Mice homozygous for this mutation showed enhanced susceptibility to bacterial and viral infection and diminished numbers of T cells and inflammatory monocytes that failed to proliferate after infection and died via the intrinsic apoptotic pathway in response to diverse proliferative stimuli. They also had a greater proportion of T cells poised to replicate DNA, and their T cells expressed a subset of activation markers, suggestive of a semi-activated state. We positionally ascribe the elektra phenotype to a mutation in the gene encoding Schlafen-2 (Slfn2). Our findings identify a physiological role for Slfn2 in the defense against pathogens through the regulation of quiescence in T cells and monocytes.


Local and intralesional therapy of in-transit melanoma metastases.
Regional relapse of melanoma may occur as satellite or in-transit metastases proximal to the primary tumor in the direction of the lymph flow. The management of in-transit metastases is challenging because the efficacy of treatment is largely dictated by the biological behavior of the patient's melanoma. This review examines local treatment modalities.


Cross-mapping clinical notes between hospitals: an application of the LOINC Document Ontology.
Standardization of document titles is essential for management as the volume of electronic clinical notes increases. The two campuses of the New York Presbyterian Hospital have over 2,700 distinct document titles. The LOINC Document Ontology (DO) provides a standard for the naming of clinical documents in a multi-axis structure. We have represented the latest LOINC DO structure in the MED, and developed an automated process mapping the clinical documents from both the West (Columbia) and East (Cornell) campuses to the LOINC DO. We find that the LOINC DO can represent the majority of our documents, and about half of the documents map between campuses using the LOINC DO as a reference. We evaluated the possibility of using current LOINC codes in document exchange between different institutions. While there is clear success in the ability of the LOINC DO to represent documents and facilitate exchange we find there are granularity issues.


Technical Assessment of Microvascular Decompression for Trigeminal Neuralgia Using a 3-Dimensional Exoscope: A Case Series.
Detailed anatomic visualization of the root entry zone of the trigeminal nerve is crucial to successfully perform microvascular decompression surgery (MVD) in patients with trigeminal neuralgia. To determine advantages and disadvantages using a 3-dimensional (3D) exoscope for MVD surgery. A 4K 3D exoscope (ORBEYE) was used by a single surgical team for MVD in a retrospective case series of 8 patients with trigeminal neuralgia in a tertiary center. Clinical and surgical data were collected, and advantages/disadvantages of using the exoscope for MVD were recorded after each surgery. Descriptive statistics were used to summarize the data. Adequate MVD of the trigeminal nerve root was possible in all patients by exclusively using the exoscope. It offered bright visualization of the cerebellopontine angle and the root entry zone of the trigeminal nerve that was comparable with a binocular operating microscope. The greatest advantages of the exoscope included good optical quality, the pronounced depth of field of the image for all observers, and its superior surgeon ergonomics. Disadvantages were revealed with overexposure at deep surgical sites and the lack of endoscope integration. In 6 patients, facial pain improved significantly after surgery (Barrow Neurological Institute pain intensity score I in 5 and III in 1 patient), whereas it did not in 2 patients (Barrow Neurological Institute score IV and V). No complications occurred. Utilization of a 3D exoscope for MVD is a safe and feasible procedure. Surgeons benefit from better ergonomics, excellent image quality, and an improved experience for observers.


Peer review as an aid to improving the completeness of psychiatric case notes.
Clinical auditing and the setting of goals for continuing education are often based on case note reviews. Deficiencies in the comprehensiveness of the recorded case history place some restrictions on the usefulness of such reviews as guides to continuing education programmes. In this study, attempts were made to improve the quality of the data in psychiatric case notes by peer discussion, and by altering the case note recording guidelines. After each educational intervention a further detailed audit of the subsequent case histories was performed. Significant differences emerged in a few subsections of the case notes, but overall there was little change. Possible explanations for these findings are discussed.


Multilayer coatings with high reflectance in the extreme-ultraviolet spectral range of 50 to 121.6 nm.
Multilayer coatings with three layers were designed to yield an increase in normal-incidence reflectance in the extreme ultraviolet over that of the available single-layer coatings. Multilayer coatings based on Al, MgF(2), and either SiC or B(4)C were demonstrated to have higher reflectance than single layers of SiC and B(4)C in the spectral region from 57.9 nm to the H Lyman-alpha line (121.6 nm) and above. The increase in reflectance was higher at wavelengths close to 121.6 nm. Reflectance degraded slightly over time in the same way as for single layers. After a few months, multilayer coatings maintained higher reflectance than their single-layer counterparts.


An evaluation of hospital discharge records as a tool for serious work related injury surveillance.
To identify and describe work related serious injuries among sawmill workers in British Columbia, Canada using hospital discharge records, and compare the agreement and capturing patterns of the work related indicators available in the hospital discharge records. Hospital discharge records were extracted from 1989 to 1998 for a cohort of sawmill workers. Work related injuries were identified from these records using International Classification of Disease (ICD-9) external cause of injury codes, which have a fifth digit, and sometimes a fourth digit, indicating place of occurrence, and the responsibility of payment schedule, which identifies workers' compensation as being responsible for payment. The most frequent causes of work related hospitalisations were falls, machinery related, overexertion, struck against, cutting or piercing, and struck by falling objects. Almost all cases of machinery related, struck by falling object, and caught in or between injuries were found to be work related. Overall, there was good agreement between the two indicators (ICD-9 code and payment schedule) for identifying work relatedness of injury hospitalisations (kappa = 0.75, p < 0.01). There was better concordance between them for injuries, such as struck against, drowning/suffocation/foreign body, fire/flame/natural/environmental, and explosions/firearms/hot substance/electric current/radiation, and poor concordance for injuries, such as machinery related, struck by falling object, overexertion, cutting or piercing, and caught in or between. Hospital discharge records are collected for administrative reasons, and thus are readily available. Depending on the coding reliability and validity, hospital discharge records represent an alternative and independent source of information for serious work related injuries. The study findings support the use of hospital discharge records as a potential surveillance system for such injuries.


Self-assembly of block copolymers.
Block copolymer (BCP) self-assembly has attracted considerable attention for many decades because it can yield ordered structures in a wide range of morphologies, including spheres, cylinders, bicontinuous structures, lamellae, vesicles, and many other complex or hierarchical assemblies. These aggregates provide potential or practical applications in many fields. The present tutorial review introduces the primary principles of BCP self-assembly in bulk and in solution, by describing experiments, theories, accessible morphologies and morphological transitions, factors affecting the morphology, thermodynamics and kinetics, among others. As one specific example at a more advanced level, BCP vesicles (polymersomes) and their potential applications are discussed in some detail.


[Diagnostic imaging of diaphragmatic trauma].
To assess the semiology, effectiveness and role of the modern diagnostic methods used to study diaphragmatic injuries. We report our personal experience acquired in the last 4 years in 23 patients. Eighteen patients had blunt and 6 penetrating diaphragmatic trauma, 10 of them involving the right and 14 the left hemidiaphragm. Plain chest X-rays were performed in 19 cases, gastrointestinal (GI) barium studies in 2, US in 5 and CT in 21 cases. Plain chest films were normal in one case (5%), not specific in 6 (32%), suggestive in 7 (37%), and diagnostic in 5 (26%). Barium studies of the GI tract were diagnostic in both patients (100%). US was suggestive in one case (20%) and diagnostic in 4 (80%). CT was not specific in 4 cases (19%), suggestive in 8 (38%) and diagnostic in 9 (43%). Plain chest radiography remains the method of choice in the study of diaphragmatic injuries. US, in our still limited experience, seems to be the most accurate method in the direct demonstration of muscular traumas and should be performed more often in the study of diaphragmatic injuries. CT has poorer accuracy and, above all, shows only indirect signs, but it is fairly effective and plays a key role in the depiction of chest and abdominal traumas. Barium studies should be reserved, possibly, to the direct identification of digestive hernias, especially in the late phase.


The sexual dimorphic association of cardiorespiratory fitness to working memory in children.
The present investigation examined the sexual dimorphic patterns of cardiorespiratory fitness to working memory in preadolescent children (age range: 7.7-10.9). Data were collected in three separate studies (Study 1: n = 97, 42 females; Study 2: n = 95, 45 females; Study 3: n = 84, 37 females). All participants completed a cardiorespiratory fitness assessment in addition to a specific measure of working memory (i.e. the operation span task, the n-back task, or the Sternberg task). Results from all three samples revealed that higher cardiorespiratory fitness levels were associated with better working memory performance only for males with no such relation observed for females. In addition, the sexually dimorphic pattern was selective for the most challenging working memory conditions in each task. Together, these findings reveal new evidence that cardiorespiratory fitness is selectively related to better working memory performance for male children. This investigation provides additional insight into how interventions aimed at improving fitness may influence cognitive development differentially among preadolescent children.


The atRA-responsive gene neuron navigator 2 functions in neurite outgrowth and axonal elongation.
Neuron navigator 2 (Nav2) was first identified as an all-trans retinoic acid (atRA)-responsive gene in human neuroblastoma cells (retinoic acid-induced in neuroblastoma 1, RAINB1) that extend neurites after exposure to atRA. It is structurally related to the Caenorhabditis elegans unc-53 gene that is required for cell migration and axonal outgrowth. To gain insight into NAV2 function, the full-length human protein was expressed in C. elegans unc-53 mutants under the control of a mechanosensory neuron promoter. Transgene expression of NAV2 rescued the defects in unc-53 mutant mechanosensory neuron elongation, indicating that Nav2 is an ortholog of unc-53. Using a loss-of-function approach, we also show that Nav2 induction is essential for atRA to induce neurite outgrowth in SH-SY5Y cells. The NAV2 protein is located both in the cell body and along the length of the growing neurites of SH-SY5Y cells in a pattern that closely mimics that of neurofilament and microtubule proteins. Transfection of Nav2 deletion constructs in Cos-1 cells reveals a region of the protein (aa 837-1065) that directs localization with the microtubule cytoskeleton. Collectively, this work supports a role for NAV2 in neurite outgrowth and axonal elongation and suggests this protein may act by facilitating interactions between microtubules and other proteins such as neurofilaments that are key players in the formation and stability of growing neurites.


Dual oxidase 2 in lung epithelia is essential for hyperoxia-induced acute lung injury in mice.
Acute lung injury (ALI) induced by excessive hyperoxia has been employed as a model of oxidative stress imitating acute respiratory distress syndrome. Under hyperoxic conditions, overloading quantities of reactive oxygen species (ROS) are generated in both lung epithelial and endothelial cells, leading to ALI. Some NADPH oxidase (NOX) family enzymes are responsible for hyperoxia-induced ROS generation in lung epithelial and endothelial cells. However, the molecular mechanisms of ROS production in type II alveolar epithelial cells (AECs) and ALI induced by hyperoxia are poorly understood. In this study, we show that dual oxidase 2 (DUOX2) is a key NOX enzyme that affects hyperoxia-induced ROS production, particularly in type II AECs, leading to lung injury. In DUOX2 mutant mice (DUOX2(thyd/thyd)) or mice in which DUOX2 expression is knocked down in the lungs, hyperoxia-induced ALI was significantly lower than in wild-type (WT) mice. DUOX2 was mainly expressed in type II AECs, but not endothelial cells, and hyperoxia-induced ROS production was markedly reduced in primary type II AECs isolated from DUOX2(thyd/thyd) mice. Furthermore, DUOX2-generated ROS are responsible for caspase-mediated cell death, inducing ERK and JNK phophorylation in type II AECs. To date, no role for DUOX2 has been defined in hyperoxia-mediated ALI despite it being a NOX homologue and major ROS source in lung epithelium. Here, we present the novel finding that DUOX2-generated ROS induce AEC death, leading to hyperoxia-induced lung injury.


Recent advances in graphene and its metal-oxide hybrid nanostructures for lithium-ion batteries.
Today, one of the major challenges is to provide green and powerful energy sources for a cleaner environment. Rechargeable lithium-ion batteries (LIBs) are promising candidates for energy storage devices, and have attracted considerable attention due to their high energy density, rapid response, and relatively low self-discharge rate. The performance of LIBs greatly depends on the electrode materials; therefore, attention has been focused on designing a variety of electrode materials. Graphene is a two-dimensional carbon nanostructure, which has a high specific surface area and high electrical conductivity. Thus, various studies have been performed to design graphene-based electrode materials by exploiting these properties. Metal-oxide nanoparticles anchored on graphene surfaces in a hybrid form have been used to increase the efficiency of electrode materials. This review highlights the recent progress in graphene and graphene-based metal-oxide hybrids for use as electrode materials in LIBs. In particular, emphasis has been placed on the synthesis methods, structural properties, and synergetic effects of metal-oxide/graphene hybrids towards producing enhanced electrochemical response. The use of hybrid materials has shown significant improvement in the performance of electrodes.


Enhancing the Conventional Culture: the Evaluation of Several Culture Media and Growth Conditions Improves the Isolation of Ruminal Bacteria.
The rumen microbiota is critical in cattle digestion. Still, its low cultivability makes it difficult to study its ecological function and biotechnological potential. To improve the recovery of ruminal microorganisms, this study combined the evaluation of several cultivation parameters with metabarcoding analysis. The parameters tested comprised eight media cultures, three sample dilutions (10-2, 10-6, 10-12), and two incubation times (3 and 7 days). Bacterial populations were determined through Illumina sequencing of 16S rRNA from three biological replicates. The results indicate that none of the culture media recovered all rumen populations and that there was an altered relative abundance of the dominant phyla. In the rumen, Bacteroidetes and Firmicutes comprised 75% and 15% of the relative abundance, respectively, while in the culture media, these were 15% and 60%, respectively. Principal coordinate analysis (PCoA) of the bacterial community revealed significant shifts in population composition due to dilution, with 10-2 and 10-6 dilutions clustered closely while the 10-12 dilution differed markedly. In contrast, incubation duration did not influence population diversity. According to the results, two media, CAN and KNT, were selected based on their ability to recover more similar populations compared to the rumen sample. The metataxonomic study showed that CAN media had consistent reproducibility over time, while KNT showed enrichment of different taxa due to the use of rumen fluid as a substrate. From these, 64 pure cultures were obtained and 54 were identified through 16S rRNA gene sequencing. Being Streptococcus the most frequently isolated genus, this prevalence contrasts with the liquid media composition, underscoring the importance of refining single colony isolation strategies. Although no culture medium could replicate the native rumen bacterial population perfectly, our findings highlight the potential of CAN and KNT media in recovering populations that are more closely aligned to natural rumen conditions. In conclusion, our study emphasizes the importance of integrating molecular approaches in selecting suitable cultivation media and parameters to depict rumen bacteria accurately.


[Correction of a post-traumatic femoral length difference using an intramedullary distraction nail].
For the operative adjustment of a leg length shortening and for correcting an angular deformity, an external fixator is the most frequently used technique today. This method may, however, be complicated by painful soft tissue and muscle fixations, pin infections and psychic strain as well as by long treatment duration with the external fixator. The intramedullary skeletal kinetic distractor (ISKD) is an internal lengthening nail, which promises a postoperative course without further complications. We used the ISKD nail in a 28-year-old traumatised motorcyclist, in whom, after removal of a comminuted femur bone fragment, a leg length shortening of 8 cm resulted. After uneventful healing of all fractures and having performed implant removal, we implanted an ISKD nail for femoral lengthening. The following distraction resulted, without considerable complications, in a complete compensation of the leg difference. The ISKD nail is a suitable procedure to compensate for post-traumatic leg length differences, which exhibits, in contrast to the frequently used external fixator, a largely uncomplicated course. It cannot be used to correct a gross transverse or rotational deformity.


Plasma treatment maintains surface energy of the implant surface and enhances osseointegration.
The surface energy of the implant surface has an impact on osseointegration. In this study, 2 surfaces: nonwashed resorbable blasting media (NWRBM; control) and Ar-based nonthermal plasma 30 days (Plasma 30 days; experimental), were investigated with a focus on the surface energy. The surface energy was characterized by the Owens-Wendt-Rabel-Kaelble method and the chemistry by X-ray photoelectron spectroscopy (XPS). Five adult beagle dogs received 8 implants (n = 2 per surface, per tibia). After 2 weeks, the animals were euthanized, and half of the implants (n = 20) were removal torqued and the other half were histologically processed (n = 20). The bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) were evaluated on the histologic sections. The XPS analysis showed peaks of C, Ca, O, and P for the control and experimental surfaces. While no significant difference was observed for BIC parameter (P > 0.75), a higher level for torque (P < 0.02) and BAFO parameter (P < 0.01) was observed for the experimental group. The surface elemental chemistry was modified by the plasma and lasted for 30 days after treatment resulting in improved biomechanical fixation and bone formation at 2 weeks compared to the control group.


Free energetics of rigid body association of ubiquitin binding domains: a biochemical model for binding mediated by hydrophobic interaction.
Weak intermolecular interactions, such as hydrophobic associations, underlie numerous biomolecular recognition processes. Ubiquitin is a small protein that represents a biochemical model for exploring thermodynamic signatures of hydrophobic association as it is widely held that a major component of ubiquitin's binding to numerous partners is mediated by hydrophobic regions on both partners. Here, we use atomistic molecular dynamics simulations in conjunction with the Adaptive Biasing Force sampling method to compute potentials of mean force (the reversible work, or free energy, associated with the binding process) to investigate the thermodynamic signature of complexation in this well-studied biochemical model of hydrophobic association. We observe that much like in the case of a purely hydrophobic solute (i.e., graphene, carbon nanotubes), association is favored by entropic contributions from release of water from the interprotein regions. Moreover, association is disfavored by loss of enthalpic interactions, but unlike in the case of purely hydrophobic solutes, in this case protein-water interactions are lost and not compensated for by additional water-water interactions generated upon release of interprotein and moreso, hydration, water. We further find that relative orientations of the proteins that mutually present hydrophobic regions of each protein to its partner are favored over those that do not. In fact, the free energy minimum as predicted by a force field based method recapitulates the experimental NMR solution structure of the complex.


Many parallel losses of infA from chloroplast DNA during angiosperm evolution with multiple independent transfers to the nucleus.
We used DNA sequencing and gel blot surveys to assess the integrity of the chloroplast gene infA, which codes for translation initiation factor 1, in >300 diverse angiosperms. Whereas most angiosperms appear to contain an intact chloroplast infA gene, the gene has repeatedly become defunct in approximately 24 separate lineages of angiosperms, including almost all rosid species. In four species in which chloroplast infA is defunct, transferred and expressed copies of the gene were found in the nucleus, complete with putative chloroplast transit peptide sequences. The transit peptide sequences of the nuclear infA genes from soybean and Arabidopsis were shown to be functional by their ability to target green fluorescent protein to chloroplasts in vivo. Phylogenetic analysis of infA sequences and assessment of transit peptide homology indicate that the four nuclear infA genes are probably derived from four independent gene transfers from chloroplast to nuclear DNA during angiosperm evolution. Considering this and the many separate losses of infA from chloroplast DNA, the gene has probably been transferred many more times, making infA by far the most mobile chloroplast gene known in plants.


Fatal cardiac tamponade associated with central venous catheter: a report of 2 cases diagnosed in autopsy.
The authors present 2 cases of fatal cardiac tamponade associated with the insertion of a central venous catheter. The first case occurred soon after the insertion of the catheter (early complication), and the second case, 4 days after (late complication). In both cases, the post-catheter insertion check chest x-ray film showed the tip of the catheter located within the heart silhouette. The diagnosis of cardiac tamponade was made only during the cadaverous examination. In the first case, the catheter was found to be in the right internal jugular vein at autopsy. The postmortem examination showed a clear liquid inside the pericardial cavity and the inferior vena cava injury. In the second case, the catheter had been inserted via the right subclavian vein puncture and there was a perforation of the right atrium at autopsy. The child was using total parenteral nutrition, and the intrapericardial liquid was milky. The incorrect placement of the catheter tip and unrecognized complications led the 2 children to death.


Bioinspired Nanofibril-Humped Fibers with Strong Capillary Channels for Fog Capture.
Bioinspired nanofibril-humped fibers (BNFs) are fabricated by using thermoplastic polyester elastomer and chitosan, via combining the electrospinning technique and fluid coating method to achieve periodic humps composed of interlaced random nanofibrils and a joint composed of aligned nanofibrils, which are highly similar to the micro/nanostructures of wetted spider silk. Especially, nanofibrils can increase the specific area of the hump to capture fog droplets effectively and transport water in channels between the nanofibrils under humid conditions, and thus the fog droplets can coalesce and be highly efficiently transported toward humps for water collection directionally. Such an ability of highly efficient fog capture is attributed to cooperation of an efficient transportation inside the outer shell of BNFs and outside transportation. Inside transportation is induced by anisotropic capillary channels between nanofibrils. When BNFs are wetted, the inside transportation mode is dominated for water collection, induced by anisotropic capillary channels between nanofibrils. BNF web is also used to investigate the droplet transportation in different cross-fiber contact modes in the process of fog capture on a large scale. This study offers an insight into the design of novel materials, which is expected to be developed for some realms of applications, such as fog harvesting engineering, filtration, and others.


Evaluation of cot mattress inner foam as a potential site for microbial generation of toxic gases.
Recent reports of biovolatilisation of phosphorus and antimony by anaerobic bacteria and of leaching of phosphorus and antimony fire-retardant additives from PVC cot mattress covers, indicate that the polyurethane inner-foam of cot mattresses could be a site for generation of toxic gases of group 15 elements. A toxic gas hypothesis for sudden infant death syndrome (SIDS) involving polyurethane foam of cot mattresses was proposed and tested experimentally. Levels of antimony, phosphorus, arsenic and bismuth were determined at four sites for 44 SIDS and 50 control (no death) cot mattress foams. There was no evidence to suggest that the levels of these elements in cot mattress foam have a causal relation to SIDS. Leaching of antimony trioxide from PVC mattress covers could account for detectable levels of this element in 52% of the cot mattress samples analysed. Volatile forms of antimony, phosphorus, arsenic and bismuth was not detected in the headspace of mixed or monoseptic cultures of anaerobic bacteria containing polyurethane foam. Past microbial activity had given rise to involatile methylated species of antimony in some of the cot mattress foams tested (61%, n = 24). Abiotic oxidation of biogenic trimethylantimony together with physical adsorption of methylantimony forms to the polyurethane foam matrix could account for the apparent absence of "escaped" volatile antimony species in culture headspaces of incubation vial. There was no evidence to suggest that levels of trimethylantimony or total methylantimony forms in cot mattress foams have a causal relation to SIDS.


Recurrence of stenoses after coronary angioplasty.
Recurrence remains a major problem after PTCA. The recurrence rate is higher in patients with diabetes, patients 70 years of age or older, and patients with severe coronary artery disease. Intimal tearing during the procedure may lower the recurrence rate. Recurrence in patients with multivessel angioplasty is higher than for those with single-vessel angioplasty, and it appears to be cumulative. The nurse can play an important role in risk-factor modification, teaching, and promoting smooth transitions in life-style changes after patients undergo angioplasty. Through education by the nurse, patients can learn to recognize angina and learn how to seek treatment for recurrence of ischemic symptoms. Lastly, the nurse can play an important role in patient follow-up. This can be done by reinforcing and encouraging patient compliance. Through further research the management and control of recurrence can be better understood.


Resorbable scaffolds from three different techniques: electrospun fabrics, salt-leaching porous films, and smooth flat surfaces.
Nanofibrous scaffolds of poly[(L-lactide)-co-(1,5-dioxepan-2-one)] generated by electrospinning have been compared with porous films obtained by solvent cast/salt leaching and homogeneous films. A comparison between the fibrous materials and the homogeneous solvent-cast films revealed that the surface of the nanofibers was more hydrophobic and that the nanofibers were degraded more rapidly in the presence of proteinase. It was obvious that the strain-to-break was reduced by the nanofiber formation, it decreased from 370% to 130% independent of fiber diameter. These values were however considerably higher than the strain-to-break of the solvent-cast/salt leaching scaffold. In addition, the nanofibrous material accelerated the adhesion and growth of the mesenchymal stem cell compared to the smooth material.


Ruthenium(II) complexes with phosphonate-substituted phenanthroline ligands as reusable photoredox catalysts.
Ru(II) complexes with polypyridyl ligands (2,2'-bipyridine = bpy, 1,10-phenanthroline = phen) play a central role in the development of photocatalytic organic reactions. In this work, we synthesized four mixed-ligand [Ru(phen)(bpy)2]2+-type complexes (Ru-Pcat-A) bearing two phosphonate substituents P(O)(OH)(OR) (R = H, Et) attached to the phen core at positions 3,8 (Ru-3,8PH and Ru-3,8PHEt) and 4,7 (Ru-4,7PH and Ru-4,7PHEt) of the heterocycle in high yields (87-99%) and characterized them using spectral methods. Single crystal X-ray diffraction was employed to determine the coordination mode of the ditopic phen ligand in Ru-4,7PH. This complex exists as the neutral species and forms a 1D hydrogen-bonded framework in the crystals. The light absorption characteristics were found to be similar for all complexes prepared in this work. However, the emission maxima in aqueous solutions were significantly affected by the substitution of the heterocycle, ranging from 629 nm for Ru-4,7PH to 661 nm for Ru-3,8PHEt. The emission quantum yields in Ar-saturated deionized water showed a strong dependence on the substitution pattern of the phen ligand, with maximal values reaching approximately 0.11 for Ru-4,7PHEt and Ru-4,7PH, which is twice as high as that of the classical [Ru(bpy)3]2+ complex (Ru-bpy). The photocatalytic performance of Ru-Pcat-A was investigated using visible light photoredox catalytic transformations of tertiary amines. With Ru-Pcat-A, we achieved the phosphonylation of N-aryl-1,2,3,4-tetrahydroisoquinolines (THIQs) and cyanation of THIQs and N,N-dimethylaniline in methanol, while a mixture of nitromethane/methanol (1 : 1 v/v) proved to be the optimal solvent for conducting the nitromethylation of THIQs. In the majority of the studied reactions, Ru-4,7PHEt exhibited greater efficiency compared to Ru-bpy, and it could be easily separated from the products using water extraction and reused in the next catalytic cycle. We successfully performed seven consecutive nitromethylation and phosphonylation of N-phenyl-1,2,3,4-tetrahydroisoquinoline using the recycled homogeneous photoredox catalyst.


Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.
The isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease. The present study determined the ability of GGDPS inhibition to slow the development of prostate cancer metastasis in a preventative murine model. Using tail vein injection of human derived PC-3 prostate cancer cells 4 d after initiating daily GGOHBP or vehicle treatments, we found GGOHBP significantly reduced whole body tumor burden, significantly slowed the development of tumors, and prolonged overall survival as compared to vehicle treated animals. The observed reduction in soft tissue tumor burden corresponded to a biochemical reduction in Rap1A geranylgeranylation, which for prostate cancer is important in its own merit and which serves as a surrogate marker for Rho family, i.e. Rac, protein modification. This effect was present in all treated mice pointing to strong target engagement, which was not observed in non-tumor burdened tissues or control mice. Our findings reiterate a role for protein geranylgeranylation in the development of prostate cancer metastasis in vivo.


Splenomegaly in Zambia.
In this paper is reported the results of spleen surveys carried out as the opportunity arose in various groups in Zambia during the period January 1965 to October 1968. The lowest spleen rates were found in urban workers and in long stay adults in leprosy and psychiatric hospitals. The highest rates were in rural school children and children in a rural hospital. Intermediate between these groups were adults in an urban and in a rural general hospital.


Organizing Psycho-Oncological Care for Cancer Patients: The Patient's Perspective.
Cancer patients often suffer from psychological distress during or after cancer treatment, but the use of psycho-oncological care among cancer patients is limited. One of the reasons might be that the way psycho-oncological care is organized, does not fit patients' preferences. This study aimed to obtain detailed insight into cancer patients' preferences regarding the organization of psycho-oncological care. 18 semi-structured interviews were conducted among cancer patients. Patients completed psycho-oncological treatment between 2015 and 2020 at the psychology department in a general hospital or a center specialized in psychological cancer care in the Netherlands. The interview comprised questions related to preferences regarding the institute where to receive treatment, the psychologist who provides treatment, and the type of treatment, as well as questions related to experienced barriers and facilitators to receive psycho-oncological care. Interviews were digitally recorded and transcribed verbatim. Data were analyzed individually by two coders into key issues and themes. Regarding the institute, easy accessibility and prompt availability of psychol-oncological care were considered important. Regarding the psychologist, most participants had a strong preference to be treated by a psychologist specialized in cancer or other somatic diseases. Individual face-to-face therapy was preferred above other types of treatment. Several barriers were mentioned to receive psycho-oncological treatment, among which poor accessibility to psycho-oncological care, lack of knowledge on the possibilities for psycho-oncological treatment, and stigma. Most frequently mentioned facilitators were being assertive to ask for help, having a good relationship with the healthcare professional, and the integration of psycho-oncological support within medical cancer care. From the patient's perspective, the organization of psycho-oncological care for cancer patients should focus on easy accessibility and availability, delivered by specialized psychologists, and integration in medical cancer care. Online and group therapy are acceptable, but individual face-to-face therapy is preferred. It is warranted to increase awareness on psycho-oncological care targeting both patients and healthcare providers.


Consecutive salinomycin treatment reduces doxorubicin resistance of breast tumor cells by diminishing drug efflux pump expression and activity.
Chemoresistance is a major challenge for the successful therapy of breast cancer. The discovery of salinomycin as an anticancer stem cell drug provides progress in overcoming chemoresistance. However, it remains to be elucidated whether salinomycin treatment is able to sensitize cancer cells to chemotherapeutic drugs. In the present study, we consecutively treated epithelial MCF-7 and BT-474 breast cancer cells as well as mesenchymal MDA-MB 231 and MDA-MB 436 cells with salinomycin, and analyzed the gene expression of the two prominent multiple drug resistance (MDR) genes, MDR1 and BCRP1. We found that repeated treatment with salinomycin generated resistance against this drug in all cell lines and increased the chemosensitivity towards doxorubicin. Drug efflux pump gene expression and pump activity of MDR1 and BCRP1 were downregulated in almost all cell lines, except for MDR1 in the MDA-MB 231 cells. Consequently, the intracellular doxorubicin accumulation was increased compared to the respective parental cells. Our findings suggest a novel treatment option for MDR tumors by sensitizing these tumors via salinomycin pretreatment.


LiGluR restores visual responses in rodent models of inherited blindness.
Inherited retinal degeneration results from many different mutations in either photoreceptor-specific or nonphotoreceptor-specific genes. However, nearly all mutations lead to a common blinding phenotype that initiates with rod cell death, followed by loss of cones. In most retinal degenerations, other retinal neuron cell types survive for long periods after blindness from photoreceptor loss. One strategy to restore light responsiveness to a retina rendered blind by photoreceptor degeneration is to express light-regulated ion channels or transporters in surviving retinal neurons. Recent experiments in rodents have restored light-sensitivity by expressing melanopsin or microbial opsins either broadly throughout the retina or selectively in the inner segments of surviving cones or in bipolar cells. Here, we present an approach whereby a genetically and chemically engineered light-gated ionotropic glutamate receptor (LiGluR) is expressed selectively in retinal ganglion cells (RGCs), the longest-surviving cells in retinal blinding diseases. When expressed in the RGCs of a well-established model of retinal degeneration, the rd1 mouse, LiGluR restores light sensitivity to the RGCs, reinstates light responsiveness to the primary visual cortex, and restores both the pupillary reflex and a natural light-avoidance behavior.


Lateral sequestration of phosphatidylinositol 4,5-bisphosphate by the basic effector domain of myristoylated alanine-rich C kinase substrate is due to nonspecific electrostatic interactions.
A peptide corresponding to the basic (+13), unstructured effector domain of myristoylated alanine-rich C kinase substrate (MARCKS) binds strongly to membranes containing phosphatidylinositol 4,5-bisphosphate (PIP(2)). Although aromatic residues contribute to the binding, three experiments suggest the binding is driven mainly by nonspecific local electrostatic interactions. First, peptides with 13 basic residues, Lys-13 and Arg-13, bind to PIP(2)-containing vesicles with the same high affinity as the effector domain peptide. Second, removing basic residues from the effector domain peptide reduces the binding energy by an amount that correlates with the number of charges removed. Third, peptides corresponding to a basic region in GAP43 and MARCKS effector domain-like regions in other proteins (e.g. MacMARCKS, adducin, Drosophila A kinase anchor protein 200, and N-methyl-d-aspartate receptor) also bind with an energy that correlates with the number of basic residues. Kinetic measurements suggest the effector domain binds to several PIP(2). Theoretical calculations show the effector domain produces a local positive potential, even when bound to a bilayer with 33% monovalent acidic lipids, and should thus sequester PIP(2) laterally. This electrostatic sequestration was observed experimentally using a phospholipase C assay. Our results are consistent with the hypothesis that MARCKS could reversibly sequester much of the PIP(2) in the plasma membrane.


Phylogeographical insights into the origins of the Squalius alburnoides complex via multiple hybridization events.
The origin, the phylogeographical structure and divergence times of hybridrogenetic Squalius alburnoides complex were analysed based on the complete mitochondrial cytochrome b gene (1140 pb). The molecular phylogenetic analyses suggest that the S. alburnoides complex has at least five asexual lineages of independent origin. The events that produced this ancestral hybridization took place over a long period of time. There have been multiple hybridization events throughout time, beginning in the upper Pliocene and probably continuing into the present. Increased humidity caused by climate changes in the Pliocene, along with tectonic lifting and vasculation of the Iberian Peninsula, led to the formation of current river drainages which, in turn, contributed to these hybridization events. We postulate that the Northwestern (Mondego and Douro) and the Southwest (Quarteira) drainages of the Iberian Peninsula delimited the border of the maternal ancestral distribution and that vicariant events led to the disappearance of the maternal ancestor in these regions, leaving today only the hybrid species. Two hypotheses have been suggested to explain the similarities between the mtDNA diversity observed in S. alburnoides and its maternal ancestor (S. pyrenaicus). The first hypothesizes that mtDNA similarity results from the recent extinction of the paternal ancestor, while the other postulates that: 'reconstituted non hybrid males' assumed the place of the extinct bisexual paternal ancestor and produced new hybridizations with S. pyrenaicus females.