[C677T polymorphism of the methylentetrahydrofolate reductase gene in mothers of children affected with neural tube defects].
Neural tube defects (NTD) are the most common congenital anomalies of the central nervous system, with a multifactorial pattern of inheritance, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene 677C>T polymorphism has been implicated as a risk factor for NTD. The main objective of this research was to investigate the association of the 677C>T polymorphism of the MTHFR gene as a genetic risk factor for NTD. Molecular analysis was performed in DNA samples from 52 mothers with antecedent of NTD offspring and from 119 healthy control mothers. Using the Polymerase Chain Reaction, a 198 bases pairs fragment was digested with the restriction enzyme Hinfi. 677T MTHFR allele frequencies for the problem and the control groups were 51.92% and 34.45%, respectively, and 677C MTHFR allele frequencies were 48.08% and 65.55%, respectively. There were significant differences in allele (p: 0.002) and genotype (p: 0.007) frequencies between these two groups. The odds ratio (OR) to the TT genotype vs. the CC genotype was estimated as OR: 4.9 [95% CI: 1,347-6.416] p: 0.002; CT+TT vs. CC: OR: 2.9 [95% CI: 1.347-6.416] p: 0.005; TT vs. CT+CC: OR: 2.675 [95% CI: 1,111-6.441] p: 0.024. The data presented in this study support the relationship between MTHFR 677C>T polymorphism and risk in mothers with antecedent of NTD offspring.


Information theoretic limits to the capacity of volume holographic optical memory.
We derive the information theoretic limit to storage capacity in volume holographic optical memories for the limiting cases of dominant intensity noise (Gaussian noise) and dominant field noise (Rician noise). These capacity bounds are compared with the performance achievable using simple Reed-Solomon error-correcting codes.


Structural perturbations in DNA caused by bis-intercalation of ditercalinium visualised by atomic force microscopy.
Atomic force microscopy (AFM) has been used to examine perturbations in the tertiary structure of DNA induced by the binding of ditercalinium, a DNA bis-intercalator with strong anti-tumour properties. We report AFM images of plasmid DNA of both circular and linearised forms showing a difference in the formation of supercoils and plectonemic coils caused at least in part by alterations in the superhelical stress upon bis-intercalation. A further investigation of the effects of drug binding performed with 292 bp mixed-sequence DNA fragments, and using increment in contour length as a reliable measure of intercalation, revealed saturation occurring at a point where sufficient drug was present to interact with every other available binding site. Moment analysis based on the distribution of angles between segments along single DNA molecules showed that at this level of bis-intercalation, the apparent persistence length of the molecules was 91.7 +/- 5.7 nm, approximately twice as long as that of naked DNA. We conclude that images of single molecules generated using AFM provide a valuable supplement to solution-based techniques for evaluation of physical properties of biological macromolecules.


Improved method for single-bolus kinetic measurements using a noncleared reference indicator.
After intravenous injection of a tracer as a single bolus, its concentration decreases as it mixes with the plasma, disperses throughout the circulation, and enters body pools. Kinetic values that are dependent on early concentrations may be in considerable error because mixing is not instantaneous throughout the circulation, and this problem is particularly acute in the mammalian fetus, with its distinctive circulatory pattern. To minimize this error, a method was developed in which the noncleared reference tracer 125I-labeled albumin was injected together with a representative, rapidly cleared metabolite 14C-labeled palmitic acid, and the former was used to correct for mixing delay. A total of 19 disappearance curves were studied after intravenous injection into seven near-term fetal sheep. Kinetic values were calculated with and without correction for mixing delay. Taking account of mixing delay increased the calculated volume of distribution 41% [from 44 +/- 4 (SE) to 62 +/- 3 ml/kg, P < 0.001], increased plasma clearance rate 13% (from 41 +/- 2 to 47 +/- 1 ml-min-1.kg-1, P < 0.002), decreased the rate constant for irreversible loss 26% (from 1.05 +/- 0.07 to 0.78 +/- 0.04 min-1, P < 0.001), and increased the calculated effective half-life 26% (0.71 +/- 0.06 to 0.90 +/- 0.05 min, P < 0.001). Thus use of the additional reference marker significantly altered calculated results and provided values believed to more accurately describe rapid disappearance from the central mixing compartment into metabolic pools.


[Hyperinsulinism probably caused by diffuse pancreatic hyperplasia].
A case history of a two years seven months old boy with hyperinsulinism and marked psychomotor retardation is presented. In this patient, biochemical analysis revealed persistent hypoglycemia. Basal insulin levels (RIA) were consistently superior to 10 mU/ml. and were higher than would be expected from the child's glycemias. Angiographic study of the celiac trunk revealed diffuse pancreatic enlargement. Therapy was initiated with oral diazoxide normalizing and stabilizing the patient's glycemia. The importance of an early diagnosis of this condition and the necessary biochemical analyses involved are discussed as well as the use of diazoxide in the medical treatment of hypoglycemia.


Comparative values of CSF-LDH isoenzymes in neurological disorders.
The present study was carried out to evaluate the usefulness of Cerebrospinal fluid (CSF) Lactate dehydrogenase (LDH) isoenzymes in the diagnosis in tuberculous meningitis (TBM), pyogenic meningitis (PM), viral encephalitis (VE) and hydrocephalus (HC). A characteristic dominance of isoenzymes in cerebrospinal fluid was observed: LDH4 in TBM while LDH3 in PM. However, in VE and HC, LDH2 and LDH1 were dominant respectively. The control subjects revealed the presence of isoenzymes LDH1 and LDH2 in very low concentrations. Pattern of LDH isoenzymes in CSF may serve as a diagnostic tool to differentiate these neurological disorders.


Connexins as therapeutic targets in lung disease.
The lung is a mechanically active system exposed to the external environment and is particularly sensitive to injury and inflammation. Studies have identified intercellular communication pathways that promote proper lung function in response to injury and disease. These pathways involve connexins (Cxs) and gap junctional intercellular communication (GJIC). The functional expression of Cxs in airway epithelium and vasculature, under normal and pathological conditions, is reviewed. Inhibition of GJIC and/or silencing of Cxs have been shown to modulate the course of disease development. Cx-based channels: i) coordinate ciliary beating and fluid transport to promote clearance of particulates, ii) regulate secretion of pulmonary surfactant, in response to deep inhalation by interconnecting type I and type II alveolar epithelial cells, and iii) are key mediators of pro- and anti-inflammatory signalling by the pulmonary endothelium, in order to modulate leukocyte recruitment from the circulation. Cx-based channels play several central roles in promoting a regulated inflammatory response and facilitating lung repair, thus enabling the pulmonary epithelium and vasculature to behave as integrated systems. Several pathologies can disrupt the normal communication pathways required for proper lung function, including acute lung injury, asthma, cystic fibrosis, pulmonary fibrosis and cancer.


High mobility group box chromosomal protein 1 in patients with renal diseases.
The high mobility group box chromosomal protein 1 (HMGB1), a nuclear DNA-binding protein, has recently been recognized as a new proinflammatory cytokine. The purpose of this study was to examine the significance of HMGB1 in patients with renal diseases. HMGB1 concentrations in sera were measured by enzyme-linked immunosorbent assay, and antibodies against HMGB1 were examined by Western blotting in patients who underwent renal biopsies and in healthy controls. Immunohistochemistry for HMGB1 was also performed. Serum HMGB1 was more likely to be positive in patients who underwent renal biopsies as compared with the controls. Patients with anti-neutrophil cytoplasmic antibody-related glomerulonephritis (ANCA-GN) and those with Henoch-Schonlein purpura nephritis showed a significantly higher tendency to be HMGB1 positive. The presence of anti-HMGB1 antibody was not associated with the presence of serum HMGB1. Immunohistochemistry revealed that HMGB1 was expressed in mononuclear cells in the interstitium or in the glomeruli of some patients with ANCA-GN or IgA nephropathy (IgAN). Subanalysis demonstrated that among patients with IgAN, those who had crescent formation showed a higher tendency to be HMGB1 positive than those who did not. HMGB1 was expressed in the sera of patients with renal diseases who underwent renal biopsies, especially among those who had vasculitis including ANCA-GN, Henoch-Schonlein purpura nephritis, and IgAN with glomerular crescents.


Spatiotemporal Analysis of Extracted Groundwater Volumes Estimated from Electricity Consumption.
Land subsidence caused by groundwater overexploitation is a serious global problem. The acquisition of spatiotemporal pumping rates and volumes is a first step for water managers to develop a strategic plan for mitigating land subsidence. This study investigates an empirical formulation to estimate the monthly maximum pumped volume over a 10-year period based on electric power consumption data. A spatiotemporal variability analysis of monthly pumped volume is developed to provide an improved understanding of seasonal pumping patterns and the role of irrigation type. The analysis of regional pumped volume provides an approximation of the spatiotemporal patterns of the variations in pumped volume. Results show the effects of climate, seasonal changes in pumping from irrigation, and the local differences in pumping caused to crop types. A seasonal pumped volume peak occurs annually, with the highest and least pumped volumes occurring in March (highest peak) and September (lowest peak), respectively. However, the majority of the historical maximum pumped volumes have occurred during the last few years. Extracted volumes continue to increase in some locations. The analysis reveals increasing trends in pumping, thereby possibly providing the locations where increased effective stresses may lead to land subsidence.


Understanding complex interactions using social network analysis.
The aim of this paper is to raise the awareness of social network analysis as a method to facilitate research in nursing research. The application of social network analysis in assessing network properties has allowed greater insight to be gained in many areas including sociology, politics, business organisation and health care. However, the use of social networks in nursing has not received sufficient attention. Review of literature and illustration of the application of the method of social network analysis using research examples. First, the value of social networks will be discussed. Then by using illustrative examples, the value of social network analysis to nursing will be demonstrated. The method of social network analysis is found to give greater insights into social situations involving interactions between individuals and has particular application to the study of interactions between nurses and between nurses and patients and other actors. Social networks are systems in which people interact. Two quantitative techniques help our understanding of these networks. The first is visualisation of the network. The second is centrality. Individuals with high centrality are key communicators in a network. Applying social network analysis to nursing provides a simple method that helps gain an understanding of human interaction and how this might influence various health outcomes. It allows influential individuals (actors) to be identified. Their influence on the formation of social norms and communication can determine the extent to which new interventions or ways of thinking are accepted by a group. Thus, working with key individuals in a network could be critical to the success and sustainability of an intervention. Social network analysis can also help to assess the effectiveness of such interventions for the recipient and the service provider.


[Effect of carbostimulin on acid-base equilibrium of the blood of racing horses during exertion].
The paper deals with possibility to regulate in a proper direction the acid-base state in race horse blood administering carbostimulin at rest and under physical exercises. The preparation is shown to favour an increase in alkaline blood reserves in race hours at rest and to prevent acidotic changes caused by physical exercises. The results obtained show a promising use of carbostimulin for the directed correction of the acid-base state of blood in race horses aimed at increasing the efficiency of the training process.


Cross-talk free and ultra-compact fiber optic sensor for simultaneous measurement of temperature and refractive index.
We propose and demonstrate a cross-talk free simultaneous measurement system for temperature and external refractive index (ERI) implemented by dual-cavity Fabry-Perot (FP) fiber interferometer. The sensing probe consists of two cascaded FP cavities formed with a short piece of multimode fiber (MMF) and a micro-air-gap made of hollow core fiber (HOF). The fabricated sensor head was ultra-compact; the total length of the sensing part was less than 600 mum. Since the reflection spectrum of the composite FP structures is given by the superposition of each cavity spectrum, the spectrum measured in the wavelength domain was analyzed in the Fourier or spatial frequency domain. The experimental results showed that temperature could be determined independently from the spatial frequency shift without being affected by the ERI, while the ERI could be also measured solely by monitoring the intensity variation in the spatial frequency spectrum. The ERI and the temperature sensitivities were approximately 16 dB/RIU for the 1.33-1.45 index range, and 8.9 nm/ degrees C at low temperature and 14.6 nm/ degrees C at high temperature, respectively. In addition, it is also demonstrated that the proposed dual-cavity FP sensor has potential for compensating any power fluctuation that might happen in the input light source.


Spine fusion for discogenic low back pain: outcomes in patients treated with or without pulsed electromagnetic field stimulation.
Sixty-one randomly selected patients who underwent lumbar fusion surgeries for discogenic low back pain between 1987 and 1994 were retrospectively studied. All patients had failed to respond to preoperative conservative treatments. Forty-two patients received adjunctive therapy with pulsed electromagnetic field (PEMF) stimulation, and 19 patients received no electrical stimulation of any kind. Average follow-up time was 15.6 months postoperatively. Fusion succeeded in 97.6% of the PEMF group and in 52.6% of the unstimulated group (P < .001). The observed agreement between clinical and radiographic outcome was 75%. The use of PEMF stimulation enhances bony bridging in lumbar spinal fusions. Successful fusion underlies a good clinical outcome in patients with discogenic low back pain.


Acute effects of nebulised epoprostenol in pulmonary hypertension due to systemic sclerosis.
Pulmonary hypertension often has a lethal outcome in systemic sclerosis and the treatment is challenging. Epoprostenol is a potent pulmonary vasodilator and its efficacy has been demonstrated when delivered by the intravenous and aerosolized routes. We report the haemodynamic and functional benefits of epoprostenol administered by inhalation to a spontaneously breathing patient with partially reversible pulmonary hypertension due to systemic sclerosis. Aerosolized epoprostenol, equivalent to the maximum tolerated intravenous dose (31.2 micrograms), produced a 58% fall in pulmonary vascular resistance, increased the cardiac output by 42% and improved functional performance by one MET (3.5 ml kg-1 min-1 of oxygen uptake) without any significant side-effects. Selective distribution of epoprostenol by the inhaled route may offer a new strategy for treatment of pulmonary hypertension.


Arrest defective 1 autoacetylation is a critical step in its ability to stimulate cancer cell proliferation.
The N-acetyltransferase arrest defective 1 (ARD1) is an important regulator of cell growth and differentiation that has emerged recently as a critical molecule in cancer progression. However, the regulation of the enzymatic and biological activities of human ARD1 (hARD1) in cancer is presently poorly understood. Here, we report that hARD1 undergoes autoacetylation and that this modification is essential for its functional activation. Using liquid chromatography-tandem mass spectrometry and site-directed mutational analyses, we identified K136 residue as an autoacetylation target site. K136R mutation abolished the ability of hARD1 to promote cancer cell growth in vitro and tumor xenograft growth in vivo. Mechanistic investigations revealed that hARD1 autoacetylation stimulated cyclin D1 expression through activation of the transcription factors beta-catenin and activator protein-1. Our results show that hARD1 autoacetylation is critical for its activation and its ability to stimulate cancer cell proliferation and tumorigenesis.


Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.
We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.


Molecular mechanism underlying Akt activation in zinc-induced cardioprotection.
Our previous study demonstrated that zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via Akt and glycogen synthetase kinase 3beta (GSK-3beta). We aimed to address the mechanism by which zinc activates Akt. Treatment of H9c2 cells with ZnCl(2) (10 microM) in the presence of the zinc ionophore pyrithione (4 microM) for 20 min enhanced Akt phosphorylation (Ser(473)), indicating that zinc can rapidly activate Akt. Zinc did not alter either phosphatase and tensin homolog deleted on chromosome 10 (PTEN) phosphorylation and total PTEN protein levels or PTEN oxidation, implying that PTEN may not play a role in the action of zinc. However, zinc-induced Akt phosphorylation was blocked by both the nonselective receptor tyrosine kinase (RTK) inhibitor genistein and the selective insulin-like growth factor-1 RTK (IGF-1RTK) inhibitor AG1024, indicating that zinc activates Akt via IGF-1RTK. Zinc-induced phosphorylation of protein tyrosine and Ser/Thr was also abolished by AG1024. In addition, zinc markedly enhanced phosphorylation of IGF-1 receptor (IGF-1R), which was again reversed by genistein and AG1024. A confocal imaging study revealed that AG1024 abolished the preventive effect of zinc on oxidant-induced mPTP opening, confirming that IGF-1RTK plays a role in zinc-induced cardioprotection. Furthermore, zinc decreased the activity of protein phosphatase 2A (PP2A), a major protein Ser/Thr phosphatase, implying that protein Ser/Thr phosphatases may also play a role in the action of zinc on Akt activity. Taken together, these findings demonstrate that exogenous zinc activates Akt via IGF-1RTK and prevents the mPTP opening in cardiac cells. Inactivation of Ser/Thr protein phosphatases may also contribute to zinc-induced Akt activation.


Cbp80 is needed for the expression of piRNA components and piRNAs.
Cap binding protein 80 (Cbp80) is the larger subunit of the nuclear cap-binding complex (nCBC), which is known to play important roles in nuclear mRNA processing, export, stability and quality control events. Reducing Cbp80 mRNA levels in the female germline revealed that Cbp80 is also involved in defending the germline against transposable elements. Combining such knockdown experiments with large scale sequencing of small RNAs further showed that Cbp80 is involved in the initial biogenesis of piRNAs as well as in the secondary biogenesis pathway, the ping-pong amplification cycle. We further found that Cbp80 knockdown not only led to the upregulation of transposons, but also to delocalization of Piwi, Aub and Ago3, key factors in the piRNA biosynthesis pathway. Furthermore, compared to controls, levels of Piwi and Aub were also reduced upon knock down of Cbp80. On the other hand, with the same treatment we could not detect significant changes in levels or subcellular distribution (nuage localization) of piRNA precursor transcripts. This shows that Cbp80 plays an important role in the production and localization of the protein components of the piRNA pathway and it seems to be less important for the production and export of the piRNA precursor transcripts.


Central pontine myelinolysis secondary to hypokalaemic nephrogenic diabetes insipidus.
Central pontine myelinolysis (CPM) has been described in alcoholic patients and in the aftermath of rapid correction of chronic hyponatraemia. We describe a case of CPM occurring secondary to nephrogenic diabetes insipidus (DI), which developed as a consequence of severe hypokalaemia. A 63-year-old man with alcohol dependence was admitted to hospital with severe pulmonary sepsis and type 1 respiratory failure. On admission, he had euvolaemic hyponatraemia of 127 mmol/L, consistent with a syndrome of inappropriate antidiuretic hormone secondary to his pneumonia. Following admission, his plasma potassium dropped from 3.2 to a nadir of 2.3 mmol/L. Mineralocorticoid excess, ectopic adrenocorticotrophic hormone production and other causes of hypokalaemia were excluded. The hypokalaemia provoked significant hypotonic polyuria and a slow rise in plasma sodium to 161 mmol/L over several days. Plasma glucose, calcium and creatinine were normal. The polyuria did not respond to desmopressin, and subsequent correction of his polyuria and hypernatraemia after normalization of plasma potassium confirmed the diagnosis of nephrogenic DI due to hypokalaemia. The patient remained obtunded, and the clinical suspicion of osmotic demyelination was confirmed on magnetic resonance imaging. The patient remained comatose and passed away 10 days later. This is the first reported case of nephrogenic DI resulting in the development of CPM, despite a relatively slow rise in plasma sodium of less than 12 mmol/L/24 h. Coexisting alcohol abuse, hypoxaemia and hypokalaemia may have contributed significantly to the development of CPM in this patient.


Transcranial ultrafast ultrasound localization microscopy of brain vasculature in patients.
Changes in cerebral blood flow are associated with stroke, aneurysms, vascular cognitive impairment, neurodegenerative diseases and other pathologies. Brain angiograms, typically performed via computed tomography or magnetic resonance imaging, are limited to millimetre-scale resolution and are insensitive to blood-flow dynamics. Here we show that ultrafast ultrasound localization microscopy of intravenously injected microbubbles enables transcranial imaging of deep vasculature in the adult human brain at microscopic resolution and the quantification of haemodynamic parameters. Adaptive speckle tracking to correct for micrometric brain-motion artefacts and ultrasonic-wave aberrations induced during transcranial propagation allowed us to map the vascular network of tangled arteries to functionally characterize blood-flow dynamics at a resolution of up to 25 μm and to detect blood vortices in a small deep-seated aneurysm in a patient. Ultrafast ultrasound localization microscopy may facilitate the understanding of brain haemodynamics and of how vascular abnormalities in the brain are related to neurological pathologies.


Genome-based analysis of the transcriptome from mature chickpea root nodules.
Symbiotic nitrogen fixation (SNF) in root nodules of grain legumes such as chickpea is a highly complex process that drastically affects the gene expression patterns of both the prokaryotic as well as eukaryotic interacting cells. A successfully established symbiotic relationship requires mutual signaling mechanisms and a continuous adaptation of the metabolism of the involved cells to varying environmental conditions. Although some of these processes are well understood today many of the molecular mechanisms underlying SNF, especially in chickpea, remain unclear. Here, we reannotated our previously published transcriptome data generated by deepSuperSAGE (Serial Analysis of Gene Expression) to the recently published draft genome of chickpea to assess the root- and nodule-specific transcriptomes of the eukaryotic host cells. The identified gene expression patterns comprise up to 71 significantly differentially expressed genes and the expression of twenty of these was validated by quantitative real-time PCR with the tissues from five independent biological replicates. Many of the differentially expressed transcripts were found to encode proteins implicated in sugar metabolism, antioxidant defense as well as biotic and abiotic stress responses of the host cells, and some of them were already known to contribute to SNF in other legumes. The differentially expressed genes identified in this study represent candidates that can be used for further characterization of the complex molecular mechanisms underlying SNF in chickpea.


YAP4 gene expression is induced in response to several forms of stress in Saccharomyces cerevisiae.
Exposure of Saccharomyces cerevisiae to several environmental insults, including conditions of oxidative, heavy metal, metalloid and heat stress, induces the expression of the YAP4 gene, previously shown to play a role in the response to hyperosmotic stress. Expression analyses in several mutant strains under pro-oxidant conditions have determined that YAP4 is regulated by the transactivators Yap1p and Msn2p. Mutation of either the Yap1p-response element (YRE), located at - 517 bp from the ATG, or the most proximal stress response element (STRE) at -430 bp, is shown to strongly compromise YAP4 gene expression under these conditions. Furthermore, these two mutations in combination lead to a severe depletion of detectable mRNA levels, indicating interplay between the transcription factors Yap1p and Msn2p in the regulation of YAP4 transcription. Transcriptional activation of this gene reflects a concomitant increase in Yap4p protein levels that appear phosphorylated upon stress and negatively regulated by protein kinase A. Yap4p amino acid residues Ser89, Ser196 and Thr241 are shown to be required for protein phosphorylation and/or protein stability.


DnaK from Bifidobacterium animalis subsp. lactis is a surface-exposed human plasminogen receptor upregulated in response to bile salts.
Bifidobacterium animalis subsp. lactis lives in the gastrointestinal tract of most mammals, including humans. Recently, for the probiotic strain B. animalis subsp. lactis BI07, a dose-dependent plasminogen-binding activity was demonstrated and five putative plasminogen-binding proteins were identified. Here we investigated the role of surface DnaK as a B. animalis subsp. lactis BI07 plasminogen receptor. DnaK was visualized on the bacterial cell surface by transmission electron microscopy. The His-tagged recombinant DnaK protein showed a high affinity for human plasminogen, with an equilibrium dissociation constant in the nanomolar range. The capability to tolerate physiological concentrations of bile salts is a crucial feature for an intestinal symbiont micro-organism. By proteome analysis we demonstrated that the long-term exposure of B. animalis subsp. lactis BI07 to bile salts results in the upregulation of important surface plasminogen receptors such as DnaK and enolase. Moreover, adaptation of B. animalis subsp. lactis BI07 to physiological concentrations of bile salts significantly increased its capacity to interact with the host plasminogen system. By enhancing the bacterial capacity to interact with the host plasminogen, the gut bile environment may facilitate the colonization of the human host by B. animalis subsp. lactis BI07.


Do gender, disability, and morbidity affect aging rate in the LLFS? Application of indices of cumulative deficits.
We used an approach of cumulative deficits to evaluate the rate of aging in 4954 participants of the Long-Life Family Study (LLFS) recruited in the U.S. (Boston, New York, and Pittsburgh) and Denmark. We used an array of 85 health-related deficits covering major health dimensions including depression, cognition, morbidity, physical performance, and disability to construct several deficit indices (DIs) with overlapping and complementary sets of deficits to test robustness of the estimates. Our study shows that the DIs robustly characterize accelerated rates of aging irrespective of specific of deficits. When a wider spectrum of health dimensions is considered these rates are better approximated by quadratic law. Exponential rates are more characteristic for more severe health dimensions. The aging rates are the same for males and females. Individuals who contracted major diseases and those who were free of them exhibited the same aging rates as characterized by the DI constructed using mild deficits. Unlike health, disability can qualitatively alter the aging patterns of the LLFS participants. We report on systemic differences in health among the LLFS centenarians residing in New York and Boston. This study highlights importance of aggregated approaches to better understand systemic mechanisms of health deterioration in long-living individuals.


Molecular cloning and characterization of Xenopus insulin-like growth factor-1 receptor: its role in mediating insulin-induced Xenopus oocyte maturation and expression during embryogenesis.
We have cloned a complementary DNA encoding the putative Xenopus insulin-like growth factor-1 (xIGF-1) receptor. Injection of messenger RNA derived from the cloned complementary DNA into Xenopus oocytes resulted in the expression and correct processing of the receptor's alpha- and beta-subunits. Using antibodies generated against protein expressed against the cloned sequence, we demonstrated that the endogenous xIGF-1 receptor in Xenopus oocytes was activated by nanomolar concentrations of mammalian IGF-1 and by insulin approximately 100-fold higher in concentration. This receptor activation profile correlated with hormone-induced Xenopus oocyte maturation. Furthermore, injection of a neutralizing antiinsulin receptor antibody into Xenopus oocytes inhibited hormone-induced xIGF-1 receptor activation. These results provide molecular and biochemical evidence supporting a role for xIGF-1 receptor in mediating insulin/IGF-1-induced Xenopus oocyte maturation. We also report here that embryonic transcription of xIGF-1 receptor is activated during the formation of the central nervous system in early Xenopus embryos.


[Quantitative analysis of morphological manifestations of cholesterosis and concomitant pathology of the gall bladder].
Morphological study of 345 cholecytectomies revealed gall bladder cholesterosis in 173 cases. Network form of cholesterosis was most frequent (73.8%), polyposis-network was in 18.5% and only 8.7% polypoid form of cholesterosis was found. The frequency was similar in males and females, the polypoid form prevailed in males, reticular form in females. Main site of cholesterosis was the gall bladder body. Combination of cholesterosis with cholelithiasis was in 151 cases (87.3%), adenomyomatosis occurred in 33 patients (19%). Cholesterol polyps were found in 47 patients, in 30 of them they were multiple. The size of cholesterol polyps varied from 2 to 17 mm. For the first time mixed glandual-cholesterol polyps are described. Morphological picture of xanthogranulomatous cholecystitis was in 7 patients. The morphological difference between foam and xanthome cells is presented.


Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review.
Erythropoietin is being used more widely in the management of sickle cell disease (SCD, inclusive of homozygous sickle beta, SS, and compound heterozygous sickle beta thalassemia, Sbeta0 thal), often in conjunction with hydroxyurea (HU). Herein, we summarize the published experience with erythropoietin use in SCD, in 39 patients (SS, n = 30; Sb0 thal, n = 9) who were treated between 1990 and 1996; and in 13 patients with sickle syndromes (SS, n = 12, compound heterozygous SC disease, n = 1) who were treated with erythropoietin or darbepoietin at the National Institutes of Health (NIH) since 2002. The dose range of erythropoietin for SCD in the published series, at a median of > 200 U/Kg/dose, is higher than that used in end-stage renal disease. The median duration of erythropoietin therapy was > or =3 months, with minimal reported side-effects. At the NIH, the median age of sickle syndrome patients who received erythropoietin or darbepoietin (both referred to as EPO in the NIH series) was 51 (24 to 70) years; 12/13 patients had sickle-associated pulmonary hypertension. Eleven out of the 13 patients were treated with both HU and EPO for > 4 months (median of 11 months on EPO) without complication. Of the 13 patients, five (all SS) with pulmonary hypertension were given EPO for reticulocytopenia (< 100,000/mL) on HU; 5/13 patients (all SS), with pulmonary hypertension, were given EPO and HU concurrently, in the light of an estimated glomerular filtration rate of < 80 mL/minute. Three of the 13 patients (2 SS, 1 SC) were treated with EPO for miscellaneous reasons. Hematologic responses, detailed herein, suggest that EPO therapy may allow more aggressive HU dosing in high-risk SCD patients and in the setting of mild renal insufficiency, common to the aging sickle cell population. Furthermore EPO appears to be safe in SCD, particularly when used in conjunction with HU. We outline our current therapeutic strategy for EPO use in SCD.


Hornbills can distinguish between primate alarm calls.
Some mammals distinguish between and respond appropriately to the alarm calls of other mammal and bird species. However, the ability of birds to distinguish between mammal alarm calls has not been investigated. Diana monkeys (Cercopithecus diana) produce different alarm calls to two predators: crowned eagles (Stephanoaetus coronatus) and leopards (Panthera pardus). Yellow-casqued hornbills (Ceratogymna elata) are vulnerable to predation by crowned eagles but are not preyed on by leopards and might therefore be expected to respond to the Diana monkey eagle alarm call but not to the leopard alarm call. We compared responses of hornbills to playback of eagle shrieks, leopard growls, Diana monkey eagle alarm calls and Diana monkey leopard alarm calls and found that they distinguished appropriately between the two predator vocalizations as well as between the two Diana monkey alarm calls. We discuss possible mechanisms leading to these responses.


Enhanced mitochondrial dysfunction and oxidative stress in the mammary gland of cows with clinical ketosis.
Ketosis is a common metabolic disorder in high-producing dairy cows during the peripartal period. Negative energy balance leads to increased circulating levels of nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHB), consequently increasing the risk of ketosis. It is well-known that NEFA and BHB can induce lipotoxicity and oxidative stress in bovine tissues/organs including the liver and adipose tissue. Although the mammary gland is one important site for NEFA and BHB metabolism, whether an overload in their concentrations within mammary cells causes oxidative stress during ketosis remains unclear. Thus, the present study compared oxidative stress status and mitochondrial function in mammary tissues harvested by biopsy from healthy (n = 15) and clinically ketotic (n = 15) dairy cows within 2 to 3 wk postpartum. Compared with healthy cows, ketotic cows had depressed daily milk yield (median: 28.92 vs. 21.56 kg) and dry matter intake (median: 22.36 vs. 19.92 kg/d), accompanied by elevated plasma NEFA (median: 0.32 vs. 1.26 mM), BHB (median: 0.52 vs. 3.69 mM), and lower plasma glucose (median: 4.55 vs. 2.13 mM). As detected by a commercial kit, a greater level of reactive oxygen species in mammary epithelial cells of ketotic cows, and greater oxidant indices including hydrogen peroxide and malondialdehyde coupled with lower antioxidant indices including glutathione peroxidase, catalase, and superoxide dismutase activities as detected by the respective biochemical kits in the homogenate of mammary tissue of ketotic cows indicated increased oxidative stress status. Lower citrate synthase activity and ATP production as detected by the respective commercial kits coupled with lower mRNA and protein abundance of mitochondrial respiratory chain oxidative phosphorylation complexes I-V (CO I-V) in ketotic cows suggested an impairment of mitochondrial function. This was supported by lower mRNA and protein abundance of nucleus-derived mitochondrial function regulators including peroxisome proliferator activated receptor gamma coactivator 1 α, mitofusin 2, nuclear respiratory factor 1, and mitochondrial transcription factor A. Lower mitochondrial membrane potential evaluated via the tetraethylbenzimidazolylcarbocyanine iodide (JC-1) labeling method and swollen mitochondria in mammary epithelial cells of ketotic cows suggested the existence of mitochondrial damage. Overall, the present study revealed extensive mitochondrial dysfunction and oxidative stress in the mammary gland of clinically ketotic cows. As such, data suggest that reduced milk yield in cows with ketosis is partly due to enhanced oxidative stress along with mitochondrial dysregulation in the mammary gland.


Pest protection conferred by a Beta vulgaris serine proteinase inhibitor gene.
Proteinase inhibitors provide a means of engineering plant resistance to insect pests. A Beta vulgaris serine proteinase inhibitor gene (BvSTI) was fused to the constitutive CaMV35S promoter for over-expression in Nicotiana benthamiana plants to study its effect on lepidopteran insect pests. Independently derived BvSTI transgenic tobacco T2 homozygous progeny were shown to have relatively high BvSTI gene transcript levels. BvSTI-specific polyclonal antibodies cross-reacted with the expected 30 kDA recombinant BvSTI protein on Western blots. In gel trypsin inhibitor activity assays revealed a major clear zone that corresponded to the BvSTI proteinase inhibitor that was not detected in the untransformed control plants. BvSTI-transgenic plants were bioassayed for resistance to five lepidopteran insect pests. Spodoptera frugiperda, S. exigua and Manduca sexta larvae fed BvSTI leaves had significant reductions in larval weights as compared to larvae fed on untransformed leaves. In contrast, larval weights increased relative to the controls when Heliothis virescens and Agrotis ipsilon larvae were fed on BvSTI leaves. As the larvae entered the pupal stage, pupal sizes reflected the overall larval weights. Some developmental abnormalities of the pupae and emerging moths were noted. These findings suggest that the sugar beet BvSTI gene may prove useful for effective control of several different lepidopteran insect pests in genetically modified tobacco and other plants. The sugar beet serine proteinase inhibitor may be more effective for insect control because sugar beet is cropped in restricted geographical areas thus limiting the exposure of the insects to sugar beet proteinase inhibitors and build up of non-sensitive midgut proteases.


Comparative efficacy of short-acting and long-acting quinidine for maintenance of sinus rhythm after electrical conversion of atrial fibrillation.
Forty patients with chronic atrial fibrillation, apparently unrelated to any overt heart disease, were randomly allocated to two groups after restoration of sinus rhythm by direct current shock. The patients in group A were given 4 daily doses of quinidine polygalacturonate, while those in group B were given 2 daily doses of a long-acting quinidine preparation, quinidine arabogalactan sulphate. The percentage of early relapses (within the first month following DC shock) was not significantly different in the two groups: 44-4% in group A and 35% in group B (P greater than 0-50). On the other hand, there were fewer late relapses with long-acting quinidine. After 18 months of treatment, 27-8% of patient in group A remained in sinus rhythm, compared with 61% in group B (P less than 0-05). The average amount of quinidine actually ingested by the patients in group A was smaller than that in group B. However, this could not entirely account for the difference observed in the incidence of relapse since with short-acting quinidine the proportion of patients remaining in sinu rhythm was similar whether the dose was decreased or not. The incidence of gastrointestinal side-effects was the same in the two groups and there were no seriou complications that could be attributed to treatment. It is concluded that long-acting quinidine preparations are more effective than conventional quinidine in preventing late relapses of atrial fibrillation.


Grapevine Microbiota Reflect Diversity among Compartments and Complex Interactions within and among Root and Shoot Systems.
Grafting connects root and shoot systems of distinct individuals, bringing microbial communities of different genotypes together in a single plant. How do root system and shoot system genotypes influence plant microbiota in grafted grapevines? To address this, we utilized clonal replicates of the grapevine 'Chambourcin', growing ungrafted and grafted to three different rootstocks in three irrigation treatments. Our objectives were to (1) characterize the microbiota (bacteria and fungi) of below-ground compartments (roots, adjacent soil) and above-ground compartments (leaves, berries), (2) determine how rootstock genotype, irrigation, and their interaction influences grapevine microbiota in different compartments, and (3) investigate abundance of microorganisms implicated in the late-season grapevine disease sour rot (Acetobacterales and Saccharomycetes). We found that plant compartment had the largest influence on microbial diversity. Neither rootstock genotype nor irrigation significantly influenced microbial diversity or composition. However, differential abundance of bacterial and fungal taxa varied as a function of rootstock and irrigation treatment; in particular, Acetobacterales and Saccharomycetes displayed higher relative abundance in berries of grapevines grafted to '1103P' and 'SO4' rootstocks and varied across irrigation treatments. This study demonstrates that grapevine compartments retain distinct microbiota and identifies associations between rootstock genotypes, irrigation treatment, and the relative abundance of agriculturally relevant microorganisms in the berries.


Tissue transgluaminase 2 expression in meningiomas.
Meningiomas are common intracranial tumors that occur in extra-axial locations, most often over the cerebral convexities or along the skull-base. Although often histologically benign these tumors frequently present challenging clinical problems. Primary clinical management of patients with symptomatic tumors is surgical resection. Radiation treatment may arrest growth or delay recurrence of these tumors, however, meningioma cells are generally resistant to apoptosis after treatment with radiation. Tumor cells are known to alter their expression of proteins that interact in the ECM to provide signals important in tumor progression. One such protein, fibronectin, is expressed in elevated levels in the ECM in a number of tumors including meningiomas. We recently reported that levels of both extracellular fibronectin and tissue transglutaminase 2 (TG2) were increased in glioblastomas. We examined the expression of fibronectin and its association TG2 in meningiomas. Both fibronectin and TG2 were strongly expressed in all meningiomas studied. TG2 activity was markedly elevated in meningiomas, and TG2 was found to co-localize with fibronectin. Treatment of meningiomas with the small molecule TG2 inhibitor, KCC009, inhibited the binding of TG2 to fibronectin and blocked disposition of linear strands of fibronectin in the ECM. KCC009 treatment promoted apoptosis and enhanced radiation sensitivity both in cultured IOMM-Lee meningioma cells and in meningioma tumor explants. These findings support a potential protective role for TG2 in meningiomas.


Worry About Daily Financial Needs and Food Insecurity Among Cancer Survivors in the United States.
A cancer diagnosis can impose substantial medical financial burden on individuals and may limit their ability to work. However, less is known about worry for nonmedical financial needs and food insecurity among cancer survivors. The National Health Interview Survey (2013-2017) was used to identify cancer survivors (age 18-39 years, n=771; age 40-64 years, n=4,269; age ≥65 years, n=7,101) and individuals without a cancer history (age 18-39 years, n=53,262; age 40-64 years, n=60,141; age ≥65 years, n=30,261). For both cancer survivors and the noncancer group, adjusted proportions were generated for (1) financial worry ("very/moderately/not worried") about retirement, standard of living, monthly bills, and housing costs; and (2) food insecurity ("often/sometimes/not true") regarding whether food would run out, the fact that food bought did not last, and the inability to afford balanced meals. Further adjusted analyses examined intensity measures ("severe/moderate/minor or none") of financial worry and food insecurity among cancer survivors only. Compared with individuals without a cancer history, cancer survivors aged 18 to 39 years reported consistently higher "very worried" levels regarding retirement (25.5% vs 16.9%; P<.001), standard of living (20.4% vs 12.9%; P<.001), monthly bills (14.9% vs 10.3%; P=.002), and housing costs (13.6% vs 8.9%; P=.001); and higher "often true" levels regarding worry about food running out (7.9% vs 4.6%; P=.004), food not lasting (7.6% vs 3.3%; P=.003), and being unable to afford balanced meals (6.3% vs 3.4%; P=.007). Findings were not as consistent for cancer survivors aged 40 to 64 years. In contrast, results were generally similar for adults aged ≥65 years with/without a cancer history. Among cancer survivors, 57.6% (age 18-39 years; P<.001), 51.9% (age 40-64 years; P<.001), and 23.8% (age ≥65 years; referent) reported severe/moderate financial worry intensity, and 27.0% (age 18-39 years; P<.001), 14.8% (age 40-64 years; P<.001), and 6.3% (age ≥65 years; referent) experienced severe/moderate food insecurity intensity. Lower income and higher comorbidities were generally associated with greater intensities of financial worry and food insecurity in all 3 age groups. Younger cancer survivors experience greater financial worry and food insecurity. In addition to coping with medical costs, cancer survivors with low income and multiple comorbidities struggle to pay for daily living needs, such as food, housing, and monthly bills.


The Pulfrich phenomenon and its alleviation with a neutral density filter.
A case is described in which a presumed vascular accident resulted in long-standing visual difficulties in both reading and the analysis of vectors of moving objects. Clinical examination revealed minimal right optic atrophy with a relative superior altitudinal visual field defect associated with a positive Pulfrich effect. A partial head turn to the right in association with paresis of saccades and pursuit eye movements to the right was also evident. Spectacles for distance which incorporated a neutral density filter before the left eye were prescribed. These practically eliminated the Pulfrich effect and alleviated the problems of vector analysis. A near correction was provided which incorporated prisms with bases to the right. This eliminated the reading difficulties. The visual problems experienced by patients suffering from a positive Pulfrich effect are described and discussed.


Recent Advancements in the Nanomaterial Application in Concrete and Its Ecological Impact.
At present, nanotechnology is a significant research area in different countries, owing to its immense ability along with its economic impact. Nanotechnology is the scientific study, development, manufacturing, and processing of structures and materials on a nanoscale level. It has tremendous application in different industries such as construction. This study discusses the various progressive uses of nanomaterials in concrete, as well as their related health risks and environmental impacts. Nanomaterials such as nanosilica, nano-TiO2, carbon nanotubes (CNTs), ferric oxides, polycarboxylates, and nanocellulose have the capability to increase the durability of buildings by improving their mechanical and thermal properties. This could cause an indirect reduction in energy usage and total expenses in the concrete industry. However, due to the uncertainties and irregularities in size, shape, and chemical compositions, some nanosized materials might have harmful effects on the environment and human health. Acknowledgement of the possible beneficial impacts and inadvertent dangers of these nanosized materials to the environment will be extremely important when pursuing progress in the upcoming years. This research paper is expected to bring proper attention to the probable effects of construction waste, together with the importance of proper regulations, on the final disposal of the construction waste.


CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA.
Cyclin-dependent kinases (CDKs) regulate cell cycle progression and the transcription of a number of genes, including lipid metabolism-related genes, and aberrant lipid metabolism is involved in prostate carcinogenesis. Previous studies have shown that CDK13 expression is upregulated and fatty acid synthesis is increased in prostate cancer (PCa). However, the molecular mechanisms linking CDK13 upregulation and aberrant lipid metabolism in PCa cells remain largely unknown. Here, we showed that upregulation of CDK13 in PCa cells increases the fatty acyl chains and lipid classes, leading to lipid deposition in the cells, which is positively correlated with the expression of acetyl-CoA carboxylase (ACC1), the first rate-limiting enzyme in fatty acid synthesis. Gain- and loss-of-function studies showed that ACC1 mediates CDK13-induced lipid accumulation and PCa progression by enhancing lipid synthesis. Mechanistically, CDK13 interacts with RNA-methyltransferase NSUN5 to promote its phosphorylation at Ser327. In turn, phosphorylated NSUN5 catalyzes the m5C modification of ACC1 mRNA, and then the m5C-modified ACC1 mRNA binds to ALYREF to enhance its stability and nuclear export, thereby contributing to an increase in ACC1 expression and lipid deposition in PCa cells. Overall, our results disclose a novel function of CDK13 in regulating the ACC1 expression and identify a previously unrecognized CDK13/NSUN5/ACC1 pathway that mediates fatty acid synthesis and lipid accumulation in PCa cells, and targeting this newly identified pathway may be a novel therapeutic option for the treatment of PCa.


The simple economics of risk-sharing agreements between the NHS and the pharmaceutical industry.
The introduction of new (and expensive) pharmaceutical products is one of the major challenges for health systems. The search for new institutional arrangements is natural. The use of the so-called risk-sharing agreements is one example. Recent discussions have somewhat neglected the economic fundamentals underlying risk-sharing agreements. We argue here that risk-sharing agreements, although attractive due to the principle of paying by results, also entail risks. Too many patients may be put under treatment. Prices are likely to be adjusted upward, in anticipation of future risk-sharing agreements between the pharmaceutical company and the third-party payer. An available instrument is a verification cost per patient treated, which allows obtaining the first-best allocation of patients to the new treatment, under the agreement. Overall, the welfare effects of risk-sharing agreements are ambiguous, and caution is urged regarding their use.


Preservation of electroencephalographic organization in patients with impaired consciousness and imaging-based evidence of command-following.
Standard clinical characterization of patients with disorders of consciousness (DOC) relies on observation of motor output and may therefore lead to the misdiagnosis of vegetative state or minimally conscious state in patients with preserved cognition. We used conventional electroencephalographic (EEG) measures to assess a cohort of DOC patients with and without functional magnetic resonance imaging (fMRI)-based evidence of command-following, and correlated the findings with standard clinical behavioral evaluation and brain metabolic activity. We enrolled 44 patients with severe brain injury. Behavioral diagnosis was established using standardized clinical assessments. Long-term EEG recordings were analyzed to determine wakeful background organization and presence of elements of sleep architecture. A subset of patients had fMRI testing of command-following using motor imagery paradigms (26 patients) and resting brain metabolism measurement using (18) fluorodeoxyglucose positron emission tomography (31 patients). All 4 patients with fMRI evidence of covert command-following consistently demonstrated well-organized EEG background during wakefulness, spindling activity during sleep, and relative preservation of cortical metabolic activity. In the entire cohort, EEG organization and overall brain metabolism showed no significant association with bedside behavioral testing, except in a few cases when EEG was severely abnormal. These findings suggest that conventional EEG is a simple strategy that complements behavioral and imaging characterization of DOC patients. Preservation of specific EEG features may be used to assess the likelihood of unrecognized cognitive abilities in severely brain-injured patients with very limited or no motor responses.


Solid-state NMR and DFT predictions of differences in COOH hydrogen bonding in odd and even numbered n-alkyl fatty acids.
For nearly 140 years n-alkyl monocarboxylic acids have been known to exhibit unusual non-monotonic melting between odd and even numbered acids. This behavior has been rationalized in terms of packing density at the hydrocarbon tails, with COOH hydrogen bonding considered to be invariant among different acids. A recent ambiguity involving the COOH conformation between two crystal structures of lauric acid suggests that COOH structure and hydrogen bonding may play a role in these differences. Here, the two conflicting lauric acid crystal structures are further refined using lattice-including DFT refinement methods. Solid-state NMR (SSNMR) (13)C chemical shift tensor data are employed to monitor refinement quality by comparing experimental and computed tensors. This comparison provides a more sensitive measure of structure than X-ray data due to SSNMR's ability to accurately locate hydrogens. Neither diffraction structure agrees with SSNMR data and an alternative is proposed involving a hydrogen disordered COOH moiety. The disordered hydrogen dynamically samples two most probable positions on the NMR timescale with O-H bond lengths of 1.16 and 1.46 Å. This disordered structure is consistent with SSNMR, IR and X-ray C-O and C[double bond, length as m-dash]O bond lengths. The hydrogen disorder appears to be restricted to even numbered acids based on undecanoic acid's (13)COOH tensor data and C-O and C[double bond, length as m-dash]O bond lengths for other n-alkyl acids. This disorder in even numbered acids results in stronger hydrogen bonds than are found in odd acids and invites a reevaluation of the melting behavior of n-alkyl acids that includes these differences in hydrogen bonding.


Zoonotic helminthes of commensal rodents in Talkha Center, Dakahlia Governorate.
Commensal rodents were trapped alive from different areas near garbage, canal edges, farm animals and the likes in Talkha Center over one year. A total of 135 rodents were collected, their species and index were Rattus norvegicus (0.11), R. r. frugivorous (0.13), R. r. alexandrinus (0.16) and Mus musculus (0.5). The zoonotic helminthes were trematodes (10 species), cestodes (4 species), and nematodes (10 species). The results were discussed on light of other works.


More than Just Minutes of Stiffness in the Morning: Report from the OMERACT Rheumatoid Arthritis Flare Group Stiffness Breakout Sessions.
Stiffness was endorsed within the rheumatoid arthritis (RA) flare core domain set at the previous Outcome Measures in Rheumatology meeting (OMERACT 11). Two stiffness breakout groups at the present OMERACT 12 RA flare workshop discussed results of new qualitative studies in RA stiffness. Results from 2 independent studies of RA stiffness were presented to breakout group participants, followed by group discussions about stiffness measurement. Both studies identified stiffness as complex, variable with the level of disease activity, and as encompassing concepts of impact, intensity, timing, location, and duration. That stiffness has an effect on multiple dimensions of health was a common finding. Participants agreed that stiffness is an important aspect of RA flare. Whether measuring only morning stiffness duration, the traditional approach in RA, was sufficient in coverage of the concept was unclear. Groups agreed that more research on stiffness measurement is needed considering the importance patients place on the effect of stiffness. Results from independent studies highlight stiffness effect as an important feature of RA, in addition to intensity, timing, location, and duration. Additional work is needed to identify optimal ways to assess stiffness in RA and other rheumatologic diseases.


Topographical Response of Retinal Neovascularization to Aflibercept or Panretinal Photocoagulation in Proliferative Diabetic Retinopathy: Post Hoc Analysis of the CLARITY Randomized Clinical Trial.
Eyes with proliferative diabetic retinopathy have a variable response to treatment with panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor agents. The location of neovascularization (NV) is associated with outcomes (eg, patients with disc NV [NVD] have poorer visual prognosis than those with NV elsewhere [NVE]). To investigate the distribution of NV in patients with proliferative diabetic retinopathy and the topographical response of NV to treatment with aflibercept or PRP. This post hoc analysis of the phase 2b randomized clinical single-masked multicenter noninferiority Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy (CLARITY) trial was conducted from November 1, 2019, to September 1, 2020, among 120 treatment-naive patients with proliferative diabetic retinopathy to evaluate the topography of NVD and NVE in 4 quadrants of the retina on color fundus photography at baseline and at 12 and 52 weeks after treatment. In the CLARITY trial, patients were randomized to receive intravitreal aflibercept (2 mg/0.05 mL at baseline, 4 weeks, and 8 weeks, and as needed from 12 weeks onward) or PRP (completed in initial fractionated sessions and then on an as-needed basis when reviewed every 8 weeks). Main outcomes were per-retinal quadrant frequencies of NV at baseline and frequencies of patterns of regression, recurrence, and new occurrence at 12-week and 52-week unmasked follow-up. The study included 120 treatment-naive patients (75 men; mean [SD] age, 54.8 [14.6] years) with proliferative diabetic retinopathy (there was a 1:1 ratio of eyes to patients). At baseline, NVD with or without NVE was observed in 42 eyes (35.0%), and NVE only was found in 78 eyes (65.0%); NVE had a predilection for the nasal quadrant (64 [53.3%]). Rates of regression with treatment were higher among eyes with NVE (89 of 102 [87.3%]) compared with eyes with NVD (23 of 43 [53.5%]) by 52 weeks, with NVD being more resistant to either treatment with higher rates of persistence than NVE (20 of 39 [51.3%] vs 29 of 100 [29.0%]). Considering NVE, the regression rate in the temporal quadrant was lowest (32 of 42 [76.2%]). Eyes treated with aflibercept showed higher rates of regression of NVE compared with those treated with PRP (50 of 52 [96.2%] vs 39 of 50 [78.0%]; difference, 18.2% [95% CI, 5.5%-30.8%]; P = .01), but no difference was found for NVD (11 of 17 [64.7%] vs 12 of 26 [46.2%]; difference, 18.6% [95% CI, -11.2% to 48.3%]; P = .23). This post hoc analysis found that NVD is less frequent but is associated with more resistance to currently available treatments than NVE. Aflibercept was superior to PRP for treating NVE, but neither treatment was particularly effective against NVD by 52 weeks. Future treatments are needed to better target NVD, which has poorer visual prognosis. isrctn.org Identifier: ISRCTN32207582.


Response of Russian wheat aphid resistance in wheat and barley to four Diuraphis (Hemiptera: Aphididae) species.
Three Diuraphis species, Diuraphis frequens (Walker), Diuraphis mexicana (McVicar Baker), and Diuraphis tritici (Gillette), were known to exist in the United States before the 1986 appearance of the Russian wheat aphid, Diuraphis noxia Kurdjumov. The Russian wheat aphid soon became a significant pest of wheat although other endemic Diuraphis species were known to infest wheat. Wheat and barley entries resistant and susceptible to Russian wheat aphid biotype 2 were evaluated against all four Diuraphis species to determine their host interrelationships. Leaf chlorosis, leaf roll, leaf number, plant height, and infestation levels were assessed 21 d after the plants were infested by aphids in a no-choice caged environment. D. mexicana was unable to survive on wheat by 21 d after infestation and effects on the plant damage variables were negligible. D. frequens survived at low levels on resistant and susceptible plant entries and had a low impact on plant damage and growth. Russian wheat aphid biotype 2 and D. tritici were damaged most wheat and barley lines except the Russian wheat aphid biotype 2-resistant wheat lines containing genes from Dn7, STARS 2414-11, and CI2401; and resistant barley containing genes from STARS 9577B and 9301B. Russian wheat aphid biotype 2 and D. tritici reduced the growth of resistant plants by 25-50% and susceptible entries by 65-75%. Reductions at this level are typical under no-choice studies but resistant cultivars do not have these reductions under field conditions. The Russian wheat aphid biotype 2 resistant wheat lines would be effective in managing both wheat pest species.


"…The times they aren't a-changin'…" rTMS does not affect basic mechanisms of temporal discrimination: a pilot study with ERPs.
In time processing, the role of different cortical areas is still under investigation. Event-related potentials (ERPs) represent valuable indices of neural timing mechanisms in the millisecond-to-second domain. We used an interference approach by repetitive TMS (rTMS) on ERPs and behavioral performance to investigate the role of different cortical areas in processing basic temporal information. Ten healthy volunteers were requested to decide whether time intervals between two tones (S1-S2, probe interval) were shorter (800ms), equal to, or longer (1200ms) than a previously listened 1000-ms interval (target interval) and press different buttons accordingly. This task was performed at the baseline and immediately after a 15-min-long train of 1-Hz rTMS delivered over the supplementary motor area, right posterior parietal cortex, right superior temporal gyrus, or an occipital control area. Task accuracy, reaction time, and ERPs during (contingent negative variation, CNV) and after the presentation of probe intervals were analyzed. At the baseline, CNV amplitude was modulated by the duration of the probe interval. RTMS had no significant effect on behavioral or ERP measures. These preliminary data suggest that stimulated cortical areas are less crucially involved than other brain regions (e.g. subcortical structures) in the explicit discrimination of auditory time intervals in the range of hundreds of milliseconds.


Neural differentiation on synthetic scaffold materials.
The potential of stem cells to differentiate into a variety of subgroups of neural cells makes stem cell differentiation and transplantation a promising candidate for neurodegenerative disorder therapies. However, selective differentiation of stem cells to neurons while preventing glial scar formation is a complex process. Mimicking the natural environment of neural tissue is pivotal, thus various synthetic materials have been developed for this purpose. The synthetic scaffolds can direct stem cells into a neural lineage by including extracellular factors that act on cell fate, which are mainly soluble signals, extracellular matrix proteins and physical factors (e.g. elasticity and topography). This article reviews synthetic materials developed for neural regeneration in terms of their extracellular matrix mimicking properties. Functionalization of synthetic materials by addition of bioactive chemical groups and adjustment of physical properties such as topography, electroactivity and elasticity are discussed.


Extended thymectomy with blood vessel resection and reconstruction improves therapeutic outcome for clinical stage III thymic carcinoma patients: a real-world research.
We examine the therapeutic efficacy of extended thymectomy with blood vessel resection and reconstruction in thymic carcinoma patients with great vessel invasion. In total 26 patients diagnosed as clinical stage III thymic carcinoma with severe great vessel invasion were enrolled in this retrospective study. Among these patients, 14 cases received adjuvant chemo- and radiotherapy (non-operation subgroup, NOG), the other 12 patients received extended thymectomy with vessel resection and reconstruction followed by the adjuvant treatment (operation subgroup, OG). All surgical procedures went smoothly with no perioperative death. R0 resection was obtained in all surgical cases, and we also observed a lymph node metastasis rate of 38.8%. The overall survival (OS) was 34 months for the whole cohort, 48 and 26 months for the OG and NOG respectively (p = 0.013). The median disease metastasis free survival (DMFS) was 47 months for the OG and 18 months for the NOG (p = 0.019). Extended thymectomy with vessel resection is feasible for patients with clinical stage III thymic carcinoma. Surgery significantly improves the overall survival and the prognosis of clinical stage III thymic carcinoma.


Racial and ethnic disparities in motor vehicle crash-related outcomes in North Carolina surrounding the COVID-19 pandemic.
Long-term impacts of the COVID-19 pandemic on racial and ethnic disparities in motor vehicle crash (MVC) injuries and death are poorly understood. This study aimed to characterize trends and investigate the heterogeneity of MVC-related disparities in North Carolina across several data sources. Crash reports, emergency department visit records, and death certificates from 2018 to 2021 were used to calculate monthly population-rates of MVC-related public health outcomes. We estimated trendlines using joinpoint regression and compared outcomes across racial and ethnic classifications. MVC and MVC-related injury rates declined in conjunction with NC's stay-at-home order, while rates of severe outcomes remained unimpacted. By December 2021 rates of MVC-related outcomes met or exceeded pre-pandemic levels, with the highest rates observed among non-Hispanic Black individuals. Racial and ethnic disparities in MVC-related outcomes remained prevalent throughout the COVID-19 pandemic. These results highlight the importance of a holistic approach to traffic injury surveillance when assessing the impact of MVCs.


Selective synthesis of silver nanoparticles onto potassium hexaniobate: structural organisation with bactericidal properties.
Silver-based nanocomposites are known to act as biocides against a series of microorganisms and are largely studied as an alternative to substitute conventional antibiotics that show decreasing efficacy. In this work, an eco-friendly method to synthesize silver nanoparticles assembled on the surface of hexaniobate crystals is reported. By means of ion exchange, K(+) ions of layered potassium hexaniobate were partially substituted by Ag(+) ions and the resulting material was exposed to UV light. The irradiation allowed the reduction of silver ions with consequent formation of silver nanoparticles located only on the hexaniobate surface, whereas Ag(+) ions located in the interlayer space remained in the ionic form. Increasing UV-light exposure times allowed controlling of the silver nanoparticle size. The antibacterial effects of the pristine potassium hexaniobate and of silver-containing hexaniobate samples were tested against Escherichia coli (E. coli). The antibacterial efficacy was determined to be related to the presence of silver in hexaniobate. An increasing activity against E. coli was observed with the decrease in silver nanoparticles size, suggesting that silver nanoparticles of distinct sizes interact differently with bacterial cell walls.


Design and implementation of a micromechanical silicon resonant accelerometer.
The micromechanical silicon resonant accelerometer has attracted considerable attention in the research and development of high-precision MEMS accelerometers because of its output of quasi-digital signals, high sensitivity, high resolution, wide dynamic range, anti-interference capacity and good stability. Because of the mismatching thermal expansion coefficients of silicon and glass, the micromechanical silicon resonant accelerometer based on the Silicon on Glass (SOG) technique is deeply affected by the temperature during the fabrication, packaging and use processes. The thermal stress caused by temperature changes directly affects the frequency output of the accelerometer. Based on the working principle of the micromechanical resonant accelerometer, a special accelerometer structure that reduces the temperature influence on the accelerometer is designed. The accelerometer can greatly reduce the thermal stress caused by high temperatures in the process of fabrication and packaging. Currently, the closed-loop drive circuit is devised based on a phase-locked loop. The unloaded resonant frequencies of the prototype of the micromechanical silicon resonant accelerometer are approximately 31.4 kHz and 31.5 kHz. The scale factor is 66.24003 Hz/g. The scale factor stability is 14.886 ppm, the scale factor repeatability is 23 ppm, the bias stability is 23 μg, the bias repeatability is 170 μg, and the bias temperature coefficient is 0.0734 Hz/°C.


Efficacy of photographic educational materials for carbohydrate counting training of adolescents with diabetes mellitus.
Carbohydrate counting (CHC) is ack - nowledged by the American Diabetes Association (ADA) as an important tool. To assess the efficacy of photographic educational materials to train adolescents with DM to perform CHC. 76 adolescents were randomly divided into two groups of CHC orientation: by means of photographic materials (Photo) or by a list of foods (List). One month afterwards, the participants were contacted via telephone to answer questions on CHC to reinforce the training (Quiz). Two days after taking the quiz, required the participants to visit an experimental kitchen to observe food portions in natura and to respond to a questionnaire on the weights in grams or carbohydrate equivalents of these portions. Statistical significance was established at p < 0.05. 54 adolescents completed the study (79.7% female), with 51.8% allocated to the Photo group and 48.1% to the List group. The mean age was 13.8 ± 2.0 years old, and the mean body mass index (BMI) was 21.0 ± 3.2 kg/m2. The participants had average of 7.9 ± 1.5 years of schooling, while their parents had 8.0 ± 3.8 years. The knowledge of CHC was similar in both groups before the intervention. After the intervention, the Photo group achieved a significantly higher hit difference on the CHC assessment test than the List group (Photo: 2.5 vs List: 1.0; p = 0.03). The photographic educational material was more effective in helping adolescents with DM understand and learn to perform carbohydrate counting.


[Surgical correction of isolated coarctation of the aorta in infants of the first year of life].
Long-term results of surgical treatment of isolated coarctation of the aorta were studied in infants from the first year of life till 14 years. In infants of the first year of life elimination of coarctation of the aorta with end-to-end anastomosis is more preferable than isthmoplasty of the aorta of the left subclavian artery, since risk of recoarctation is less, the subclavian artery remains preserved, the ductal tissues are completely dissected. An important condition of success of the operation with elimination of the end-to-end CA is thought to be maximal mobilization of the aorta from the surrounding tissues which leads to greater mobility, less tension in the anastomosis zone. The operations in newborns do not cause recoarctations more often than in infants from one month till one year, so the operative treatment is possible in such young age.


A two-tiered compensatory response to loss of DNA repair modulates aging and stress response pathways.
Activation of oxidative stress-responses and downregulation of insulin-like signaling (ILS) is seen in Nucleotide Excision Repair (NER) deficient segmental progeroid mice. Evidence suggests that this is a survival response to persistent transcription-blocking DNA damage, although the relevant lesions have not been identified. Here we show that loss of NTH-1, the only Base Excision Repair (BER) enzyme known to initiate repair of oxidative DNA damage inC. elegans, restores normal lifespan of the short-lived NER deficient xpa-1 mutant. Loss of NTH-1 leads to oxidative stress and global expression profile changes that involve upregulation of genes responding to endogenous stress and downregulation of ILS. A similar, but more extensive, transcriptomic shift is observed in the xpa-1 mutant whereas loss of both NTH-1 and XPA-1 elicits a different profile with downregulation of Aurora-B and Polo-like kinase 1 signaling networks as well as DNA repair and DNA damage response genes. The restoration of normal lifespan and absence oxidative stress responses in nth-1;xpa-1 indicate that BER contributes to generate transcription blocking lesions from oxidative DNA damage. Hence, our data strongly suggests that the DNA lesions relevant for aging are repair intermediates resulting from aberrant or attempted processing by BER of lesions normally repaired by NER.


B-cell lymphoma of recipient origin 9 years after allogeneic bone marrow transplantation for T-cell acute lymphoblastic leukaemia.
A 25-year-old woman developed an immunoblastic lymphoma 9 years after HLA-identical allogeneic bone marrow transplantation for T-cell acute lymphoblastic leukaemia in second remission. The B-cell origin of the second malignancy was confirmed by gene rearrangement studies. Despite continued donor engraftment, two separate genotypic analyses identified the lymphoma to be of recipient origin. This is the longest latency of a post-transplant recipient lymphoma yet reported and illustrates that recipient B-cells may survive the transplant conditioning regimen and undergo malignant transformation in the presence of donor haemopoiesis.


Standardless Quantitative Electron-Excited X-ray Microanalysis by Energy-Dispersive Spectrometry: What Is Its Proper Role?
: Electron beam X-ray microanalysis with semiconductor energy-dispersive spectrometry (EDS) performed with standards and calculated matrix corrections can yield quantitative results with a distribution such that 95% of analyses fall within +/-5% relative for major and minor constituents. Standardless methods substitute calculations for the standard intensities, based either on physical models of X-ray generation and propagation (first principles) or on mathematical fits to remotely measured standards (fitted standards). Error distributions have been measured for three different standardless analysis procedures with a suite of microanalysis standards including metal alloys, glasses, minerals, ceramics, and stoichiometric compounds. For the first-principles standardless procedure, the error distribution placed 95% of analyses within +/-50% relative, whereas for two commercial fitted standards procedures, the error distributions placed 95% of analyses within +/-25% relative. The implication of these error distributions for the accuracy of analytical results is considered, and recommendations for the use of standardless analysis are given.


Phylogenetic species delimitation for crayfishes of the genus Pacifastacus.
Molecular genetic approaches are playing an increasing role in conservation science by identifying biodiversity that may not be evident by morphology-based taxonomy and systematics. So-called cryptic species are particularly prevalent in freshwater environments, where isolation of dispersal-limited species, such as crayfishes, within dendritic river networks often gives rise to high intra- and inter-specific genetic divergence. We apply here a multi-gene molecular approach to investigate relationships among extant species of the crayfish genus Pacifastacus, representing the first comprehensive phylogenetic study of this taxonomic group. Importantly, Pacifastacus includes both the widely invasive signal crayfish Pacifastacus leniusculus, as well as several species of conservation concern like the Shasta crayfish Pacifastacus fortis. Our analysis used 83 individuals sampled across the four extant Pacifastacus species (omitting the extinct Pacifastacus nigrescens), representing the known taxonomic diversity and geographic distributions within this genus as comprehensively as possible. We reconstructed phylogenetic trees from mitochondrial (16S, COI) and nuclear genes (GAPDH), both separately and using a combined or concatenated dataset, and performed several species delimitation analyses (PTP, ABGD, GMYC) on the COI phylogeny to propose Primary Species Hypotheses (PSHs) within the genus. All phylogenies recovered the genus Pacifastacus as monophyletic, within which we identified a range of six to 21 PSHs; more abundant PSHs delimitations from GMYC and ABGD were always nested within PSHs delimited by the more conservative PTP method. Pacifastacus leniusculus included the majority of PSHs and was not monophyletic relative to the other Pacifastacus species considered. Several of these highly distinct P. leniusculus PSHs likely require urgent conservation attention. Our results identify research needs and conservation priorities for Pacifastacus crayfishes in western North America, and may inform better understanding and management of P. leniusculus in regions where it is invasive, such as Europe and Japan.


Ketogenic diet increases mitochondria volume in the liver and skeletal muscle without altering oxidative stress markers in rats.
Ketogenic diets (KD) consist of high fat, moderate protein and low carbohydrates. Studies have suggested that KD may influence oxidative stress by affecting mitochondrial quantity and/or quality, and perhaps lengthen lifespan. Therefore, we determined the effects of KD on multi-organ mitochondria volume and oxidative stress markers in rats. Ten month-old male Fisher 344 rats (n = 8 per group) were provided with one of two isocaloric diets: standard chow (SC) or KD. Rats were euthanized if: a) vitality scores exceeded a score of 16, b) rapid weight loss, or c) veterinarian deemed euthanasia necessary. The median lifespan of rats was higher in KD (762 days) compared to SC (624 days). Citrate synthase activity (i.e. estimate of mitochondria volume) was higher in the liver (p = 0.034) and gastrocnemius (p = 0.041) of KD compared to SC. Liver superoxide dismutase 1 and catalase antioxidant protein levels were higher in KD, albeit not significant (p = 0.094 and p = 0.062, respectively). No significant differences in protein levels of other antioxidants or markers of lipid and protein oxidative damage were observed in either the gastrocnemius, liver, or brain. In summary, KD increased mitochondria volume in liver and gastrocnemius and median lifespan in rats. Additionally, our data show that the increase in mitochondrial volume occurred without changes in oxidative damage or antioxidant protein levels in the gastrocnemius, liver, or brain.


Severe neonatal hyperbilirubinemia in the Netherlands.
The occurrence of severe neonatal hyperbilirubinemia (SH) is partly attributed to nonhospitalized perinatal care. The Netherlands have a high frequency of home births and nonhospitalized perinatal care, and the incidence of SH is unknown. To assess the effects of home births and early hospital discharge on the incidence of SH in term-born infants in the Netherlands. In this nationwide prospective surveillance study between 2005 and 2009, infants (≥37 weeks GA) were included if total serum bilirubin (TSB) was ≥500 µmol/l or if they received an exchange transfusion when TSB was ≥340 µmol/l. Seventy-one infants had SH (incidence 10.4/100,000); 43 had a TSB ≥500 μmol/l (incidence 6.3/100,000) and 45 (63%) underwent an exchange transfusion. 26% of the infants with SH were born at home, which is similar to 22% of all term infants who are born at home in the Netherlands (p = 0.41). Maximum TSB levels were similar in infants born at home (523 ± 114 μmol/l) and infants born in hospital (510 ± 123 μmol/l; p = 0.70). Of the 51 infants born in hospital, 33 were discharged and readmitted with SH, with maximal TSB levels (567 ± 114 μmol/l), which were higher than in infants who remained hospitalized (406 ± 47 μmol/l; p = 0.0001). The incidence of severe hyperbilirubinemia in term-born infants in the Netherlands is 10.4 per 100,000, which is similar to other developed countries. Home birth and early hospital discharge do not necessarily lead to a higher incidence of SH, provided that perinatal home care is well organized.


ALKBH5 promotes the development of lung adenocarcinoma by regulating the polarization of M2 macrophages through CDCA4.
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, with high morbidity and mortality. N6-methyladenosine (m6A) is an important regulator of LUAD progression. Here, we investigated the potential biological functions of ALKBH5 (a m6A demethylated enzyme) and cell division cycle associated protein 4 (CDCA4) in the progression of LUAD. The expressions of CDCA4, METTL3, ALKBH5, FTO, YTHDC2 and YTHDC1 mRNA and proteins in LUAD and adjacent tissues, as well as NCI-H1299 and NCI-H157 cells were detected by RT-qPCR and western blot. Meanwhile, the role of ALKBH5 and CDCA4 in macrophage polarization was explored through tumor formation in Lewis lung carcinoma (LLC) mice and the co-culture system of NCI-H1299 and NCI-H157/THP-1 cells. Cell characterization was further analyzed. The expression of Ki-67 in tumor tissue was tested by immunohistochemistry. The scale of M1 and M2 macrophages was determined by flow cytometry. CDCA4 was significantly overexpressed in NCI-H1299 and NCI-H157 cell lines compared with BEAS-2B cells. The fold enrichment of CDCA4 m6A level in the overexpression (oe)-METTL3 or short hairpin (sh)-ALKBH5 cells was enhanced. Overexpression of CDCA4 promoted the cell viability, proliferation and migration, and inhibited apoptosis, which was reversed by sh-ALKBH5 intervention. Overexpression of YTHDC2 (not YTHDC1) inhibited the effect of CDCA4 on sh-ALKBH5 cells. sh-CDCA4 inhibited tumor growth and weight of LLC cells in mice, and promoted M1/M2 ratio in LLC mice and NCI-H1299/THP-1 and NCI-H157/THP-1 co-culture systems. Oe-CDCA4 promoted the volume and weight of tumor and inhibited the M1/M2 ratio of tumor tissue in LLC mice, but was reversed by sh-ALKBH5 intervention. m6A demethylase ALKBH5 promotes the development of LUAD through CDCA4 regulation of malignant characterization and M1/M2 macrophage polarization.


Antipsychotics for treatment of delirium in hospitalised non-ICU patients.
Guidelines suggest limited and cautious use of antipsychotics for treatment of delirium where nonpharmacological interventions have failed and symptoms remain distressing or dangerous, or both. It is unclear how well these recommendations are supported by current evidence. Our primary objective was to assess the efficacy of antipsychotics versus nonantipsychotics or placebo on the duration of delirium in hospitalised adults. Our secondary objectives were to compare the efficacy of: 1) antipsychotics versus nonantipsychotics or placebo on delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects; and 2) atypical vs. typical antipsychotics for reducing delirium duration, severity, and resolution, hospital mortality and length of stay, discharge disposition, health-related quality of life, and adverse effects. We searched MEDLINE, Embase, Cochrane EBM Reviews, CINAHL, Thomson Reuters Web of Science and the Latin American and Caribbean Health Sciences Literature (LILACS) from their respective inception dates until July 2017. We also searched the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database, Web of Science ISI Proceedings, and other grey literature. We included randomised and quasi-randomised trials comparing 1) antipsychotics to nonantipsychotics or placebo and 2) typical to atypical antipsychotics for the treatment of delirium in adult hospitalised (but not critically ill) patients. We examined titles and abstracts of identified studies to determine eligibility. We extracted data independently in duplicate. Disagreements were settled by further discussion and consensus. We used risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect for dichotomous outcomes, and between-group standardised mean differences (SMD) with 95% CI for continuous outcomes. We included nine trials that recruited 727 participants. Four of the nine trials included a comparison of an antipsychotic to a nonantipsychotic drug or placebo and seven included a comparison of a typical to an atypical antipsychotic. The study populations included hospitalised medical, surgical, and palliative patients.No trial reported on duration of delirium. Antipsychotic treatment did not reduce delirium severity compared to nonantipsychotic drugs (standard mean difference (SMD) -1.08, 95% CI -2.55 to 0.39; four studies; 494 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (SMD -0.17, 95% CI -0.37 to 0.02; seven studies; 542 participants; low-quality evidence). There was no evidence antipsychotics resolved delirium symptoms compared to nonantipsychotic drug regimens (RR 0.95, 95% CI 0.30 to 2.98; three studies; 247 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (RR 1.10, 95% CI 0.79 to 1.52; five studies; 349 participants; low-quality evidence). The pooled results indicated that antipsychotics did not alter mortality compared to nonantipsychotic regimens (RR 1.29, 95% CI 0.73 to 2.27; three studies; 319 participants; low-quality evidence) nor was there a difference between typical and atypical antipsychotics (RR 1.71, 95% CI 0.82 to 3.35; four studies; 342 participants; low-quality evidence).No trial reported on hospital length of stay, hospital discharge disposition, or health-related quality of life. Adverse event reporting was limited and measured with inconsistent methods; in those reporting events, the number of events were low. No trial reported on physical restraint use, long-term cognitive outcomes, cerebrovascular events, or QTc prolongation (i.e. increased time in the heart's electrical cycle). Only one trial reported on arrhythmias and seizures, with no difference between typical or atypical antipsychotics. We found antipsychotics did not have a higher risk of extrapyramidal symptoms (EPS) compared to nonantipsychotic drugs (RR 1.70, 95% CI 0.04 to 65.57; three studies; 247 participants; very-low quality evidence); pooled results showed no increased risk of EPS with typical antipsychotics compared to atypical antipsychotics (RR 12.16, 95% CI 0.55 to 269.52; two studies; 198 participants; very low-quality evidence). There were no reported data to determine whether antipsychotics altered the duration of delirium, length of hospital stay, discharge disposition, or health-related quality of life as studies did not report on these outcomes. From the poor quality data available, we found antipsychotics did not reduce delirium severity, resolve symptoms, or alter mortality. Adverse effects were poorly or rarely reported in the trials. Extrapyramidal symptoms were not more frequent with antipsychotics compared to nonantipsychotic drug regimens, and no different for typical compared to atypical antipsychotics.


Sensory ERPs predict differences in working memory span and fluid intelligence.
The way our brain reacts to sensory stimulation may provide important clues about higher-level cognitive function and its operation. Here we show that short-latency (< 200 ms) sensory cortical responses elicited by visual and auditory stimuli differ dramatically between subjects with high and low working-memory span, as well as between subjects scoring high and low on a fluid intelligence test. Our findings also suggest that this link between sensory responses and complex cognitive tasks is modality specific (visual sensory measures correlate with visuo-spatial tasks whereas auditory sensory measures correlate with verbal tasks). We interpret these findings as indicating that people's effectiveness in controlling attention and gating sensory information is a critical determinant of individual differences in complex cognitive abilities.


Toxic Keratoconjunctivitis.
Toxic keratoconjunctivitis (TK) is an underrecognized complication of ophthalmic drug use and various environmental or occupational exposures. A detailed history and clinical examination are important to identify the offending agent(s). Common drug-related causes of TK include preservatives in ophthalmic medications, topical antimicrobials, and topical anesthetics. Alternatives to benzalkonium chloride as well as preservative-free formulations should be considered in patients requiring long-term topical medication. More advanced cases of TK may require preservative-free topical steroids and/or antibiotics, and occasionally surgical intervention. Early recognition and appropriate management of TK may help prevent permanent ocular and visual damage.


Two-color SERS microscopy for protein co-localization in prostate tissue with primary antibody-protein A/G-gold nanocluster conjugates.
SERS microscopy is a novel staining technique in immunohistochemistry, which is based on antibodies labeled with functionalized noble metal colloids called SERS labels or nanotags for optical detection. Conventional covalent bioconjugation of these SERS labels cannot prevent blocking of the antigen recognition sites of the antibody. We present a rational chemical design for SERS label-antibody conjugates which addresses this issue. Highly sensitive, silica-coated gold nanoparticle clusters as SERS labels are non-covalently conjugated to primary antibodies by using the chimeric protein A/G, which selectively recognizes the Fc part of antibodies and therefore prevents blocking of the antigen recognition sites. In proof-of-concept two-color imaging experiments for the co-localization of p63 and PSA on non-neoplastic prostate tissue FFPE specimens, we demonstrate the specificity and signal brightness of these rationally designed primary antibody-protein A/G-gold nanocluster conjugates.


Lone Hepatocellular Carcinoma: An Isolated Chest Wall Malignancy.
Herein we describe the case of an elderly diabetic gentleman presenting with a two-week history of dyspnea and nonproductive cough, found to have a large left anterolateral chest wall mass. Further characterization through computed tomography (CT) of the chest revealed a soft tissue mass in the left anterior lower hemithorax found to be hepatocellular carcinoma (HCC). The liver, spleen, and pancreas were unremarkable. Diagnostic labs were unremarkable. The patient had no history of hepatitis, alcohol abuse, or illicit substance use. Pathological examination and immunohistochemical staining of the chest mass biopsy were consistent with metastatic hepatocellular carcinoma (HCC). The patient opted to pursue no further medical intervention and expired two weeks later. To the authors' knowledge, this is one of very few descriptions of isolated hepatocellular carcinoma found in the absence of a primary liver lesion and classical risk factors for hepatocarcinogenesis. This case highlights that HCC may present independently of liver lesions seen on imaging in a patient without clear signs or symptoms of liver. HCC should be considered in cases of isolated tumors with unclear primaries as ectopic carcinogenesis and occult primary malignancy are possibilities.


Enabling robust assessment of QTc prolongation in early phase clinical trials.
Since the implementation of the International Conference on Harmonization (ICH) E14 guideline in 2005, regulators have required a "thorough QTc" (TQT) study for evaluating the effects of investigational drugs on delayed cardiac repolarization as manifested by a prolonged QTc interval. However, TQT studies have increasingly been viewed unfavorably because of their low cost effectiveness. Several researchers have noted that a robust drug concentration-QTc (conc-QTc) modeling assessment in early phase development should, in most cases, obviate the need for a subsequent TQT study. In December 2015, ICH released an "E14 Q&As (R3)" document supporting the use of conc-QTc modeling for regulatory decisions. In this article, we propose a simple improvement of two popular conc-QTc assessment methods for typical first-in-human crossover-like single ascending dose clinical pharmacology trials. The improvement is achieved, in part, by leveraging routinely encountered (and expected) intrasubject correlation patterns encountered in such trials. A real example involving a single ascending dose and corresponding TQT trial, along with results from a simulation study, illustrate the strong performance of the proposed method. The improved conc-QTc assessment will further enable highly reliable go/no-go decisions in early phase clinical development and deliver results that support subsequent TQT study waivers by regulators.


FKBP binding characteristics of cardiac microsomes from diverse vertebrates.
FK506 binding protein (FKBP) is a cytosolic receptor for the immunosuppressive drug FK-506. The common isoform, FKBP12, was found to be associated with the calcium release channel (ryanodine receptor 1) of different species of vertebrate skeletal muscle, whereas 12.6, a novel FKBP isoform was found to be associated with canine cardiac ryanodine receptor (ryanodine receptor 2). Until recently, canine cardiac sarcoplasmic reticulum was considered to be the prototype for studying heart RyR2 and its interactions with FKBP. In this study, cardiac microsomes were isolated from diverse vertebrates: human, rabbit, rat, mice, dog, chicken, frog, and fish and were analyzed for their ability to bind or exchange with FKBP isoforms 12 and 12.6. Our studies indicate that RyR2 from seven out of the eight animals contain both FKBP12 and 12.6. Dog is the exception. It can now be concluded that the association of FKBP isoforms with RyR2 is widely conserved in the hearts of different species of vertebrates.