Effects of behavioural interventions on postpartum retention and adherence among women with HIV on lifelong ART: the results of a cluster randomized trial in Kenya (the MOTIVATE trial).
Retention in HIV care and adherence to antiretroviral therapy (ART) during pregnancy and postpartum for women living with HIV (WLWH) are necessary to optimize health outcomes for women and infants. The objective of this study was to evaluate the impact of two evidenced-based behavioural interventions on postpartum adherence and retention in WLWH in Kenya. The Mother-Infant Visit Adherence and Treatment Engagement (MOTIVATE) study was a cluster-randomized trial enrolling pregnant WLWH from December 2015 to August 2017. Twenty-four health facilities in southwestern Kenya were randomized to: (1) standard care (control), (2) text-messaging, (3) community-based mentor mothers (cMM) or (4) text-messaging and cMM. Primary outcomes included retention in care and ART adherence at 12 months postpartum. Analyses utilized generalized estimating equations and competing risks regression. Per-protocol analyses examined differences in postpartum retention for women with high versus low levels of exposure to the interventions. We enrolled 1331 pregnant WLWH (mean age 28 years). At 12 months postpartum, 1140 (85.6%) women were retained in care, 96 women (7.2%) were lost-to-follow-up (LTFU) and 95 (7.1%) were discontinued from the study. In intention-to-treat analyses, the relative risk of being retained at 12-months postpartum was not significantly higher in the intervention arms versus the control arm. In time-to-event analysis, the cMM and text arm had significantly lower rates of LTFU (hazard ratio 0.44, p = 0.019). In per-protocol analysis, the relative risk of 12-month postpartum retention was 24-29% higher for women receiving at least 80% of the expected intervention compared to the control arm; text message only risk ratio (RR) 1.24 (95% confidence interval [CI] 1.16-1.32, p<0.001), cMM only RR 1.29 (95% CI 1.21-1.37, p<0.001) and cMM plus text RR 1.29 (1.21-1.37, p<0.001). Women LTFU were younger (p<0.001), less likely to be married (p<0.001) and more likely to be newly diagnosed with HIV during pregnancy (p<0.001). Self-reported ART adherence did not vary by study arm. Behavioural interventions using peer support and text messages did not appear to improve 12-month postpartum retention and adherence in intention-to-treat analyses. Higher levels of exposure to the interventions may be necessary to achieve the desired effects.


Optimal Scaling of Critical Size for Metamorphosis in the Genus Drosophila.
Juveniles must reach a critical body size to become a mature adult. Molecular determinants of critical size have been studied, but the evolutionary importance of critical size is still unclear. Here, using nine fly species, we show that interspecific variation in organism size can be explained solely by species-specific critical size. The observed variation in critical size quantitatively agrees with the interspecific scaling relationship predicted by the life history model, which hypothesizes that critical size mediates an energy allocation switch between juvenile and adult tissues. The mechanism underlying critical size scaling is explained by an inverse relationship between growth duration and growth rate, which cancels out their contributions to the final size. Finally, we show that evolutionary changes in growth duration can be traced back to the scaling of ecdysteroid hormone dynamics. We conclude that critical size adaptively optimizes energy allocation, and has a central role in organism size determination.


Crystal structure of trans-(1,8-dibutyl-1,3,6,8,10,13-hexa-aza-cyclo-tetra-decane-κ(4) N (3),N (6),N (10),N (13))bis-(5-methyltetra-zolato-κN)nickel(II) from synchrotron data.
The structure of the title compound, [Ni(C2H3N4)2(C16H38N6)], has been characterized from synchrotron radiation. The asymmetric unit consists of one half of the Ni(II) complex mol-ecule, which is related to the other half-mol-ecule by an inversion center. The Ni(II) ion is coordinated by four secondary N atoms of the macrocyclic ligand in a square-planar fashion in the equatorial plane and by two N atoms of the 5-methyltetra-zolate anions in axial positions, resulting in a tetra-gonally distorted octa-hedral geometry. The average equatorial Ni-N bond length [2.060 (8) Å] is shorter than the axial Ni-N bond length [2.2183 (11) Å]. An intra-molecular N-H⋯N hydrogen bond between the secondary amine N atom of the macrocyclic ligand and the non-coordinating N atom of the 5-methyltetra-zolate ion stabilizes the mol-ecular structure. Moreover, an inter-molecular N-H⋯N hydrogen bond between the macrocyclic ligand and 5-methyltetra-zolate group gives rise to a supra-molecular sheet structure parallel to the bc plane.


Rapid quantitation of Trypanosoma cruzi in host tissue by real-time PCR.
A real-time PCR technique that allows for accurate and sensitive quantitation of tissue parasite burden in animals infected with the protozoan parasite Trypanosoma cruzi was developed. The utility of this method was demonstrated by confirmation of higher parasite load in mice with acute infections in comparison to chronically infected mice, detection of tissue-restricted parasite persistence in different parasite:host strain combinations, and the observation of increased tissue parasite burden with higher infective doses. This method should be a useful tool for monitoring parasite burden in hosts under various treatment regimens.


Effects of age-related tympanic-membrane material properties on sound transmission in the middle ear in a three-dimensional finite-element model.
The Young's modulus of the tympanic membrane (TM) is an important modeling parameter in computer simulations of the sound transmission in the ear. Understanding the material mechanics of the TM is essential to improve the coupling between the tympanic membrane and the auditory ossicles. However, the impact of the age-related Young's modulus of the TM on sound transmission is not well known. The objective of this study was to use a comprehensive finite element (FE) model to assess the impact of Young's modulus on sound transmission from the ear canal to the stapes footplate over acoustic frequencies. The FE model of the ear canal, the middle ear, and the inner ear, was constructed. The model was constructed with identical geometries and boundary conditions, but with three different Young's moduli for the TMs. The auditory ossicles, suspensory ligaments and tendons, and manubrium were also modeled as isotropic elastic materials. Beside, we evaluated the age-related Young's moduli of the TMs on sound transmission with the FE element fluid-structural interaction (FSI) model under acoustic loading conditions. The impact of the age-related Young's moduli on the sound pressure distributions in the ear canal was significant over two frequency ranges of 1.4-3.2 and 8.6-10 kHz. Meanwhile, the significant differences of the displacement of the stapes occurred at around 1.6 kHz, where the displacement of the stapes decreased from 0.352 nm to 0.287 nm. The FSI model could demonstrate the influence of Young's modulus of the TM on the transfer of sound-induced vibrations form the ear canal to the stapes footplate. The FE model may provide appropriate information to the medical device development of artificial ossicles and hearing aids.


Mutagens in the feces of 3 South-African populations at different levels of risk for colon cancer.
The incidence of mutagens in the feces of 3 South-African populations at different risk levels for colon cancer has been determined. Lyophilized fecal samples were extracted with ether and the mutagenicity of the extracts determined using the Salmonella/mammalian microsome mutagenicity test. 19% of the samples from urban white South-Africans, a population at a high risk for colon cancer, were mutagenic using Salmonella typhimurium strain TA100. This incidence was significantly greater (p less than 0.001) than the incidence of mutagen excretion in the low-risk populations of urban blacks (2%) and rural blacks (0%). This pattern was also obtained using Salmonella typhimurium strain TA98. The incidence of mutagen excretion for urban whites was 10%, as compared to 5% and 2% for urban and rural blacks, respectively.


Application of response surface methodology for studying the product characteristics of extruded rice-cowpea-groundnut blends.
Response surface methodology (with central composite rotatable design for k=3) was used to investigate the product properties of extruded rice-cowpea-groundnut blends in a single screw extruder. The combined effect of cowpea (0-20%), groundnut (0-10%), and feed moisture (14-48%) levels were used for formulation of the products. The product moisture, expansion ratio, bulk density and total colour change were studied using standard analytical methods. Well-expanded rice-legume blend extrudates of less bulk density and lower moisture content were produced at low feed moisture. Increasing legume addition affected the various shades of colour in the product. Models developed for the indices gave R(2) values ranging from 52.8% (for the b-value) to 86.5% (for bulk density). The models developed suggested that the optimal process variables for the production of a puffed snack with an enhanced nutrition and spongy structure from a rice-cowpea-groundnut blend are low feed moisture of 14-20% and maximum additions of 20% cowpea and 10% groundnut. A lack-of-fit test showed no significance, indicating that the models adequately fitted the data.


Survey for fumonisin B1 in Korean corn-based food products.
Seventy-six corn-based foods collected in Seoul, Korea, including corn flakes, corn snack, cornstarch, corn for popping, roasted corn for tea, canned sweet corn and other corn products were analysed for the occurrence of fumonisin B(1) (FB(1)) by using direct competitive enzyme-linked immunosorbent assay (dcELISA) and high-performance liquid chromatography (HPLC). The average recoveries of FB(1) from the corn flakes sample in the range 5-1000 ng g(-1) were 104% by dcELISA and 82% by HPLC. The limits of detection were approximately 5 ng g(-1) by dcELISA and 20 ng g(-1) by HPLC. The incidences and mean levels of FB were 73.3, 78.6, 50, 58.3, 17.6 and 40% and 41.8, 67.9, 114, 256, 172 and 22 ng g(-1) from corn flakes, corn snack, corn starch, corn for popping, roasted corn for tea and other corn products, respectively, by dcELISA. No FB(1) was found in canned sweet corn. The results obtained by dcELISA were correlated to those by HPLC for FB(1) (r(2) = 0.992). This is the first report on the occurrence of FB(1) in corn-based foods in Korea.


A novel natural GRAS-grade enteric coating for pharmaceutical and nutraceutical products.
In this study, enteric coatings based exclusively on naturally occurring ingredients were reported. Alginate (Alg) and pectin (Pec) blends with or without naturally occurring glyceride, glycerol monostearate (GMS), were initially used to produce solvent-casted films. Incorporating GMS in the natural polymeric films significantly enhanced the acid-resistance properties in gastric medium. Theophylline tablets coated with Alg-Pec blends without GMS disintegrated shortly after incubation in gastric medium (pH 1.2), leading to a premature and complete release of theophylline. Interestingly, tablets coated with Alg-Pec blends that contain the natural glyceride (GMS) resisted the gastric environment for 2 h with minimal drug release (<5%) and disintegrated rapidly following introduction to the intestinal medium, allowing a fast and complete drug release. Furthermore, the coating system proved to be stable for six months under accelerated conditions. These findings are particularly appealing to nutraceutical industry as they provide the foundation to produce naturally-occurring GRAS based enteric coatings.


[Scar tissue, organ atrophy and hypertrophy in the computed tomogram after abdominal surgery].
After resection of parenchymal abdominal organs the developing scar tissue is characterised by fat (-30 to -50 H.U.) in connection with mesenchymal funicles. Differential diagnosis presents no problem. Atrophy and hypertrophy may sometimes be demonstrated in CT. This is valid for compensating hypertrophy of the remaining parts of the liver, splenic regeneration or an accessory spleen. Furthermore, involution of the tail of the pancreas after proximal duodenopancreatectomy could be shown in CT. One pancreatic calcification decreased after drainage of a pseudocyst.


Three-dimensional structure, specificity and catalytic mechanism of renin.
Renin is an aspartyl proteinase that catalyses the first, and rate-limiting, step in the conversion of angiotensinogen to the hormone angiotensin II. The catalysis is highly specific, and plays an important physiological part in the regulation of blood pressure. For this reason inhibitors of renin are of potential value in the treatment of certain forms of hypertension. Although progress has been made in the design of inhibitors for clinical use by modification of angiotensinogen sequences, and as pepstatin analogues or with reduced peptide bonds, we have now provided the basis for a more rational approach by the use of interactive computer graphics techniques to build a three-dimensional model of renin. The model is based on the three-dimensional structure of endothia pepsin and the primary structure of mouse renin, which is very similar to that of the human enzyme. We show that renin may have a three-dimensional structure similar to that of other aspartyl proteinases.


Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective.
A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. Recent clinical and experimental studies have noted that increased release of tumor necrosis factor alpha (TNF-alpha) can contribute to LV myocardial remodeling. Experimental studies have noted that the induction of TNF-alpha can result in LV dilation and proceed to LV pump dysfunction. The biological effects of TNF-alpha are mediated through TNF receptors that are present on all nucleated cells in the heart. TNF receptor activation can induce a number of cellular and molecular events which contribute to LV remodeling in CHF, and include changes in myocyte size and viability and alterations in myocardial structure/composition. In vitro studies have demonstrated that TNF receptor activation can cause the induction of a proteolytic system. This proteolytic system, the matrix metalloproteinases (MMPs), is upregulated in models of LV dysfunction and possesses the capacity to degrade a wide variety of extracellular matrix components. Therefore, one pathway by which TNF-alpha can influence LV myocardial remodeling is through the induction of a specific portfolio of MMP species. Future basic and clinical studies which directly alter TNF receptor activity and measure myocardial MMP species and the relation to LV remodeling will provide new insight into this disease process and future therapeutic modalities.


Vigilance: discussion of related concepts and proposal for a definition.
We reviewed current definitions of vigilance to propose a definition, applicable in sleep medicine. As previous definitions contained terms such as attention, alertness, and arousal, we addressed these concepts too. We defined alertness as a quantitative measure of the mind state governing sensitivity to stimuli. Arousal comprises a stimulus-induced upward change in alertness, irrespective of the subsequent duration of the increased level of alertness. Vigilance is defined as the capability to be sensitive to potential changes in one's environment, ie the capability to reach a level of alertness above a threshold for a certain period of time rather than the state of alertness itself. It has quantitative and temporal dimensions. Attention adds direction towards a stimulus to alertness, requiring cognitive control: it involves being prepared to process stimuli coming from an expected direction. Sustained attention corresponds to a state in which some level of attention is purposefully maintained, adding a time factor to the definition of attention. Vigilance differs from sustained attention in that the latter in addition implies a direction to which attention is cognitively directed as well as a specification of duration. Attempts to measure vigilance, however, are often in fact measurements of sustained attention.


Postoperative cognitive functions in patients with benign intracranial lesions.
The aim of this study was to assess pre- and postoperative cognitive functions in patients who underwent surgery for benign intracranial lesions. In total, 58 patients (21 men, 37 women, mean age 51.6 years [range 24-76 years]) with benign intracranial lesions (including benign tumors and vascular lesions) and neuralgia of the trigeminal nerve were included in this prospective study. Extensive cognitive testing was used to categorize attention, memory, and executive functions. Mood and pain were assessed preoperatively (t0, mean 3.7 days before surgery), immediately after surgery/during inpatient stay (t1, mean 7.6 days after surgery), and at first outpatient check-up (t2, mean 99.5 days after surgery). All 58 patients were tested at t0 and t1, but at t2 only 24 patients were available at t2. The data were categorized as improvement/stable condition or deterioration and shown as percentages. The pre- and postoperative values of BDI-II and mood were compared by the Wilcoxon test for paired samples. Binary logistic regression analyses were performed to identify parameters influencing cognition in the subgroup of meningioma patients. Immediately after surgery (t1), the percentage of patients with improvement/stable condition was > 50% in all categories in the majority of subtests (attention: 12/14 subtests, memory: 11/13 subtests, executive functions: 6/9 subtests). Similar results were shown at t2. Mood and pain did not change significantly after surgery. Factors like age, Karnofsky performance status, and tumor volume were not shown as significant influencing factors for cognitive functions in meningioma patients. The results of this study suggest that-in contrast to neuroepithelial tumors-cognitive functions do not deteriorate after surgery of benign intracranial lesions. Further studies are necessary to evaluate the results of this study.


Modulating the timing of flowering.
Several genes that are normally involved in flower initiation have recently been shown to induce early flowering when expressed ectopically in transgenic plants. These findings permit the development of strategies for the rational manipulation of flowering time in agronomically important plants.


Cardiac Targeting Peptide : From Identification to Validation to Mechanism of Transduction.
Cell-penetrating peptides (CPPs), also known as protein transduction domains, were first identified 25 years ago. They are small, ~6-30 amino acid long, synthetic, or naturally occurring peptides, able to carry a variety of cargoes across the cellular membranes in an intact, functional form. These cargoes can range from other small peptides, full-length proteins, nucleic acids including RNA and DNA, nanoparticles, and viral particles as well as radioisotopes and other fluorescent probes for imaging purposes. However, this ability to enter all cell types indiscriminately, and even cross the blood-brain barrier, hinders their development into viable vectors. Hence, researchers have adopted various strategies ranging from pH activatable cargoes to using phage display to identify tissue-specific CPPs. Use of this phage display strategy has led to an ever-expanding number of tissue-specific CPPs. Using phage display, we identified a 12-amino acid, non-naturally occurring peptide that targets the heart with peak uptake at 15 min after a peripheral intravenous injection, that we termed Cardiac Targeting Peptide (CTP). In this chapter, we use CTP as an example to describe techniques for validation of cell-specific transduction as well as provide details on a technology to identify binding partner(s) for these ever-increasing plethora of tissue-specific peptides. Given the myriad cargoes CTP can deliver, as well as rapid uptake after an intravenous injection, it can be applied to deliver radioisotopes, miRNA, siRNA, peptides, and proteins of therapeutic potential for acute cardiac conditions like myocardial infarction, where the window of opportunity for salvaging at-risk myocardium is limited to 6 hrs.


A Diarylpentanoid with Potential Activation of the p53 Pathway: Combination of in silico Screening Studies, Synthesis, and Biological Activity Evaluation.
In silico studies of a library of diarylpentanoids led us to the identification of potential new MDM2/X ligands. The diarylpentanoids with the best docking scores obeying the druglikeness and ADMET prediction properties were subsequently synthesized and evaluated for their antiproliferative activity on colon cancer HCT116 and fibroblasts HFF-1 cells. The effect on p53-MDM2/X interactions was evaluated through yeast-based assays for compounds showing potent antiproliferative activity in HCT116 cells and low toxicity in normal cells, resulting in the identification of a potential dual inhibitor. Moreover, its antiproliferative effect was significantly reduced in the absence of p53 and in MDA-MB-231 cells expressing a mutant p53 form. The antiproliferative effect of this compound was associated with induction of cell cycle arrest, apoptosis, PARP cleavage and increased p53 and its transcriptional targets, p21 and PUMA, in HCT116 cells. Docking poses and residues involved in the inhibition of p53-MDM2/X interactions were predicted by docking studies.


Regional distribution of muscarinic receptors preferring gallamine in the rat brain.
The regional distribution of muscarinic receptors recognized by the antagonist gallamine was determined autoradiographically by the ability of gallamine to reduce the binding of [3H]quinuclidinyl benzilate in rat brain slices. The inhibition data obtained from indirect binding assays on whole slices indicated that gallamine distinguished at least two sites with differing affinities. Analysis using a two-site model gave Kh = 0.6 microM, K1 = 10 microM. The regions of highest and lowest affinity for gallamine were apparent qualitatively by visual inspection of the autoradiograms. A number of regions in coronal sections at three different levels were compared by microdensitometry. Gallamine possessed greater overall affinity for the diencephalon and brainstem than for the forebrain. Within the forebrain, the septal nucleus was unique in that it displayed high affinity for gallamine. Within the brainstem, the superior colliculus had the greatest proportion of sites with high affinity for gallamine. In general, the binding profile of gallamine was opposite to that of the antagonist pirenzepine and similar to that of the agonist carbachol, suggesting that gallamine is selective for M2 muscarinic receptors.


The epigenetic regulation of cancer cell recovery from therapy exposure and its implications as a novel therapeutic strategy for preventing disease recurrence.
The ultimate goal of cancer therapy is the elimination of disease from patients. Most directly, this occurs through therapy-induced cell death. Therapy-induced growth arrest can also be a desirable outcome, if prolonged. Unfortunately, therapy-induced growth arrest is rarely durable and the recovering cell population can contribute to cancer recurrence. Consequently, therapeutic strategies that eliminate residual cancer cells reduce opportunities for recurrence. Recovery can occur through diverse mechanisms including quiescence or diapause, exit from senescence, suppression of apoptosis, cytoprotective autophagy, and reductive divisions resulting from polyploidy. Epigenetic regulation of the genome represents a fundamental regulatory mechanism integral to cancer-specific biology, including the recovery from therapy. Epigenetic pathways are particularly attractive therapeutic targets because they are reversible, without changes in DNA, and are catalyzed by druggable enzymes. Previous use of epigenetic-targeting therapies in combination with cancer therapeutics has not been widely successful because of either unacceptable toxicity or limited efficacy. The use of epigenetic-targeting therapies after a significant interval following initial cancer therapy could potentially reduce the toxicity of combination strategies, and possibly exploit essential epigenetic states following therapy exposure. This review examines the feasibility of targeting epigenetic mechanisms using a sequential approach to eliminate residual therapy-arrested populations, that might possibly prevent recovery and disease recurrence.


Hypothalamic hamartomas: seven cases and review of the literature.
Hypothalamic hamartomas constitute rare developmental lesions associated with gelastic epilepsy and/or precocious puberty (PP). We elected to review cases encountered at our center (7 patients) and the existing literature (277 patients) to obtain a better understanding of the clinical aspects, pathogenesis, and treatment of this entity. Evidence suggests that gelastic seizures are due to intrinsic epileptogenicity. The cause of the subsequent development of other seizure types, cognitive decline, and diffuse spike-and-wave pattern remains unresolved and is addressed. Anticonvulsants often fail to control seizures and different surgical options are available. Available evidence suggests that a resection through a subtemporal approach is best for lesions that are pedunculated or with a significant prepontine component, while a transcallosal approach is more appropriate for sessile lesions with an intraventricular component. Gamma knife surgery may be especially useful for small sessile lesions, failed partial resections, or patients not appropriate or refusing open surgery.


Flower-like NiO to flower-like NiO/Ni@C microspheres: An effective strategy to comprehensively improve the loss capabilities.
It was well recognized that the penetrated electromagnetic (EM) wave could be dissipated by means of magnetic loss, polarization loss and conduction loss. In order to improve their loss capacities and take full advantage of flower-like geometrical morphology, in this study, we proposed a simple route for the production of flower-like core@shell structure NiO/Ni@C microspheres through the carbon thermal reaction using NiO microflowers as precursor. The obtained results revealed that our proposed strategy successfully synthesized the core@shell structure magnetic carbon-based multicomponent nanocomposites without destroying the geometrical morphology of precursor. By regulating the annealing temperature, the as-prepared NiO/Ni@C microspheres with different contents of Ni and degrees of graphitization could be selectively synthesized, which effectively boosted their magnetic loss, polarization loss and conduction loss capabilities. Therefore, the elaborately designed NiO/Ni@C microspheres displayed the superior microwave absorption performances including strong absorption capability, broad absorption bandwidth and thin matching thicknesses compared to the NiO precursor. In summary, our findings not only provided a simple route to design and synthesize flower-like core@shell structure magnetic carbon-based nanocomposites as novel microwave absorbers, but also presented an effective strategy to comprehensively improve their loss capacities.


Strategy for high-throughput identification of protein complexes by array-based multi-dimensional liquid chromatography-mass spectrometry.
Comprehensive elucidation of the composition of multiprotein complexes in model organisms is essential to understand conserved biological systems, but large-scale mapping physical association networks is still challenging due to limited throughput of present methods. In this work, a strategy coupling array-based online two-dimensional liquid chromatography (array-based 2D-LC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was demonstrated for high throughput and in-depth identification of protein complexes from cultured human HeLa cell extracts. Mixed-bed ion-exchange column was employed as the first dimensional (1stD) separating mode and an array consisting of eight reversed phase columns was developed as the second dimensional (2ndD) mode. Taking advantage of array parallel strategy, this online system showed an 8-fold increase in throughput. After array-based online 2D-LC separation, altogether 256 × 2ndD fractions were collected for further LC-MS/MS analysis. Public databases of protein-protein interaction (PPI) and co-elution curves identified by LC-MS were applied to reconstruct the protein complexes. A rigorous inspection was operated by cataloging the protein complexes into chromatographic fractions to minimize the number of false positives. As result, a total number of 4,436 proteins were identified and 26,092 elution curves were graphed. A network consisting of 47,745 PPIs was established among 2,201 proteins and presented 1,530 putative protein complexes with high confidence. Most of the identified PPIs were linked to diverse biological processes and may reveal further disease mechanism and therapeutic strategy.


Enhancement of pyruvate productivity in Torulopsis glabrata: Increase of NAD+ availability.
This study aimed at increasing the pyruvate productivity from a multi-vitamin auxotrophic yeast Torulopsis glabrata, by increasing the availability of NAD+. We examined two strategies for increasing availability of NAD+. To supplement nicotinic acid (NA), the precursor of NAD+; and to increase the activity of alcohol dehydrogenase integrating with addition acetaldehyde as exterior electron acceptor. The addition of 8 mg l(-1) NA to the fermentation medium resulted in a significant increase in the glucose consumption rate (48.4%) and the pyruvate concentration (29%). An ethanol-utilizing mutant WSH-13 was screened and selected after nitrosoguanidine mutagenesis of the parent strain T. glabrata CCTCC M202019. Compared with the parent strain, the alcohol dehydrogenase activity of the mutant WSH-13 increased about 110% and the mutant could utilize ethanol as the sole carbon source for growth (1.8 g l(-1) dry cell weight). When growing with glucose, the addition of 4 mg l(-1) acetaldehyde to the mutant WSH-13 culture broth led to a significant increase in the glucose consumption rate (26.3%) and pyruvate production (22.5%), but the ratio of NADH/NAD+ decreased to 0.22. Acetaldehyde did not affect the glucose and energy metabolism at high dissolved oxygen (DO) concentration. However, at lower DO concentration (20%), maintaining the acetaldehyde concentration in the mutant culture broth at 4 mg l(-1) caused an increased NAD+ concentration but a decreased NADH concentration. As a consequence, the pyruvate production rate, the pyruvate yield on glucose and the pyruvate concentration were 68, 44 and 45% higher, respectively, than the corresponding values of the control (without acetaldehyde). The strategy for increasing the glycolytic flux and the pyruvate productivity in T. glabrata by increasing the availability of NAD+ may provide an alternative approach to enhance the metabolites productivity in yeast.


Fatigue in inflammatory rheumatic diseases: current knowledge and areas for future research.
Fatigue is a complex phenomenon and an important health concern for many people with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, primary Sjögren syndrome and systemic lupus erythematosus. Although some clinical trials have shown the benefits of cognitive behavioural therapy in fatigue management, the effect of this approach is relatively modest, and no curative treatment has been identified. The pathogenesis of fatigue remains unclear. Despite many challenges and limitations, a growing body of research points to roles for the immune system, the central and autonomic nervous systems and the neuroendocrine system in the induction and maintenance of fatigue in chronic diseases. New insights indicate that sleep, genetic susceptibility, metabolic disturbances and other biological and physiological mechanisms contribute to fatigue. Furthermore, understanding of the relationships between psychosocial factors and fatigue is increasing. However, the interrelationships between these diverse mechanisms and fatigue remain poorly defined. In this Review, we outline various biological, physiological and psychosocial determinants of fatigue in inflammatory rheumatic diseases, and propose mechanistic and conceptual models of fatigue to summarize current understanding, stimulate debate and develop further research ideas.


The Computerized Cognitive Composite (C3) in an Alzheimer's Disease Secondary Prevention Trial.
Computerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). Multi-center international study. Clinically normal (CN) older adults (65-85; n=4486). Participants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer's Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC. C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants. These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.


Increased sensitivity to phagocytosis of Staphylococcus E-46 after growth in artificial media.
Staphylococcus E-46, which exhibits high virulence in mice mainly due to resistance to phagocytosis, gradually lost its virulence during growth in artificial media [Heart-Infusion (HI) slants]. Staphylococcus E-46 is coagulase-negative and DNase-positive, and has a capsule-like structure, and the less-virulent derivative (LVD) strain seemed not to be changed in this respect. The bacteria which had been exposed to HI slants for more than one year (= LVD strain) became more sensitive to phagocytosis by mouse peritoneal macrophages than bacteria which were kept in a lyophilized state. The chemiluminescent response of macrophages to the LVD strain was remarkably higher than that to the original Staphylococcus E-46. When the LVD or the sera for opsonization were heated, the chemiluminescence to the LVD was as low as that to the original Staphylococcus E-46. Polyacrylamide gel electrophoresis of sonication-released membrane protein from the LVD strain showed a unique band with a molecular weight of about 40,000. The factor concerned with the virulence of Staphylococcus E-46 is discussed based on these results.


Patch Test Practice Patterns of Members of the American Contact Dermatitis Society.
Patch testing is the criterion standard for diagnosis and management of allergic contact dermatitis. Limitations on the number of allergens tested can negatively impact patient care. This study reports clinical practice patterns of American Contact Dermatitis Society (ACDS) members. In October and November 2018, the US-based members of the ACDS received an electronic survey regarding their procedures and experiences with patch testing. We evaluated the type of practice, number of patients tested, type of screening and supplemental series, number of allergens tested, and billing and reimbursement concerns. There were 149 respondents; 62% use ACDS Core 80, 70% "sometimes" or "always" test with supplemental series, and 70% "sometimes" or "always" test patient products. Participants estimated that supplemental series identify relevant allergens 35% of the time. Approximately 66% most commonly test more than 81 allergens per patient, and 78% expressed concerns regarding fair reimbursement. Most ACDS members routinely test more than 81 allergens per patient. Barriers to fair payment for beyond a fixed number of patches at any one visit may impede the diagnosis of allergic contact dermatitis, prolong suffering, and worsen outcomes.


[Prognostic value of histopathological parameters in epidermoid carcinoma of the vocal cords in T-1 stage].
In this paper are studied macro- and microscopically, 14 histopathologic parameters belonging to 37 patients suffering from vocal cord squamous cell carcinoma, stage T-la. All patients were submitted to cordectomy and followed up during a 5 years term, as a minimum. A discriminant analysis was performed in order to establish the relation between histopathologic parameters and local failure. Only two of them were statistically significative (p < 0.01): the structural type and the differential degree of tumor cells. The histopathological study allowed the prediction of 82 percent of local recurrences.


Genetic parameters for growth performance of the Malaysian local goats and their crossbreds with the German (improved) Fawn goats.
Growth performance data of the local goats of Malaysia and their crossbreds with the German (Improved) Fawn goats were analysed using animal models with maternal effects, in order to estimate additive genetic and crossbreeding parameters. Two different genetic models, the Dickerson (1969, 1973) model and the Kinghorn (1980, 1983) model, were used to estimate crossbreeding parameters. Coefficients of additive breed, heterosis (dominance), and recombination (epistatic) loss were fitted in the animal models as covariates. In general, the individual breed effects for birth, 6-month, and 9-month weights, and maternal breed effects for traits until weaning, were significant, indicating large differences for growth performance between the German Fawn and the local breeds. Heterosis effects by the Dickerson model were small and non-significant, while dominance effects by the Kinghorn model, for some of traits, were large and significant. Highly significant individual recombination loss effects by the Dickerson model, and epistatic loss effects by the Kinghorn model, were obtained for birth and 9-month weights. The estimates of total heritability by an animal model incorporating maternal effects were moderate (0.18-0.35). The differences between heritabilities, estimated by different genetic models (the Dickerson model vs. the Kinghorn model), were small. ZUSAMMENFASSUNG: Genetische Parameter von Wachstumseigenschaften Malaysischer Lokalziegen und ihrer Kreuzung mit Deutscher Rehbrauner Ziege Die Daten wurden mittels Tiermodellen mit Maternalwirkung zur Schätzung additiv genetischer und Kreuzungsparameter analysiert. Zur Schätzung letzterer wurden Modelle von Dickerson (1969, 1973) und Kinghorn (1980, 1983) angewendet. Koeffizienten der additiven Rassenwirkungen, Heterosis (Dominanz) und Rekombinations-wirkungen wurden im Tiermodell als Kovarialbe berücksichtigt. Im allgemeinen waren individuelle Rassenwirkungen für Geburts-, 6- und 9-Monatsgewicht und maternale Rassenwirkungen für Merkmale während der Säugezeit signifikant, eine Folge großer Rassenunterschiede. Das Dickerson Modell führte zu geringen, nicht signifikanten Heterosiswirkungen, während beim Kinghorn Modell diese sich für mehrere Merkmale als groß und signifikant erwiesen haben. Hoch signifikante individuelle Rekombinationsverluste und epistatische Verluste ergaben sich bei beiden Modellen für Geburtsgewicht und 9 Monatsgewicht. Heritabilitätswerte waren mäßig hoch (0.18 bis 0.35), enthielten auch die maternalen Wirkungen und unterschieden sich zwischen beiden Modellen nur geringfügig.


Estrogenic action of estriol fatty acid esters.
Recent studies suggest that, estriol, like estradiol, is biosynthetically esterified with fatty acids. We have synthesized the stearate estriol, at C-16 alpha, C-17 beta and the diester, C-16 alpha,17 beta and tested these D-ring esters for their estrogenic action both in vivo and in vitro, comparing them to estradiol, estriol and estradiol-17-stearate. None of the estriol esters bind to the estrogen receptor. They are only weakly estrogenic in a microtiter plate estrogen bioassay: stimulation of alkaline phosphatase in the Ishikawa endometrial cells. However, both estriol monoesters are extremely potent estrogens when injected subcutaneously (in aqueous alcohol) into ovariectomized mice. Compared to the free steroids, they produced a dramatically increased uterine weight with a greatly prolonged duration of stimulation. The 16 alpha,17 beta-diester also induced a protracted uterotrophic response, but the stimulation of uterine weight was comparatively low. Since the esters of estradiol and estriol do not bind to the estrogen receptor, their estrogenic signal must be generated through the action of esterase enzymes. These naturally occurring esters have the potential of being extremely useful pharmacological agents for long-lived estrogenic stimulation.


A study of glaucoma after penetrating keratoplasty.
To identify the incidence and risk factors associated with the development of glaucoma after penetrating keratoplasty. A retrospective study was carried out in 228 patients who underwent penetrating keratoplasty from January 1995 to January 2000 at the Cornea Section of the Ophthalmology Service at the School of Medicine, Federal University of Uberlândia MG, Brazil. Follow-up time ranged from 4 to 60 months (mean, 17.14 +/- 13.65). Two hundred twenty-eight patients undergoing penetrating keratoplasty were evaluated and 49 (21.5%) developed glaucoma. Risk factors for developing glaucoma were bullous keratopathy [relative risk (RR) = 2.1774), herpesvirus (RR = 1.8979), and trauma (RR = 1.0575). Mean intraocular pressure before transplantation was 15.26 +/- 5.37 mm Hg. Intraocular pressure after transplantation ranged from 22 to 58 mm Hg, with a mean value of 30.04 +/- 7.06 mm Hg. Thirty-six (73.5%) patients had medical treatment, 10 (20.4%) had medical and surgical treatment, and three (6.1%) had surgical treatment. Final intraocular pressure ranged from 4 to 34 mm Hg (mean, 16.79 +/- 5.36). The incidence of glaucoma after penetrating keratoplasty is high, and the risk factors include aphakic/pseudophakic bullous keratopathy, herpes simplex virus, and trauma.


Phenotypical and genotypical differences among Leishmania (Leishmania) amazonensis isolates that caused different clinical frames in humans and dogs: A systematic review.
Leishmania (Leishmania) amazonensis is an important etiological agent of American cutaneous leishmaniasis (ACL) in Brazil. The species causes a large spectrum of clinical manifestations in humans and dogs, ranging from cutaneous, cutaneous diffuse, mucocutaneous, and visceral involvement, however, the factors that drive the development of different disease forms by the same species are not yet fully known. In the present work, it was systematically reviewed the studies addressing phenotypic and genotypic characteristics of Leishmania (L.) amazonensis isolates causing cutaneous and visceral clinical frames in humans and dogs, comparing the results observed. For this, four research databases were searched for the following keywords: (Leishmania amazonensis AND visceral leishmaniasis) AND (tropism OR virulence OR visceralization OR adaptations OR mutation OR clinical presentation OR resistance OR survival OR wide spectrum). The results revealed that the complexity disease seems to involve the combination of genetic factors of the parasite (as modifications in molecules related to the virulence and metabolism) and also of the host's immune background and status. Nonetheless, the exact mechanism that leads to different clinical manifestations between strains of the same species is still uncertain and future studies must be developed to better elucidate this phenomenon.


Developmental validation of the PowerPlex® ESX 16 and PowerPlex® ESX 17 Systems.
We describe the developmental validation study performed on the PowerPlex(®) ESX 16 (European Standard Extended 16) and the PowerPlex(®) ESX 17 Systems, part of a suite of four new DNA profiling kits developed by Promega in response to the ENFSI and EDNAP groups' call for new STR multiplexes for Europe. The PowerPlex(®) ESX 16 System combines the 11 loci compatible with the UK National DNA Database, contained within the AmpFlSTR(®) SGM Plus(®) PCR Amplification Kit, with five additional loci: D2S441, D10S1248, D22S1045, D1S1656 and D12S391. The multiplex was designed to incorporate these five new loci as mini- and midi-STRs while maintaining the loci found in the AmpFlSTR(®) SGM Plus(®) kit as standard size. The PowerPlex(®) ESX 17 System amplifies the same loci as the PowerPlex(®) ESX 16 System, but with the addition of a primer pair for the SE33 locus. Tests were designed to address the developmental validation guidelines issued by the Scientific Working Group on DNA Analysis Methods (SWGDAM), and those of the DNA Advisory Board (DAB). Samples processed include DNA mixtures, PCR reactions spiked with inhibitors, a sensitivity series, and 306 United Kingdom donor samples to determine concordance with data generated with the AmpFlSTR(®) SGM Plus(®) kit. Allele frequencies from 242 white Caucasian samples collected in the United Kingdom are also presented. The PowerPlex(®) ESX 16 and ESX 17 Systems are robust and sensitive tools, suitable for the analysis of forensic DNA samples. Full profiles were routinely observed with 62.5 pg of a fully heterozygous single source DNA template. In mixture analysis, a range of 52-95% of unique minor contributor alleles was observed at 19:1 mixture ratios where only 25 pg of the minor component was present. Improved sensitivity combined with the robustness afforded by smaller amplicons has substantially improved the quantity of information obtained from degraded samples, and the improved chemistry confers exceptional tolerance to high levels of laboratory prepared inhibitors.


Trelagliptin stimulates osteoblastic differentiation by increasing runt-related transcription factor 2 (RUNX2): a therapeutic implication in osteoporosis.
Osteoporosis, an aging-associated bone metabolic disease, is affecting millions of people worldwide. The deregulated process of osteoblastic differentiation has been linked with the progression of osteoporosis. Trelagliptin is a long-acting inhibitor of DPP-4 used for the management of type 2 diabetes mellitus. However, it is unknown whether Trelagliptin possesses a beneficial effect in osteoblastic differentiation. Interestingly, we found that treatment with Trelagliptin enhanced differentiation and promoted the mineralization of MC3T3-E1 cells. Firstly, Trelagliptin increased the activity of alkaline phosphatase (ALP) and promoted osteoblastic calcium deposition. Additionally, treatment with Trelagliptin upregulated ALP, osteocalcin (OCN), osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2). Notably, Trelagliptin increased RUNX2, a major regulator of osteoblastic differentiation. Mechanistically, Trelagliptin upregulated the levels of p-AMPKα. Blockage of AMPK with compound C abolished the effects of Trelagliptin in RUNX2 and osteoblastic differentiation, suggesting the involvement of AMPK. Our findings suggest that Trelagliptin might possess a potential for the treatment of osteoporosis.


Inflammation in Health and Disease: New Insights and Therapeutic Avenues.
The inflammatory response is an adaptive mechanism that evolved to fight against infections and tissue damage [...].


Passive air sampling of organochlorine pesticides in a northeastern state of India, Manipur.
Thirty-six polyurethane foam disk passive air samplers (PUF-PAS) were deployed over a year during January to December, 2009 at three locations, i.e., Imphal (urban site), Thoubal (rural site) and Waithou (alpine site) of Manipur, to assess the seasonal local atmospheric emission of selected organochlorine pesticides (OCPs). The average concentration of HCHs monitored at mountain site during hot season (Mar, Apr, and May) and rainy seasons (Jun, Jul, Aug, and Sep) were 403 and 349 pg/m3, respectively. DDTs had a high concentration with 384 pg/m3 at rural site and 379 pg/m3 at urban site during hot seasons. Endosulfans and chlordane were found high in concentration during hot seasons (260 pg/m3) and low during retreating monsoon seasons (44 pg/m3) at rural site. Most of the OCPs concentrations were high during cultivation period. The OCP concentrations of rainy season were highly correlated (p < 0.01) with OCPs of hot seasons. Further, positive correlation (p < 0.05) was also obtained between cold seasons and retreating monsoon. Principal component analysis showed a significant correlation among the four seasons and distribution pattern of OCPs in air. Back trajectory analysis by using HYPSLIT model showed a long range air transport of OCPs to the present study area. Present OCP levels at Manipur is an outcome of both local emission and also movement of air mass by long range atmospheric transport.


Response of the microbial community associated with sweet potato (Ipomoea batatas) to Bacillus safensis and Bacillus velezensis strains.
Sweet potato is a subsistence crop cultivated worldwide. Although it is generally considered tolerant to different diseases, it is quite susceptible to the fungus Plenodomus destruens that causes foot-rot disease. Plant growth-promoting bacteria associated with sweet potato remain poorly studied, but some Bacillus strains may have potential as biological control agents. Here, we evaluate the persistence of two bacterial strains-Bacillus safensis T052-76 and Bacillus velezensis T149-19-in pot experiments and assess their impact on indigenous bacterial and fungal communities associated with sweet potato. Numbers of cells of both strains introduced into pots remained stable in the rhizosphere of sweet potato over the 180-day experiment. Denaturing gradient gel electrophoresis based on the rrs gene encoding bacterial 16S rRNA and the fungal ribosomal internal transcribed spacer region showed that bands corresponding to the introduced strains were not detected in plant endosphere. PERMANOVA and non-metric multidimensional scaling statistical analyses showed that: (1) strain T052-76 altered the structure of the indigenous bacterial community (rhizosphere and soil) more than strain T149-19; (2) T052-76 slightly altered the structure of the indigenous fungal community (rhizosphere and soil) and (3) strain T149-19 did not disturb the fungal community. Our results demonstrate the stability of both Bacillus strains in the sweet potato rhizosphere and, apart from the influence of B. safensis T052-76 on the bacterial community, their limited impact on the microbial community associated with this important crop plant.


Genomic structure and promoter activity of the E1AF gene, a member of the ETS oncogene family.
E1AF is a member of the ETS oncogene family and is thought to be a human homologue of mouse PEA3. We have isolated a genomic clone of E1AF and analyzed the promoter activity of its 5'-flanking region. We identified a variation in exon 1, which depends on the cell type. There was no typical TATA box in the 5'-flanking region, but putative binding sites of a number of transcription factors including PEA3 as well as CAAT boxes were seen. A luciferase reporter assay indicated that the 5'-flanking region possesses promoter activity. Northern blot studies demonstrated significant expression of the E1AF gene in restricted tissues such as the pituitary gland, placenta, and fetal kidney. Moreover, the E1AF promoter was activated by E1AF itself and estrogen receptor. These findings suggest that E1AF is a housekeeping gene, whose expression is controlled in specific tissues.


Assessing the impact of twin pregnancies on the pelvic floor using 3-dimensional sonography: a pilot study.
The purpose of this study was to compare the morphologic characteristics of the pelvic floor musculature between women with twin and singleton pregnancies. We conducted a cross-sectional case-control study of 40 nulliparous women aged 20 to 38 years to compare women with singleton pregnancies (n = 23) to women with twin pregnancies (n = 17). Biometric measurements of the levator hiatus and the sagittal and coronal diameters were made by transperineal 3-dimensional sonography between the 28th and 38th gestational weeks. Comparisons were statistically assessed by the unpaired Student t test and Mann-Whitney U test. For the women with singleton pregnancies, the mean sagittal diameters at rest, during the Valsalva maneuver, and during pelvic floor contraction were 5.3, 5.7, and 4.5 cm, respectively, and the mean coronal diameters under these conditions were 3.8, 4.1, and 3.6 cm. For the women with twin pregnancies, the corresponding values were as follows: mean sagittal diameters, 5.3, 5.8, and 4.6 cm; and mean coronal diameters, 4.3, 4.3, and 3.8 cm. The differences in coronal diameters were statistically significant at rest (P < .01) and during contraction (P = .04). The mean levator hiatal areas for the women with singleton pregnancies were 14.6, 16.9, and 11.7 cm(2) at rest, during Valsalva, and during contraction, respectively; for the women with twin pregnancies, these values were 16.0, 18.6, and 12.6 cm(2). Hiatal measurements were higher in twin than in singleton pregnancies, with coronal diameters reaching significance at rest and during contraction, suggesting that pelvic support undergoes greater changes during twin pregnancy.


The effects of cytochrome C on the extent of myocardial infarction and regional function of the ischemic myocardium.
The effects of cytochrome C, an electron carrier in the process of oxidative phosphorylation, on infarct size and regional left ventricular function after a coronary artery occlusion were investigated. Thus, in 30 dogs, 1 minute after left anterior descending coronary artery occlusion, 99mTc-labeled albumin microspheres (8 mCi) were injected into the left atrium for subsequent assessment of the hypoperfused zone, that is, the area at risk of infarction. Fifteen minutes after coronary artery occlusion, dogs were randomized into a control group (n = 15) and a cytochrome C-treated group (n = 15). The latter immediately received cytochrome C, 2.5 mg/kg intravenously. Six hours after coronary artery occlusion the dogs were sacrificed and their left ventricles were cut into 3 mm thick slices. Infarct size was determined by triphenyltetrazolium chloride staining and measured by planimetry. The same slices were then submitted to autoradiography and the hypoperfused zone was then measured by planimetry. The hypoperfused zone was 22 +/- 2% and 23 +/- 2% of the left ventricle in the control and treated groups, respectively (NS), indicating that the extent of myocardium at risk before treatment was similar. The extent of the hypoperfused zone which evolved to necrosis was 90 +/- 3% in the control group but only 50 +/- 7% in the treated group (p less than 0.001). Myocardial salvage in the treated group was paralleled by improvement in systolic wall thickness of the ischemic segment as measured by two-dimensional echocardiography. Thus, cytochrome C reduced the extent of myocardial necrosis by 44% and improved systolic function of the ischemic myocardium.


Interaction of norepinephrine and superior cervical ganglion input in the rat pineal body.
The effects of superior cervical ganglion stimulation and the local application of norepinephrine or its antagonist propranolol were studied in 18 pineal cells. In 61% of the pineal cells, stimulation elicited excitation; the same cells also responded by excitation to norepinephrine ejection. When stimulation and norepinephrine ejection were applied together, summation (of the excitation) was observed in these cells. Several cells that failed to respond to stimulation did respond to norepinephrine ejection, but with the opposite pattern, i.e., decrease of firing rates. Propranolol prevented the norepinephrine-induced excitation and inhibition, as well as the excitation produced by stimulation. We suggest that norepinephrine regulates pineal activity by two routes: activation of the sympathetic neuronal input and inhibition by way of the circulation.


Case of recurrent Achromobacter xylosoxidans bacteraemia and PICC (peripherally-inserted central catheter) line infection in an immunocompromised patient.
This report describes recurrent A. xylosoxidans bloodstream and PICC (peripherally-inserted central catheter) line infection in an immunocompromised patient. A 64-year-old female with acute promyelocytic leukaemia presented during a non-neutropenic febrile episode, and A. xylosoxidans was isolated from multiple PICC and peripheral blood cultures, and from the tip of the line on removal. The patient was treated with meropenem and a new PICC line was inserted after sterile blood cultures. Six weeks later, she represented with A. xylosoxidans from multiple cultures from the line. She was treated with piperacillin-tazobactam and the line was removed. There was no evidence of deep-seated infection. Further discussion revealed that the patient was using a sponge to clean, and a sleeve to cover her PICC-line while bathing. A. xylosoxidans was cultured from both the sponge and the swab. Whole Genome Sequencing performed on two blood culture isolated and both environmental isolates confirmed all four isolates were indistinguishable. The patient was advised not to use the sponge/sleeve in future and we have incorporated specific advice in this regard into our patient information. Achromobacter xylosoxidans is an aerobic, non-lactose fermenting gram-negative bacillus usually considered an opportunistic pathogen. It is associated with infection in immunocompromised patients, and is an emerging pathogen in catheter-related infections, sometimes associated with contaminated water. This case of recurrent A. xylosoxidans line infection highlights diagnostic and management challenges associated with catheter-related infections. Treatment is challenging because of intrinsic and acquired resistance mechanisms. Empiric treatment with anti-pseudomonal penicillins or carbapenems with line removal is typically required.


Mobile element insertions and associated structural variants in longitudinal breast cancer samples.
While mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and associated structural variants in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. We identified 11 mobile element insertions or associated structural variants and found that the majority of these occurred early in tumor progression. Most of the variants impact intergenic regions; however, we identified a translocation interrupting MAP2K4 involving Alu elements and a deletion in YTHDF2 involving mobile elements that likely inactivate reported tumor suppressor genes. The high variant allele fraction of the translocation, the loss of the other copy of MAP2K4, the recurrent loss-of-function mutations found in this gene in other cancers, and the important function of MAP2K4 indicate that this translocation is potentially a driver mutation. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.


Effect of plasticity of the cladding with different thicknesses on the bearing capacity of the brittle base wall of RPV under PTS loads.
In the research field of reactor pressure vessel (RPV) subjected to pressurized thermal shock (PTS), the traditional linear elastic analytical method generally ignores the plastic properties of cladding. In fact, the neutron irradiation in RPV is easy to cause the embrittlement of the base material rather than cladding. So the elastic-plastic parameters of cladding are introduced into the FE model of the RPV with a sub-clad crack. The stress distributions in the thermal-mechanical coupling fields related to the base wall and cladding of different thicknesses are then obtained. The XFEM is used to simulate the crack growth in the nozzle area. The allowable internal pressure in the dangerous moment of the PTS is calculated to show the ultimate bearing capacity of the structure. The numerical results are compared with those only considering the elasticity of cladding. Furthermore, the law of the effect of plasticity of cladding on the structural safety is summarized.


Noncigarette Tobacco Product Use Among Smoking-Susceptible and Nonsusceptible Adolescent Never Smokers, 2009-2021.
Examine trends in noncigarette tobacco use among smoking susceptible and nonsusceptible adolescents from 2009-2021. Data came from cross-sectional samples of the National Youth Tobacco Survey (N = 183,198). Using Pierce's smoking susceptibility scale, participants were classified as either susceptible or nonsusceptible to cigarette smoking. Their use of noncigarette tobacco products was classified into four mutually exclusive categories: nonuse, noncigarette combustibles use, noncombustibles use, and noncigarette combustibles and noncombustibles dual use. We produced covariate-adjusted predicted marginal proportions of noncigarette tobacco use for 12 National Youth Tobacco Survey years, which were entered into Joinpoint trend analysis software to determine (a) trends in noncigarette tobacco use from 2009-2021 using the average annual percent changes (AAPCs) and (b) changes in each time segment using the average percent change. Models were fitted by smoking susceptibility, sex, and race/ethnicity. Nonuse was lower among susceptible (vs. nonsusceptible) adolescents whereas noncigarette tobacco use was higher. Trends show significant declines in nonuse (nonsusceptible: AAPC = -0.3%) and noncigarette combustibles use (susceptible: AAPC = -12%) between 2009-2021, increases in noncombustibles use (susceptible: AAPC = 18%, nonsusceptible: AAPC = 19%) between 2009 and 2019, and steadiness in dual use. Parallel trends were observed when stratified by sex and race/ethnicity with notable increases in noncombustibles use among females and Latinos. Noncigarette tobacco use differed by smoking susceptibility. Observed trends, especially when stratified by sex and race/ethnicity, raise concerns about tobacco use disparities among females and Latinos. Smoking susceptibility can help identify at-risk adolescents for current or future tobacco use.


Is peritoneal dialysis suitable technique CKD patients over 65 years? A prospective multicenter study.
Chronic kidney disease (CKD) is increasing in patients older than 65 years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. PD should be offered to patients over 65 years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. To describe PD treatment and outcomes in patients > 65 years, to compare their results with patients < 65 years and to identify areas with room for improvement in a real-life study. Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. We included 2,435 PD patients, 31.9% were older than 65 years; there was a difference of 25 years between both groups. Median follow up was 2.1 years. Older than 65 years group had more comorbidity: Diabetes (29.5% vs 17.2%; p < 0.001), previous CV events 34.5% vs 14.0%; p < 0.001), Charlson index (3.8 vs 3.0; p < 0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65 years group (0.65 vs 0.45 episodes/patient/year; p < 0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65 years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1 years). The main cause of PD withdrawal was transplant in group < 65 years (48.3%) and transfer to HD in group > 65 years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). Multivariate Cox regression analysis showed a relation (HR [95%CI]) between mortality and age > 65 years 2.4 [1.9-3.0]; DM 1.6 [1.3-2.1]; CV events 2.1 [1.7-2.7]. Multivariate Cox regression analysis identify a relation between technique failure and age > 65 years 1.5 [1.3-1.9]; DM 1.6 [1.3-1.9] and previous transplant 1.5 [1.2-2.0]. Patients older than 65 years fulfilled PD adequacy criteria during the follow up. We believe PD is a valid option for patients older 65 years. It is necessary to try to prevent infections and patient/caregiver fatigue, to avoid HD transfer for reasons not related to technique failure.


Dynamic Open Coordination Cage from Nonsymmetrical Imidazole-Pyridine Ditopic Ligands for Turn-On/Off Anion Binding.
This work demonstrates a new nonconventional ligand design, imidazole/pyridine-based nonsymmetrical ditopic ligands (1 and 1S ), to construct a dynamic open coordination cage from nonsymmetrical building blocks. Upon complex formation with Pd2+ at a 1:4 molar ratio, 1 and 1S initially form mononuclear PdL4 complexes (Pd2+ (1)4 and Pd2+ (1S )4 ) without formation of a cage. The PdL4 complexes undergo a stoichiometrically controlled structural transition to Pd2 L4 open cages ((Pd2+ )2 (1)4 and (Pd2+ )2 (1S )4 ) capable of anion binding, leading to turn-on anion binding. The structural transitions between the Pd2 L4 open cage and the PdL4 complex are reversible. Thus, stoichiometric addition (2 equiv) of free 1S to the (Pd2+ )2 (1S )4 open cage holding a guest anion ((Pd2+ )2 (1S )4 ⋅G- ) enables the structural transition to the Pd2+ (1S )4 complex, which does not have a cage and thus causes the release of the guest anion (Pd2+ (1S )4 +G- ).


Ingestion of small flat disc batteries.
Management of ingestions of small flat disc batteries has been controversial. The Nassau County Medical Center's Long Island Regional Poison Control Center has had 30 calls concerning battery ingestions in the past 16 months. In 1976, the National Clearinghouse for Poison Control Centers reported 42 battery ingestions for the entire nation. Only one of our cases required surgery because the battery remained in the cecum for five days. The battery was removed intact. Management guidelines for ingestions of batteries containing alkali or toxic metals are suggested.


A student paper: music in critical care setting for clients on mechanical ventilators: a student perspective.
This article written by baccalaureate nursing students briefly discusses the use of music therapy in clients on mechanical ventilation in intensive care units. The article explores the possible benefits of music therapy and its use in other aspects of health care.


Cerebral Microvascular Injury in Severe COVID-19.
Microvascular lesions are common in patients with severe COVID-19. Radiologic-pathologic correlation in one case suggests a combination of microvascular hemorrhagic and ischemic lesions that may reflect an underlying hypoxic mechanism of injury, which requires validation in larger studies. To determine the incidence, distribution, and clinical and histopathologic correlates of microvascular lesions in patients with severe COVID-19. Observational, retrospective cohort study: March to May 2020. Single academic medical center. Consecutive patients (16) admitted to the intensive care unit with severe COVID-19, undergoing brain MRI for evaluation of coma or focal neurologic deficits. Not applicable. Hypointense microvascular lesions identified by a prototype ultrafast high-resolution susceptibility-weighted imaging (SWI) MRI sequence, counted by two neuroradiologists and categorized by neuroanatomic location. Clinical and laboratory data (most recent measurements before brain MRI). Brain autopsy and cerebrospinal fluid PCR for SARS-CoV 2 in one patient who died from severe COVID-19. Eleven of 16 patients (69%) had punctate and linear SWI lesions in the subcortical and deep white matter, and eight patients (50%) had >10 SWI lesions. In 4/16 patients (25%), lesions involved the corpus callosum. Brain autopsy in one patient revealed that SWI lesions corresponded to widespread microvascular injury, characterized by perivascular and parenchymal petechial hemorrhages and microscopic ischemic lesions. SWI lesions are common in patients with neurological manifestations of severe COVID-19 (coma and focal neurologic deficits). The distribution of lesions is similar to that seen in patients with hypoxic respiratory failure, sepsis, and disseminated intravascular coagulation. Collectively, these radiologic and histopathologic findings suggest that patients with severe COVID-19 are at risk for multifocal microvascular hemorrhagic and ischemic lesions in the subcortical and deep white matter.


Chemical Synthesis of PDZ Domains.
Developments in chemical protein synthesis have enabled the generation of tailor-made proteins including incorporation of many types of modifications into proteins, enhancing our ability to control site-specificity of protein posttranslational modifications (PTMs), modify protein backbones and introduce photocrosslinking probes. For PDZ (postsynaptic density protein, disks large, zonula occludens) protein domains, expressed protein ligation (EPL) has been employed to introduce analogs of cognate amino acids, amide-to-ester bond mutations, and phosphorylations in the study of PDZ domain-mediated protein-protein interactions (PPIs). Here, we present protocols for EPL of PDZ domains focusing on phosphorylation and amide-to-ester modifications in the PDZ domain proteins.


Comparison between normal saline and a polyelectrolyte solution for fluid resuscitation in severely dehydrated infants with acute diarrhoea.
The optimal intravenous solution for rehydration of infants and children with severe dehydration is debated. The aim was to compare the efficacy of a polyelectrolyte solution (group PS) with sodium chloride 0.9% solution (group NS) in rapid parenteral rehydration of severely dehydrated infants with acute diarrhoea. Primary outcomes were volume and time to hydration. Secondary outcomes were urea, creatinine, electrolytes, glucose, arterial pH and bicarbonate levels. Patients were assigned randomly and openly to one of the two treatment groups. Severe dehydration was defined as one or more of the following associated with any other sign of dehydration: depressed consciousness, a weak or absent pulse or capillary refill time > 10 sec. Peripheral blood samples for chemical pathology were collected before and after rapid fluid therapy. The mean age of the 36 enrolled infants was 9.1 mths. All had depressed consciousness or severe hypotension/shock. The fluid infusion rate was 50 ml/kg/hr until haemodynamic stability was restored (absence of severe hypotension and two urine emissions). Fluid volume, time to rehydration and weight before and after rehydration were recorded. All infants recovered full pulse within 1 hr; most had a better level of consciousness or capillary refill <3 sec. Group NS (15 infants) showed (before and after treatment, respectively) a decrease of plasma potassium (3.4 to 3.1 mmol/L, p=0.07), bicarbonate (13.3 to 12.2 mmol/L, p=0.01) and glucose (8.2 to 5.8 mmol/L, p<0.01). Group PS (21 infants) showed a decrease of potassium (4.4 to 3.2 mmol/L, p<0.01) but an increase in bicarbonate (11.6 to 13.3 mmol/L, p<0.01) and glucose (11.4 to 14.8 mmol/L, p=0.08). Polyelectrolyte solution was as effective as normal saline on volume expansion and better for correcting acidosis.


Pervasive Downward Bias in Estimates of Liability-Scale Heritability in Genome-wide Association Study Meta-analysis: A Simple Solution.
Single nucleotide polymorphism-based heritability is a fundamental quantity in the genetic analysis of complex traits. For case-control phenotypes, for which the continuous distribution of risk in the population is unobserved, observed-scale heritability estimates must be transformed to the more interpretable liability scale. This article describes how the field standard approach incorrectly performs the liability correction in that it does not appropriately account for variation in the proportion of cases across the cohorts comprising the meta-analysis. We propose a simple solution that incorporates cohort-specific ascertainment using the summation of effective sample sizes across cohorts. This solution is applied at the stage of single nucleotide polymorphism-based heritability estimation and does not require generating updated meta-analytic genome-wide association study summary statistics. We began by performing a series of simulations to examine the ability of the standard approach and our proposed approach to recapture liability-scale heritability in the population. We went on to examine the differences in estimates obtained from these 2 approaches for real data for 12 major case-control genome-wide association studies of psychiatric and neurologic traits. We found that the field standard approach for performing the liability conversion can downwardly bias estimates by as much as approximately 50% in simulation and approximately 30% in real data. Prior estimates of liability-scale heritability for genome-wide association study meta-analysis may be drastically underestimated. To this end, we strongly recommend using our proposed approach of using the sum of effective sample sizes across contributing cohorts to obtain unbiased estimates.


Virenscarotins A-M, thirteen undescribed carotane sesquiterpenes from the fungus Trichoderma virens.
A document investigation on the fungus Trichoderma virens led to the isolation of thirteen undescribed carotane sesquiterpenes and homologous. All structures were elucidated on the basis of NMR and HRESIMS data, and their absolute configurations were assigned by ECD calculation. Especially, virenscarotins A and B were first ramifications forged by aldol condensation of 4-hydroxy-3-isopentenyl-benzaldehyde with two hydroxyl groups in ring A of traditional carotane sesquiterpenes. Ring rearrangement/expansion and oxidative cleavage of normal carotane sesquiterpenes lead to the six-membered ring A of compound virenscarotin C and the ring A cleavage of compound virenscarotin D. All compounds were evaluated for cytotoxic, anti-inflammatory, and seed germination inhibitory activities.


Outcomes After Endovascular Therapy With Procedural Sedation vs General Anesthesia in Patients With Acute Ischemic Stroke: The AMETIS Randomized Clinical Trial.
General anesthesia and procedural sedation are common practice for mechanical thrombectomy in acute ischemic stroke. However, risks and benefits of each strategy are unclear. To determine whether general anesthesia or procedural sedation for anterior circulation large-vessel occlusion acute ischemic stroke thrombectomy are associated with a difference in periprocedural complications and 3-month functional outcome. This open-label, blinded end point randomized clinical trial was conducted between August 2017 and February 2020, with final follow-up in May 2020, at 10 centers in France. Adults with occlusion of the intracranial internal carotid artery and/or the proximal middle cerebral artery treated with thrombectomy were enrolled. Patients were assigned to receive general anesthesia with tracheal intubation (n = 135) or procedural sedation (n = 138). The prespecified primary composite outcome was functional independence (a score of 0 to 2 on the modified Rankin Scale, which ranges from 0 [no neurologic disability] to 6 [death]) at 90 days and absence of major periprocedural complications (procedure-related serious adverse events, pneumonia, myocardial infarction, cardiogenic acute pulmonary edema, or malignant stroke) at 7 days. Among 273 patients evaluable for the primary outcome in the modified intention-to-treat population, 142 (52.0%) were women, and the mean (SD) age was 71.6 (13.8) years. The primary outcome occurred in 38 of 135 patients (28.2%) assigned to general anesthesia and in 50 of 138 patients (36.2%) assigned to procedural sedation (absolute difference, 8.1 percentage points; 95% CI, -2.3 to 19.1; P = .15). At 90 days, the rate of patients achieving functional independence was 33.3% (45 of 135) with general anesthesia and 39.1% (54 of 138) with procedural sedation (relative risk, 1.18; 95% CI, 0.86-1.61; P = .32). The rate of patients without major periprocedural complications at 7 days was 65.9% (89 of 135) with general anesthesia and 67.4% (93 of 138) with procedural sedation (relative risk, 1.02; 95% CI, 0.86-1.21; P = .80). In patients treated with mechanical thrombectomy for anterior circulation acute ischemic stroke, general anesthesia and procedural sedation were associated with similar rates of functional independence and major periprocedural complications. ClinicalTrials.gov Identifier: NCT03229148.


Large Nonlinear Optical Activity of a Near-infrared-absorbing Bithiophene-based Polymer with a Head-to-head Linkage.
Although the production of near-infrared (NIR)-absorbing organic polymers with an excellent nonlinear optical (NLO) response is vital for various optoelectronic devices and photodynamic therapy, the molecular design and relevant photophysical investigation still remain challenging. In this work, large NLO activity is observed for an NIR-absorbing bithiophene-based polymer with a unique head-to-head linkage in the NIR region. The saturable absorption coefficient and modulation depth of the polymer are determined as ∼-3.5×105 cm GW-1 and ∼32.43%, respectively. Notably, the polymer exhibits an intrinsic nonlinear refraction index up to ∼-9.36 cm2 GW-1 , which is six orders of magnitude larger than that of CS2 . The maximum molar-mass normalized two-photon absorption cross-section (σ2 /M) of this polymer can be up to ∼14 GM at 1200 nm. Femtosecond transient absorption measurements reveal significant spectral overlap between the 2PA and excited state absorption in the 1000-1400 nm wavelength range and an efficient triplet quantum yield of ∼36.7%. The results of this study imply that this NIR-absorbing polymer is promising for relevant applications.


The Zellweger syndrome: subcellular pathology, neuropathology, and the demonstration of pneumocystis carinii pneumonitis in two siblings.
The first Scandinavian cases of Zellweger syndrome (ZS) are described. A brother and sister, children of first cousins, had the typical clinical symptoms and pathological findings. Extensive metabolic studies in the boy were negative. Pipecolic acid in the urine was not elevated. Both children died at 14 weeks of age. Two months earlier the girl had suffered severe intestinal bleeding. Both had pneumocystic carinii pneumonia at autopsy although no evidence of immune deficiency had been found in the boy. The girl had used up her visible iron depots while the boy still had abundant but probably physiologic amounts of hemosiderin in the RES. Most of the cerebral abnormalities are unspecfic and possibly related to anoxia or other causes of delayed maturation. The white matter abnormalities in ZS patients may only be quantitatively different from the common "fatty metamorphosis" in infants. Previously reported ultrastructural abnormalities (absence of peroxisomes and very sparse smooth endoplasmic reticulum, as well as mitochondrial abnormalities) which are possibly unique for ZS, are confirmed. It is stressed that these were seen despite phenobarbital treatment which normally stimulates the formation of smooth endoplasmic reticulum.


Engineering fiber anisotropy within natural collagen hydrogels.
It is well known that biophysical properties of the extracellular matrix (ECM), including stiffness, porosity, composition, and fiber alignment (anisotropy), play a crucial role in controlling cell behavior in vivo. Type I collagen (collagen I) is a ubiquitous structural component in the ECM and has become a popular hydrogel material that can be tuned to replicate the mechanical properties found in vivo. In this review article, we describe popular methods to create 2-D and 3-D collagen I hydrogels with anisotropic fiber architectures. We focus on methods that can be readily translated from engineering and materials science laboratories to the life-science community with the overall goal of helping to increase the physiological relevance of cell culture assays.


Crew time in a space greenhouse using data from analog missions and Veggie.
Crew time requirements for human space exploration missions is as critical as mass, energy, and volume requirements. However, it has only been sporadically recorded in past analog and space missions for plant cultivation. In this retrospective study on crew time data collected in various analog facilities and on the Veggie hardware on ISS, we propose a methodology for efficient categorizing and reporting of crew time in space plant growth systems. Crew time is difficult to capture in operational environments, and this study intends to harmonize these efforts among different locations. This article also provides a current database for required crew time in several plant growth hardware and facilities, on the ISS, and on Earth. These data could serve mission planners as a baseline to establish standardized activities and extrapolate crew time needed to operate future plant growth units. Finally, we discuss how crew time needed for plant cultivation will change in future exploration missions, based on choices made for plant species, watering systems, level of automation, and use of virtual assistants, among others. Crew time will need to be accounted for as a decisive factor to design future space greenhouse modules.


On the immune response to barley in celiac disease: Biased and public T-cell receptor usage to a barley unique and immunodominant gluten epitope.
Celiac disease (CeD) is driven by CD4+ T-cell responses to dietary gluten proteins of wheat, barley, and rye when deamidated gluten epitopes are presented by certain disease-associated HLA-DQ allotypes. About 90% of the CeD patients express HLA-DQ2.5. In such patients, five gluten epitopes dominate the anti-gluten T-cell response; two epitopes unique to wheat, two epitopes present in wheat, barley, and rye and one epitope unique to barley. Despite presence of barley in commonly consumed food and beverages and hence being a prominent source of gluten, knowledge about T-cell responses elicited by barley in CeD is scarce. Therefore, in this study, we explored T-cell response toward the barley unique epitope DQ2.5-hor-3 (PIPEQPQPY) by undertaking HLA-DQ:gluten peptide tetramer staining, single-cell T-cell receptor (TCR) αβ sequencing, T-cell cloning, and T-cell proliferation studies. We demonstrate that majority of the CeD patients generate T-cell response to DQ2.5-hor-3, and this response is characterized by clonal expansion, preferential TCR V-gene usage and public TCR features thus echoing findings previously made for wheat gluten epitopes. The knowledge that biased and public TCRs underpin the T-cell response to all the immunodominant gluten epitopes in CeD suggests that such T cells are promising diagnostic and therapeutic targets.


Reconstruction of the ulnar artery in Guyon's canal with an arterial graft: Anatomical study.
Ulnar artery thrombosis in Guyon's canal can lead to vascular insufficiency in the fingers. The recommended treatment is resection and reconstruction of the pathological area. A bypass may be necessary, which may be venous or arterial. Arterial bypasses have better long-term patency; however, they are a source of donor-site complications. We carried out an anatomical study on 11 upper limbs and 7 lower limbs from cadavers to identify a technically accessible arterial graft, of a diameter suitable for bypassing the ulnar artery in Guyon's canal and with acceptable scar sequelae (few predicted postoperative complications, discreet size and/or location of scar). Three grafts were considered: anterior interosseous artery, radial recurrent artery and descending genicular artery. The various grafts were dissected and harvested from cadaver specimens, then their lengths and diameters were measured. The diameter of the candidate grafts was compared to the diameter of the distal ulnar artery. The diameter of the descending genicular artery matched the ulnar artery better than the radial recurrent artery or the anterior interosseous artery (103% vs 44% and 67%, respectively). Mean graft length was 6.6 cm. The anatomical configuration of the descending genicular artery allowed Y-shaped bypasses to be performed. Harvesting this artery appears to cause little damage and allows bypasses up to 6 cm to be performed. Despite its smaller diameter making it necessary to perform a microvascular size adjustment, the anterior interosseous artery is a candidate graft because it is long enough (119 mm) and located near the surgical site. LEVEL OF EVIDENCE: V.


Occipital horn syndrome in a woman: skeletal radiological findings.
Ehlers-Danlos type IX syndrome, also called occipital horn syndrome (OHS), is a milder and rare form of Menkes disease where the patient reaches adulthood. As an X-linked disease, it typically occurs in male subjects, while female subjects are usually healthy carriers. OHS is mainly characterized by connective tissue disorders and slightly subnormal intelligence or signs of autonomic dysfunction are the only apparent neurological abnormalities, in connection with molecular defects in copper metabolism. Our purpose is to report on radiological skeletal findings that may be incidental or investigated when OHS is suspected and to underline the possible involvement and expression in the female. Moreover, the impact of skeletal findings is also highlighted in the prevention of serious complications of the disease.


Human biomonitoring of toxic and essential metals in younger elderly, octogenarians, nonagenarians and centenarians: Analysis of the Healthy Ageing and Biomarkers Cohort Study (HABCS) in China.
Metals can be either toxic or essential to health, as they play different role in oxidative stress and metabolic homeostasis during the ageing process. Population-based biomonitoring have documented levels and ranges in concentrations among general population of 0-79 years of age. In people aged 80 and above, toxic metals and essential metals may have different risk profiles, and thus need to be better studied. Our aim is to investigate concentrations of toxic metals (arsenic, cadmium, lead and mercury) and essential metals (chromium, cobalt, molybdenum, manganese, nickel and selenium) and their role in diseases, nutritional status among younger elderly, octogenarians, nonagenarians and centenarians. A total of 932 younger elderly, 643 octogenarians, 540 nonagenarians, 386 centenarians were included from the cross-sectional Healthy Aging and Biomarkers Cohort Study in 2017-2018. Blood or urine biological substrates were collected from each participant to determine the concentrations of toxic metals and essential metals by inductively coupled plasma mass spectrometry. Random forest was constructed to rank the importance of toxic metals and essential metals in longevity. LASSO penalized regressions were performed to select the most significant metals associated with diseases and nutritional status, of which simultaneously included all metals and adjusted for the confounding factors. Compared to women, we found higher biomarker concentrations in men for toxic metals (41.2 µg/L vs 34.4 µg/L for blood lead, 1.56 µg/L vs 1.19 µg/L for blood mercury) and lower concentration of essential metals (0.48 µg/L vs 0.58 µg/L for blood molybdenum, 10.0 µg/L vs 11.1 µg/L for blood manganese). These factors may contribute to gender difference observed in longevity, that women live longer than men. Blood lead and urine cadmium tended to increase with age (P <0.001); blood cobalt, molybdenum, manganese increased with age, blood selenium decreased with age while the prevalence of selenium deficiency was extremely low in centenarians. Among toxic metals and essential metals, LASSO penalized regression identified the most significant metals associated with chronic kidney disease was cadmium and arsenic; and it was manganese, cobalt, and selenium for diabetes; it was selenium, molybdenum, lead for anemia; it was mercury for underweight. In random forest model, the top four important metals in longevity were selenium, arsenic, lead and manganese both in men and women. Generally, toxic metals levels were significantly higher while essential metals were relatively sufficient in Chinese centenarians. Toxic metals and essential metals played different role in diseases, nutritional status and longevity in the process of aging. Our research provided real world evidence of biomonitoring reference values to be used for the ongoing population health surveillance in longevity.


Evaluation of safety and immunogenicity of receptor-binding domain-based COVID-19 vaccine (Corbevax) to select the optimum formulation in open-label, multicentre, and randomised phase-1/2 and phase-2 clinical trials.
We assessed the efficacy of a receptor-binding domain (RBD)-based protein subunit COVID-19 vaccine. A randomised Phase-1/2 trial followed by a Phase-2 trial were conducted to assess the safety and immunogenicity of the COVID-19 vaccine Corbevax and select to an optimum formulation. Healthy adults (n=460) without COVID-19 vaccination or SARS-CoV-2 infection in the Phase-1/2 study were randomly divided into four vaccine formulation groups. A low incidence of adverse events was reported post-vaccination. All formulations showed similar profiles of humoral and cellular immune responses that were associated with the content of CpG1018 adjuvant in the vaccine. In the Phase-2 study, 750 µg of CpG1018 showed significant improvement (> 4-fold increase from baseline) in immune responses, including the titres of anti-RBD IgG and neutralising antibody (nAb), and cellular immune responses, while maintaining the safety profile. Antibodies persisted consistently for 12 months after the second dose of vaccine. Corbevax (two-dose schedule with 28 days of interval between doses) was well tolerated with no observed safety concerns. Previous observations from efficacy studies by Moderna and AstraZeneca and the correlation between nAb titres post-vaccination and a human convalescent serum panel showed that Corbevax induced significantly high nAb titres. These studies were prospectively registered with the Clinical Trial Registry of India (CTRI/2021/06/034014 and CTRI/2020/11/029032). Bill & Melinda Gates Foundation, BIRAC-Division of Department of Biotechnology, Govt of India, and the Coalition for Epidemic Preparedness Innovations funded this study.


Complications of bone marrow transplantation in Chinese.
Forty-three patients with hematopoietic disease were treated with intensive chemotherapy and radiotherapy, followed by allogeneic bone marrow transplantation (BMT) from 28 HLA-identical and 10 one to two antigen haploidentical sibling donors and autologous BMT (5 cases). Of these cases, there were 21 with acute nonlymphocytic leukemia (ANLL), 5 with acute lymphocytic leukemia (ALL), 6 with chronic myelocytic leukemia (CML), 2 with Hodgkin's disease (HD), 8 with severe-form aplastic anemia (SAA) and 1 with thalassemia. Complications of BMT were evaluated including acute graft-versus-host disease (GVHD), interstitial pneumonia (IP), veno-occlusive liver disease (VOD), abnormalities of liver function (LF), and alteration of hepatitis B virus (HBV) markers. In thirty-three patients who were followed up for more than 3 months, we found that the incidence of moderate to severe acute GVHD (9.1%) and IP (two cases, 4.7%) were low. No VOD occurred in our series. During the follow-up period, 27 out of 35 patients (77%) had high alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, even up to 1000 U/liter; however, only one patient succumbed to a hepatitis-related complication. Previous hepatic damage from HBV infection before BMT does not appear to increase the risk of posttransplant morbidity and mortality.


Chiral phosphoric acid catalyzed transfer hydrogenation: facile synthetic access to highly optically active trifluoromethylated amines.
Amines to an end: highly optically active α-CF(3)-functionalized amines can be obtained using metal-free reaction conditions. The method involves the transfer hydrogenation of CF(3)-substituted ketimines catalyzed by 1 and reductive amination of CF(3)-substituted ketones. The synthetic utility of this method was demonstrated by the synthesis of a CF(3) analogue of NPS R-568. PMP=para-methoxyphenyl.


Using quantitative imaging techniques to assess vascularity in AIDS-related Kaposi's sarcoma.
Three quantitative and non-invasive techniques were used to monitor angiogenesis in Kaposi's sarcoma patients: thermography, laser Doppler imaging (LDI), and near-infrared spectroscopy. Before and after combination cytotoxic and anti-angiogenesis therapy, blood volume, oxygenated hemoglobin, temperature, and blood flow were analyzed. These three techniques are objective, easy to perform, and appear to be very sensitive in assessing changes in the lesions upon administration of therapy.


An unusual cause for Coffin-Lowry syndrome: Three brothers with a novel microduplication in RPS6KA3.
Coffin-Lowry syndrome (CLS) is a rare X-linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high-resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS. qRT-PCR analyses performed on mRNA from the peripheral blood of the three siblings revealed a marked reduction of RPS6KA3 levels suggesting a loss-of-function mechanism. PCR analysis of the patients' cDNA detected a band greater than expected for an exon 4-10 amplicon, suggesting this was likely a direct duplication that lies between exons 4 through 10, which was later confirmed by Sanger sequencing. This microduplication is only the third intragenic duplication of RPS6KA3, and the second and smallest reported to date thought to cause CLS. Our study further supports the clinical utility of methods such as next-generation sequencing and high-resolution genomic arrays to detect small intragenic duplications. These methods, coupled with expression studies and cDNA structural analysis have the capacity to confirm the diagnosis of CLS in these rare cases.


[The inhibitive effects of the ethanol extract from Radix et Rhizoma Rhei on the secretion of HBsAg and HBeAg].
To study the anti-HBV effects of the ethanol extract from Radix et Rhizoma Rhei. The influence of the ethanol extract from Radix et Rhizoma Rhei on the secretion of HBeAg and HBsAg was observed through the culture of the 2.2.15 cell with the ethanol extract. 11 days after the ethanol extract's action on the 2.2.15 cell, its 50% concentration dose (CD50) is 39.69 g/L; inhibiting dose (ID50) to HBsAg and HBeAg are 3.29 g/L and 2.34 g/L respectively, and TI 12.06 and 16.96 respectively. The ethanol extract from Radix et Rhizoma Rhei can markedly inhibit the secretion of HBsAg and HBeAg in 2.2.25 cell lines.


rkDNA-graphene oxide as a simple probe for the rapid detection of miRNA21.
In this study we developed a novel diagnostic tool for the detection of miRNA21, based on the fluorescent nucleotide morpholine naphthalimide deoxyuridine (dUrkTP). We incorporated dUrkTP into DNA through primer extension to obtain rkDNA displaying high fluorescence. We then used lambda exonuclease, a specific nuclease for 3́-monophosphate-containing DNA, to separate rkDNA from its complementary sequence. The fluorescence of the free rkDNA was quenched dramatically upon interacting with graphene oxide (GO). Our rkDNA-GO fluorescence probing system exhibited high sensitivity and selectivity for the detection of miRNA21. This inexpensive probing system, employing simple primer extension and exonuclease degradation, required only 30 min to detect its target miRNA. This strategy appears suitable for the detection of diverse types of miRNA.