Predictors of ventriculostomy infection in a large single-center cohort.
External ventricular drain (EVD) placement is a common neurosurgical procedure. While this procedure is simple and effective, infection is a major limiting factor. Factors predictive of infection reported in the literature are not conclusive. The aim of this retrospective, single-center large series was to assess the rate and independent predictors of ventriculostomy-associated infection (VAI). The authors performed a retrospective chart review of consecutive patients who underwent EVD placement between January 2012 and January 2018. A total of 389 patients were included in the study. The infection rate was 3.1% (n = 12). Variables that were significantly associated with VAI were EVD replacement (OR 10, p = 0.001), bilateral EVDs (OR 9.2, p = 0.009), duration of EVD placement (OR 1.1, p = 0.011), increased CSF output/day (OR 1.0, p = 0.001), CSF leak (OR 12.9, p = 0.001), and increased length of hospital stay (OR 1.1, p = 0.002). Using multivariate logistic regression, independent predictors of VAI were female sex (OR 7.1, 95% CI 1.1-47.4; p = 0.043), EVD replacement (OR 8.5, 95% CI 1.44-50.72; p = 0.027), increased CSF output/day (OR 1.01, 95% CI 1.0-1.02; p = 0.023), and CSF leak (OR 15.1, 95% CI 2.6-87.1; p = 0.003). The rate of VAI was 3.1%. Routine CSF collection (every other day or every 3 days) and CSF collection when needed were not associated with VAI. The authors recommend CSF collection when clinically needed rather than routinely.


Synergistic and Non-synergistic Associations for Cigarette Smoking and Non-tobacco Risk Factors for Cardiovascular Disease Incidence in the Atherosclerosis Risk In Communities (ARIC) Study.
Cigarette smoking, various metabolic and lipid-related factors and hypertension are well-recognized cardiovascular disease (CVD) risk factors. Since smoking affects many of these factors, use of a single imprecise smoking metric, for example, ever or never smoked, may allow residual confounding and explain inconsistencies in current assessments of interactions. Using a comprehensive model in pack-years and cigarettes/day for the complex smoking-related relative risk (RR) of CVD to reduce residual confounding, we evaluated interactions with non-tobacco risk factors, including additive (non-synergistic) and multiplicative (synergistic) forms. Data were from the prospective Atherosclerosis Risk in Communities (ARIC) Study from four areas of the United States recruited in 1987-1989 with follow-up through 2008. Analyses included 14 127 participants, 207 693 person-years and 2857 CVD events. Analyses revealed distinct interactions with smoking: including statistical consistency with additive (body mass index [BMI], waist to hip ratio [WHR], diabetes mellitus [DM], glucose, insulin, high density lipoproteins [HDL] and HDL(2)); and multiplicative (hypertension, total cholesterol [TC], low density lipoproteins [LDLs], apolipoprotein B [apoB], TC to HDL ratio and HDL(3)) associations, as well as indeterminate (apolipoprotein A-I [apoA-I] and triglycerides) associations. The forms of the interactions were revealing but require confirmation. Improved understanding of joint associations may help clarify the public health burden of smoking for CVD, links between etiologic factors and biological mechanisms, and the consequences of joint exposures, whereby synergistic associations highlight joint effects and non-synergistic associations suggest distinct contributions. Joint associations for cigarette smoking and non-tobacco risk factors were distinct, revealing synergistic/multiplicative (hypertension, TC, LDL, apoB, TC/HDL, HDL(3)), non-synergistic/additive (BMI, WHR, DM, glucose, insulin, HDL, HDL(2)) and indeterminate (apoA-I and TRIG) associations. If confirmed, these results may help better define the public health burden of smoking on CVD risk and identify links between etiologic factors and biologic mechanisms, where synergistic associations highlight joint impacts and non-synergistic associations suggest distinct contributions from each factor.


Modeling Current Sources for Neural Stimulation in COMSOL.
Background: Computational modeling provides an important toolset for designing and analyzing neural stimulation devices to treat neurological disorders and diseases. Modeling enables efficient exploration of large parameter spaces, where preclinical and clinical studies would be infeasible. Current commercial finite element method software packages enable straightforward calculation of the potential distributions, but it is not always clear how to implement boundary conditions to appropriately represent metal stimulating electrodes. By quantifying the effects of different electrode representations on activation thresholds for model axons, we provide recommendations for accurate and efficient modeling of neural stimulating electrodes. Methods: We quantified the effects of different representations of current sources for neural stimulation in COMSOL Multiphysics for monopolar, bipolar, and multipolar electrode designs. Results: We recommend modeling each electrode contact as a thin platinum domain, modeling the electrode substrate with the conductivity of silicone, and either using a point current source in the center of each electrode contact or using a boundary current source. Alternatively, to avoid possible numerical instabilities associated with a large range of conductivity values (i.e., platinum and silicone) and to eliminate the small mesh elements required for thin electrode contacts, the electrode substrate can be assigned the conductivity of platinum by using insulating boundaries between the substrate and surrounding medium, and within the substrate to isolate the contacts from each other. When modeling more than one contact, we recommend using superposition by solving the model once for each contact, leaving inactive contacts floating, and superposing the resulting potentials. We computed comparable errors in activation thresholds across the different implementations in a simplified model (electrode in a homogeneous, isotropic medium), and in realistic models of rat spinal cord stimulation (SCS) and human deep brain stimulation, indicating that the recommended approaches are applicable to different stimulation targets.


A test of clathrin function in protein secretion and cell growth.
Clathrin-coated membranes are intimately associated with a variety of protein transport processes in eukaryotic cells, yet no direct test of clathrin function has been possible. The data presented demonstrate that Saccharomyces cerevisiae does not require clathrin for either cell growth or protein secretion. Antiserum to the yeast clathrin heavy chain has been used to isolate a molecular clone of the heavy chain gene (CHC1) from a library of yeast DNA in lambda gt11. Clathrin-deficient mutant yeast have been obtained by replacing the single chromosomal CHC1 gene with a disrupted version of the cloned DNA. Cells harboring a nonfunctional chc1 allele produce no immunoreactive heavy chain polypeptide, and vesicles prepared from mutant cells are devoid of clathrin heavy and light chains. Although clathrin-deficient cells grow two to three times more slowly than normal, secretion of invertase occurs at a nearly normal rate. Therefore protein transport through the secretory pathway is not obligately coupled to the formation of clathrin-coated vesicles.


Development and clinical application of meniscal unicompartmental arthroplasty.
About one-third of osteoarthritic patients requiring knee replacement have focal lesions limited mainly to the medial compartment and can achieve excellent postoperative function after medial unicompartmental replacement. However, late failures of many unicompartmental prostheses require revision at a rate about twice that of total knee replacement. The use of a fully conforming mobile-bearing meniscal unicompartmental prosthesis in the hands of experienced surgeons can reduce revision rates to levels equivalent to the best results achieved with total knee replacement. The paper argues the case for such a prosthesis and demonstrates that the usual modes of failure of unicompartmental arthroplasty, most of them biomechanical, can thereby be avoided.


Clinical characteristics of patients with COVID-19 admitted to the COVID-19 Emergency Field Hospital of Bangkalan, Indonesia.
Background: Following the surge of coronavirus disease 2019 (COVID-19) cases in the epicenter of East Java Province, this study aimed to determine the clinical characteristics of patients with COVID-19 at one of the emergency field hospitals in Indonesia. Methods: This was a single-centered, retrospective descriptive study of 763 patients admitted to the COVID-19 Emergency Field Hospital of Bangkalan from July 5 2021 to September 30 2021. The demographic data, clinical signs and symptoms, pre-existing comorbidities, therapy, and clinical outcomes of the patients were analyzed using SPSS. Results: The clinical characteristics of patients with COVID-19 at the emergency hospital were varied. A total of 763 patients were included. The most common age was between 40 and 49 years (31.1%), a slight majority were women (51.5%), and most had travelled abroad in the last 14 days (99.1%). Of the 763 patients, 70.9% had no comorbidities. Half of the patients were asymptomatic (49.4%), 46% were mild cases, 4.1% were moderate, and 0.5% severe. The most common symptoms were productive cough (15.7%) and headache (15.3%). Supportive and comorbidity therapy were given which showed excellent clinical outcomes. Conclusions: The majority of COVID-19 patients were asymptomatic, female, middle aged and had recently been overseas. Therapy without antibiotics or antivirals showed positive outcomes in COVID-19 patients.


Analysis of 90 Mb of the potato genome reveals conservation of gene structures and order with tomato but divergence in repetitive sequence composition.
The Solanaceae family contains a number of important crop species including potato (Solanum tuberosum) which is grown for its underground storage organ known as a tuber. Albeit the 4th most important food crop in the world, other than a collection of approximately 220,000 Expressed Sequence Tags, limited genomic sequence information is currently available for potato and advances in potato yield and nutrition content would be greatly assisted through access to a complete genome sequence. While morphologically diverse, Solanaceae species such as potato, tomato, pepper, and eggplant share not only genes but also gene order thereby permitting highly informative comparative genomic analyses. In this study, we report on analysis 89.9 Mb of potato genomic sequence representing 10.2% of the genome generated through end sequencing of a potato bacterial artificial chromosome (BAC) clone library (87 Mb) and sequencing of 22 potato BAC clones (2.9 Mb). The GC content of potato is very similar to Solanum lycopersicon (tomato) and other dicotyledonous species yet distinct from the monocotyledonous grass species, Oryza sativa. Parallel analyses of repetitive sequences in potato and tomato revealed substantial differences in their abundance, 34.2% in potato versus 46.3% in tomato, which is consistent with the increased genome size per haploid genome of these two Solanum species. Specific classes and types of repetitive sequences were also differentially represented between these two species including a telomeric-related repetitive sequence, ribosomal DNA, and a number of unclassified repetitive sequences. Comparative analyses between tomato and potato at the gene level revealed a high level of conservation of gene content, genic feature, and gene order although discordances in synteny were observed. Genomic level analyses of potato and tomato confirm that gene sequence and gene order are conserved between these solanaceous species and that this conservation can be leveraged in genomic applications including cross-species annotation and genome sequencing initiatives. While tomato and potato share genic features, they differ in their repetitive sequence content and composition suggesting that repetitive sequences may have a more significant role in shaping speciation than previously reported.


Neurospora crassa protein arginine methyl transferases are involved in growth and development and interact with the NDR kinase COT1.
The protein arginine methyltransferaseas (PRMTs) family is conserved from yeast to human, and regulates stability, localization and activity of proteins. We have characterized deletion strains corresponding to genes encoding for PRMT1/3/5 (designated amt-1, amt-3 and skb-1, respectively) in Neurospora crassa. Deletion of PRMT-encoding genes conferred altered Arg-methylated protein profiles, as determined immunologically. Δamt-1 exhibited reduced hyphal elongation rates (70% of wild type) and increased susceptibility to the ergosterol biosynthesis inhibitor voriconazole. In ▵amt-3, distances between branches were significantly longer than the wild type, suggesting this gene is required for proper regulation of hyphal branching. Deletion of skb-1 resulted in hyper conidiation (2-fold of the wild type) and increased tolerance to the chitin synthase inhibitor polyoxin D. Inactivation of two Type I PRMTs (amt-1 and amt-3) conferred changes in both asymmetric as well as symmetric protein methylation profiles, suggesting either common substrates and/or cross-regulation of different PRMTs. The PRMTs in N. crassa apparently share cellular pathways which were previously reported to be regulated by the NDR (Nuclear DBF2-related) kinase COT1. Using co-immunprecipitation experiments (with MYC-tagged proteins), we have shown that SKB1 and COT1 physically interacted and the abundance of the 75 kDa MYC::COT1 isoform was increased in a Δskb-1 background. On the basis of immunological detection, we propose the possible involvement of PRMTs in Arg-methylation of COT1.


Structures and characteristics of carbohydrates in diets fed to pigs: a review.
The current paper reviews the content and variation of fiber fractions in feed ingredients commonly used in swine diets. Carbohydrates serve as the main source of energy in diets fed to pigs. Carbohydrates may be classified according to their degree of polymerization: monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Digestible carbohydrates include sugars, digestible starch, and glycogen that may be digested by enzymes secreted in the gastrointestinal tract of the pig. Non-digestible carbohydrates, also known as fiber, may be fermented by microbial populations along the gastrointestinal tract to synthesize short-chain fatty acids that may be absorbed and metabolized by the pig. These non-digestible carbohydrates include two disaccharides, oligosaccharides, resistant starch, and non-starch polysaccharides. The concentration and structure of non-digestible carbohydrates in diets fed to pigs depend on the type of feed ingredients that are included in the mixed diet. Cellulose, arabinoxylans, and mixed linked β-(1,3) (1,4)-d-glucans are the main cell wall polysaccharides in cereal grains, but vary in proportion and structure depending on the grain and tissue within the grain. Cell walls of oilseeds, oilseed meals, and pulse crops contain cellulose, pectic polysaccharides, lignin, and xyloglucans. Pulse crops and legumes also contain significant quantities of galacto-oligosaccharides including raffinose, stachyose, and verbascose. Overall, understanding the structure, characteristics and measurable chemical properties of fiber in feed ingredients may result in more accurate diet formulations, resulting in an improvement in the utilization of energy from less expensive high-fiber ingredients and a reduction in reliance on energy from more costly cereal grains.


Growth hormone treatment in short children with intrauterine growth retardation.
The aim of this prospective controlled study was to assess the effect of rhGH in short prepubertal children with intrauterine growth retardation and normal growth hormone status. Twenty-six children were randomized into treatment (12F, 4M) and control (6F, 4M) groups. Mean ages were 5.3 (1.3) yr and 4.3 (1.7) yr, respectively. rhGH (Genotropin) was used at a dose of 0.2 IU/kg/day as daily s.c. injections for two years. In the treated group, mean height SDS increased from -3.0 (0.5) to -1.9 (0.7) and height velocity SDS showed a significant increase from -1.3 (2.0) to 3.7 (1.8) in the first year (p < 0.001) and 1.6 (1.8) (p < 0.01) in the second year of treatment. In the controls, height SDS, initially -2.7 (1.4), and height velocity SDS, initially -0.9 (1.1), remained essentially the same during two years of follow-up. Height SDS for bone age changed by 0.6 in the treated group and 0.4 in the control group. Target height SDS--initial height SDS in the treated group improved by 1.1 SD but declined in the control group. IGF-I levels increased from 9.5 (4.2) nmol/l (72 [31.8] ng/ml) to 32.5 (27.0) nmol/l (244.4 [202.8] ng/ml) (p = 0.004) in the treated group while no change was observed in the controls. No adverse effects were encountered during rhGH therapy. It was concluded that rhGH treatment induces a significant increase in growth velocity in the short term. This outcome, as opposed to the unchanged indices in the control group over the same period, may be indicative of an improved height prognosis in short children born with intrauterine growth retardation treated with rhGH.


Typhoid fever outbreak associated with frozen mamey pulp imported from Guatemala to the western United States, 2010.
Fifty-four outbreaks of domestically acquired typhoid fever were reported between 1960 and 1999. In 2010, the Southern Nevada Health District detected an outbreak of typhoid fever among persons who had not recently travelled abroad. We conducted a case-control study to examine the relationship between illness and exposures. A case was defined as illness with the outbreak strain of Salmonella serotype Typhi, as determined by pulsed-field gel electrophoresis (PFGE), with onset during 2010. Controls were matched by neighborhood, age, and sex. Bivariate and multivariate statistical analyses were completed using logistic regression. Traceback investigation was completed. We identified 12 cases in 3 states with onset from 15 April 2010 to 4 September 2010. The median age of case patients was 18 years (range, 4-48 years), 8 (67%) were female, and 11 (92%) were Hispanic. Nine (82%) were hospitalized; none died. Consumption of frozen mamey pulp in a fruit shake was reported by 6 of 8 case patients (75%) and none of the 33 controls (matched odds ratio, 33.9; 95% confidence interval, 4.9). Traceback investigations implicated 2 brands of frozen mamey pulp from a single manufacturer in Guatemala, which was also implicated in a 1998-1999 outbreak of typhoid fever in Florida. Reporting of individual cases of typhoid fever and subtyping of isolates by PFGE resulted in rapid detection of an outbreak associated with a ready-to-eat frozen food imported from a typhoid-endemic region. Improvements in food manufacturing practices and monitoring will prevent additional outbreaks.


To Express or to End? Personality Traits Are Associated With the Reasons and Patterns for Using Emojis and Stickers.
Emojis and stickers are becoming increasingly popular in computer-mediated communications. The present study examined the associations between personality traits and people's reasons and patterns for using both emojis and stickers. Participants (n = 312) completed three online questionnaires assessing shyness, the Big Five personality traits, and why and how they used emojis and stickers. Results revealed that shyness, neuroticism, extraversion, and agreeableness were correlated with different reasons of usage. Moreover, some participants exhibited a tendency to adjust frequency of usage depending on who the target person was and whether they were in a private or group chat. People who showed such tendencies were found to differ in personality with those who did not. Some differences in usage patterns were also observed between emojis and stickers. Together, the present study has produced more insight into how emojis and stickers can help people with different personality traits to achieve different purposes in their daily communication.


Orotic acid in clinical urine specimens by capillary zone electrophoresis using polyvinyl alcohol coated capillaries.
Orotic acid is an important compound in the investigation of several inherited metabolic diseases, and capillary zone electrophoresis provides an effective assay method for this analyte in the clinical laboratory setting. Capillaries with a polyvinyl alcohol (PVA) coating performed well in this application. However, it was necessary to employ several specimen preparation steps to achieve good assay precision.


[Cognitive evoked potentials in panic disorders].
Sixteen healthy people and 79 patients with panic disorders (PD), including 50 patients with neurosis (ICD-10 F40-41), 18 with personality disorder (F60) and 11 with schizotypal disorder (F21) have been studied. The main investigation method is recording of cognitive evoked potentials (P300 parameters). Mental and neuropsychological status of patients has been assessed as well. Despite the common clinical presentations of PD, peculiarities of evoked potentials reflecting sensory, activation and cognitive processes in different group of patients are revealed. The reduction of activation processes is observed in patients with neurosis and personality disorder combined with emotional instability in the latter ones. The increase of latency in response to non-target stimuli (a sensory component) is shown in schizotypal patients, the latter may be related to the decrease of activation of frontal-central brain areas.


A qualitative study of women in polygynous marriages.
Polygyny, the practice of taking more than one wife at the same time is a common practice in several countries including Africa. This study, conducted in Ghana, West Africa, investigated married women's experiences in polygyny and their ways of coping. Using exploratory qualitative methodology, data were collected from 15 married women who consented to in-depth interviews. The study was conducted in the summer of 2005 with approval from an institutional review board and permission from community leaders from the study site. Three themes emerged from the study: infertility, co-wives' relationships and ways of coping. The findings indicated that infertility was the number one reason that women allowed for co-wives in their marriages because this was necessary to protect the marriage rather than divorce. Unhappiness, loneliness, sense of competition and jealousy, and lack of intimacy with the spouse were identified as disadvantages of polygyny. The perceived advantages of polygyny included sharing of house chores and child rearing. The women's ways of coping included the use of religion, faith and a strong sisterly bond formed with the co-wives. Though the majority of the women disapproved of polygyny unions, divorce was not an option. These findings have implications for nursing and policy-makers. Nurses can provide education and implement programmes that teach coping mechanisms and stress management. Policy-makers should be made aware of the implications of polygynous marriages on women's health and well-being. There is the need to conduct more research to investigate the effects of polygyny on women's mental health and the need to develop programmes to support women.


Intramolecular vibrations enhance the quantum efficiency of excitonic energy transfer.
We study the impact of underdamped intramolecular vibrational modes on the efficiency of the excitation energy transfer in a dimer in which each state is coupled to its own underdamped vibrational mode and, in addition, to a continuous background of environmental modes. For this, we use the numerically exact hierarchy equation of motion approach. We determine the quantum yield and the transfer time in dependence of the vibronic coupling strength, and in dependence of the damping of the incoherent background. Moreover, we tune the vibrational frequencies out of resonance with the excitonic energy gap. We show that the quantum yield is enhanced by up to 10% when the vibrational frequency of the donor is larger than at the acceptor. The vibronic energy eigenstates of the acceptor acquire then an increased density of states, which leads to a higher occupation probability of the acceptor in thermal equilibrium. We can conclude that an underdamped vibrational mode which is weakly coupled to the dimer fuels a faster transfer of excitation energy, illustrating that long-lived vibrations can, in principle, enhance energy transfer, without involving long-lived electronic coherence.


Maleic hydrazide elicits global transcriptomic changes in chemically topped tobacco to influence shoot bud development.
Transcriptomic analysis revealed maleic hydrazide suppresses apical and axillary bud development by altering the expression of genes related to meristem development, cell division, DNA replication, DNA damage and recombination, and phytohormone signaling. Topping (removal of apical buds) is a common agricultural practice for some crop plants including cotton, cannabis, and tobacco. Maleic hydrazide (MH) is a systemic suckercide, a chemical that inhibits shoot bud growth, used to control the growth of apical (ApB) and axillary buds (AxB) following topping. However, the influence of MH on gene expression and the underlying molecular mechanism of controlling meristem development are not well studied. Our RNA sequencing analysis showed that MH significantly influences the transcriptomic landscape in ApB and AxB of chemically topped tobacco. Gene ontology (GO) enrichment analysis revealed that upregulated genes in ApB were enriched for phosphorelay signal transduction, and the regulation of transition timing from vegetative to reproductive phase, whereas downregulated genes were largely associated with meristem maintenance, cytokinin metabolism, cell wall synthesis, photosynthesis, and DNA metabolism. In MH-treated AxB, GO terms related to defense response and oxylipin metabolism were overrepresented in upregulated genes. GO terms associated with cell cycle, DNA metabolism, and cytokinin metabolism were enriched in downregulated genes. Expression of KNOX and MADS transcription factor (TF) family genes, known to be involved in meristem development, were affected in ApB and AxB by MH treatment. The promoters of MH-responsive genes are enriched for several known cis-acting elements, suggesting the involvement of a subset of TF families. Our findings suggest that MH affects shoot bud development in chemically topped tobacco by altering the expression of genes related to meristem development, DNA repair and recombination, cell division, and phytohormone signaling.


X-linked inhibitor of apoptosis: a chemoresistance factor or a hollow promise.
The X-linked inhibitor of apoptosis (XIAP) is the only cellular protein that has evolved to potently inhibit the enzymatic activity of mammalian caspases and promotes resistance to apoptosis. Given its role in apoptosis and its frequently elevated expression in malignant cells, XIAP has garnered the most attention as a promising therapeutic target in cancer to overcome drug resistance. Accordingly, XIAP is thought to render tumor cells resistant to chemotherapy through its ability to inhibit caspases, and it is on this basis that XIAP has been proposed as an important adverse biomarker for chemoresistance in cancer patients. Here, the current understanding of the role of XIAP in cancer is reviewed. Further, the notion is explored that the elevated XIAP expression frequently observed in malignant tissues is, at least, not exclusively responsible for the resistance of tumor cells to conventional therapeutic treatment; rather, the function of XIAP seems to be conducive to the process of malignant transformation and/or progression.


Associations between risk of Alzheimer's disease and obstructive sleep apnea, intermittent hypoxia, and arousal responses: A pilot study.
Obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD). However, potential associations among sleep-disordered breathing, hypoxia, and OSA-induced arousal responses should be investigated. This study determined differences in sleep parameters and investigated the relationship between such parameters and the risk of AD. Patients with suspected OSA were recruited and underwent in-lab polysomnography (PSG). Subsequently, blood samples were collected from participants. Patients' plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aβ42) were measured using an ultrasensitive immunomagnetic reduction assay. Next, the participants were categorized into low- and high-risk groups on the basis of the computed product (Aβ42 × T-Tau, the cutoff for AD risk). PSG parameters were analyzed and compared. We included 36 patients in this study, of whom 18 and 18 were assigned to the low- and high-risk groups, respectively. The average apnea-hypopnea index (AHI), apnea, hypopnea index [during rapid eye movement (REM) and non-REM (NREM) sleep], and oxygen desaturation index (≥3%, ODI-3%) values of the high-risk group were significantly higher than those of the low-risk group. Similarly, the mean arousal index and respiratory arousal index (R-ArI) of the high-risk group were significantly higher than those of the low-risk group. Sleep-disordered breathing indices, oxygen desaturation, and arousal responses were significantly associated with an increased risk of AD. Positive associations were observed among the AHI, ODI-3%, R-ArI, and computed product. Recurrent sleep-disordered breathing, intermittent hypoxia, and arousal responses, including those occurring during the NREM stage, were associated with AD risk. However, a longitudinal study should be conducted to investigate the causal relationships among these factors.


Dendrimer-based macromolecular MRI contrast agents: characteristics and application.
Numerous macromolecular MRI contrast agents prepared employing relatively simple chemistry may be readily available that can provide sufficient enhancement for multiple applications. These agents operate using a approximately 100-fold lower concentration of gadolinium ions in comparison to the necessary concentration of iodine employed in CT imaging. Herein, we describe some of the general potential directions of macromolecular MRI contrast agents using our recently reported families of dendrimer-based agents as examples. Changes in molecular size altered the route of excretion. Smaller-sized contrast agents less than 60 kDa molecular weight were excreted through the kidney resulting in these agents being potentially suitable as functional renal contrast agents. Hydrophilic and larger-sized contrast agents were found better suited for use as blood pool contrast agents. Hydrophobic variants formed with polypropylenimine diaminobutane dendrimer cores created liver contrast agents. Larger hydrophilic agents are useful for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents, which also might be employed as therapeutic drugs for either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.


Quantative trait loci of seed traits for soybean in multiple environments.
Seed length and seed width are an important factor to the soybean yield. So the quantitative trait loci (QTL) location for seed length and seed width could assistant the breeding of soybean. In this study, the QTL underlying seed length and seed width were studied. A recombinant inbred line population of soybeans derived from a cross between the American semi-draft cultivars Charleston and Dongnong 594 were used in 7 environments. The quantitative trait loci underlying seed length, seed width, and seed length/seed width were analyzed by the method of composite interval mapping. Then, the epistatic effects and the QTL-environment (QE) interaction effects were also analyzed. Some valuable QTL sites found had great effect to the seed trait. Results showed that 7 QTLs underlying seed length were identified mainly on linkage groups D1a, C2, B1, A1, G, and A2. For the seed width, 7 QTLs were identified on linkage groups D1a and O. Two QTLs of seed length/seed width were identified on linkage groups D1b and C2. No QE interaction was found for QTLs of seed length and seed width in 7 environments. QTLs of seed length/seed width on linkage groups A1 and I had a QE interaction in 7 environments. Seven pairs of QTLs were identified that affected additive x additive epistatic effect of seed length, seed width, and seed length/seed width, which occurred among 8 linkage groups. These results supply a good foundation for molecular assistant breeding for soybean seed trait.


Endotoxin detection and elimination in biotechnology.
Endotoxins liberated by gram-negative bacteria are frequent contaminants of aqueous and physiological solutions. Because of their potent biological effects in vivo and in vitro, their detection and removal are essential for the safe parenteral administration of products produced from natural sources, as well as those produced by recombinant DNA technology. Traditional methods of endotoxin detection include the U.S. Pharmacopeia rabbit test and the Limulus amebocyte lysate test. Elimination of endotoxins, however, continues to be a problem. Standard methods of sterilization, such as autoclaving or sterile filtration, have little effect on endotoxin levels. Various techniques for the prevention of endotoxin contamination and endotoxin removal have been discussed. The overall role of endotoxin prevention, detection, and elimination in biotechnology is emphasized.


A 140 GHz prepolarizer for dissolution dynamic nuclear polarization.
Apart from their very classical use to build polarized targets for particle physics, the methods of dynamic nuclear polarization (DNP) have more recently found application for sensitivity enhancement in high-resolution NMR, both in the solid and in the liquid state. It is often thought that the possible signal enhancement in such applications deteriorates when the DNP is performed at higher fields. We show that for a dissolution-DNP method that uses conventional (2,2,6,6-tetramethylpiperidine 1-oxyl) radicals as the paramagnetic agent, this is not the case for fields up to 5 T.


Time-varying spectrum estimation of heart rate variability signals with Kalman smoother algorithm.
A time-varying parametric spectrum estimation method for analyzing dynamics of heart rate variability (HRV) signals is presented. In the method, HRV signal is first modeled with a time-varying autoregressive model and the model parameters are solved recursively with a Kalman smoother algorithm. Time-varying spectrum estimates are then obtained from the estimated model parameters. The obtained spectrum can be further decomposed into separate components, which is especially advantageous in HRV applications where low frequency (LF) and high frequency (HF) components are generally aimed to be distinguished. As case studies, the dynamics of HRV signals recorded during 1) orthostatic test, 2) exercise test and 3) simulated driving task are analyzed.


PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis.
PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort. Case series, January 2010 to March 2016. Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease. Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate. The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54-0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10-3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%-14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5%-81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n=36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD. Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers. Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out.


Genome-wide scan for adult onset primary open angle glaucoma.
Adult onset primary open angle glaucoma is a leading cause of blindness throughout the world. The disease results in an apoptotic death of retinal ganglion cells that is usually associated with an elevation of intraocular pressure. Familial aggregation of the disorder provides evidence for strong genetic influences that are likely to be the result of multiple susceptibility genes. A two-stage genome scan to identify the genomic locations of glaucoma susceptibility genes was performed using an initial pedigree set of 113 affected sibpairs and a second pedigree set of 69 affected sibpairs. Linkage analysis was performed using both model-dependent (lod score) and model-independent affected relative pair and sibpair methods. Twenty-five regions identified by the initial scan were further investigated using the second pedigree set. In the combined data analysis, regions located on chromosomes 2, 6, 9, 11, 14, 17 and 19 continued to produce model-dependent lod scores and/or an MLS >1.0, while five regions (2, 14, 17p, 17q and 19) produced an MLS >2. 0. Multipoint analysis using ASPEX also showed significant results on chromosomes 2, 14, 17p, 17q and 19. These results are an important step towards the identification of genes responsible for the genetic susceptibility to this blinding condition.


Treatment options for extended-spectrum beta-lactamase-producers.
A review of antibiotic options for the treatment of infections caused by extended-spectrum beta-lactamase-producing isolates is presented. The use of the third-generation cephalosporin, cefotaxime, for infections caused by isolates producing ceftazidimase-type extended-spectrum beta-lactamases is controversial, despite in vitro susceptibility to the antibiotic in many instances. The fourth-generation cephalosporin, cefipime, although active against most extended-spectrum beta-lactamases, is reported to show a marked inoculum effect. The cephamycins, such as cefoxitin. are generally effective against Enterobacteriaceae producing TEM- and SHV-derived extended-spectrum beta-lactamases, but Klebsella pneumoniae strains are prone to cephamycin resistance as a result of porin loss. The use of beta-lactamase inhibitor combinations is variable. Sulbactam is less effective than clavulanate for the inhibition of SHV-derived extended-spectrum beta-lactamases and a marked inoculum effect has been noted, while the efficacy of tazobactam against SHV-derived extended-spectrum beta-lactamase producers is controversial. Furthermore, extended-spectrum beta-lactamases are often encoded by multi-resistant plasmids carrying genes conferring resistance to aminoglycosides, chloramphenicol, sulfonamides, trimethoprim and other antimicrobials, severely limiting even alternative therapies. Extensive susceptibility testing before the institution of antibiotic therapy is thus vital.


Epitope-Specific Anti-C1q Autoantibodies in Systemic Lupus Erythematosus.
In patients with systemic lupus erythematosus (SLE) complement C1q is frequently targeted by autoantibodies (anti-C1q), that correlate best with active renal disease. Anti-C1q bind to largely unknown epitopes on the collagen-like region (CLR) of this highly functional molecule. Here we aimed at exploring the role of epitope-specific anti-C1q in SLE patients. First, 22 sera of SLE patients, healthy controls and anti-C1q positive patients without SLE were screened for anti-C1q epitopes by a PEPperMAP® microarray, expressing CLR of C1q derived peptides with one amino acid (AA) shift in different lengths and conformations. Afterwards, samples of 378 SLE patients and 100 healthy blood donors were analyzed for antibodies against the identified epitopes by peptide-based ELISA. Relationships between peptide-specific autoantibodies and SLE disease manifestations were explored by logistic regression models. The epitope mapping showed increased IgG binding to three peptides of the C1q A- and three of the C1q B-chain. In subsequent peptide-based ELISAs, SLE sera showed significantly higher binding to two N-terminally located C1q A-chain peptides than controls (p < 0.0001), but not to the other peptides. While anti-C1q were associated with a broad spectrum of disease manifestations, some of the peptide-antibodies were associated with selected disease manifestations, and antibodies against the N-terminal C1q A-chain showed a stronger discrimination between SLE and controls than conventional anti-C1q. In this large explorative study anti-C1q correlate with SLE overall disease activity. In contrast, peptide-antibodies are associated with specific aspects of the disease suggesting epitope-specific effects of anti-C1q in patients with SLE.


Genomic abnormalities of Waldenström macroglobulinemia and related low-grade B-cell lymphomas.
Waldenström macroglobulinemia (WM) is a lymphoproliferative disease characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and monoclonal immunoglobulin M production. WM shows similarities in presentations with related B-cell malignancies, sometimes making it difficult to distinguish them. To better characterize the genetic basis of WM, we performed a comparative genomic analysis with the related entities, lymphoplasmacytic lymphomas without monoclonal immunoglobulin M protein, marginal zone lymphomas, chronic lymphocytic leukemia, and monoclonal gammopathy of undetermined significance. Overall, WM shows a very stable karyotype and shares most of the chromosomal abnormalities with most of the indolent B-cell malignancies. Trisomy 4 is unique to WM; however, no candidate genes have been identified in the chromosome. Abnormalities that affect myeloid differentiation primary response 88 (MYD88)--interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor kappa B (NF-κB) signaling pathways were found in a significant proportion of WM cases, which suggest their relevance in the pathogenesis of the disease and opening new avenues that may be a guide to design novel therapeutic approaches.


Aphid resistance in Capsicum maps to a locus containing LRR-RLK gene analogues.
A QTL for aphid resistance on pepper chromosome 2 was identified and validated. This QTL affects aphid survival and reproduction, and was fine mapped to a locus containing LRR-RLK analogues. Myzus persicae is one of the most threatening insect pests that adversely affects pepper (Capsicum) cultivation. Resistance to aphids was previously identified in Capsicum baccatum. This study aimed at elucidating the genetics of aphid resistance in C. baccatum. A QTL analysis was carried out for M. persicae resistance in an F2 population derived from an intraspecific cross between a highly resistant plant and a susceptible plant. Survival and reproduction were used as resistance parameters. Interval mapping detected two QTLs affecting aphid survival (Rmpas-1) and reproduction (Rmprp-1), respectively, both localized in the same area and sharing the same top marker on chromosome 2. Use of this marker as co-factor in multiple-QTL mapping analysis revealed a second, minor QTL (Rmprp-2) only affecting aphid reproduction, on chromosome 4. Fine mapping confirmed the effects of Rmpas-1 and Rmprp-1 and narrowed the major QTL Rmprp-1 down to a genomic region of 96 kb which is predicted to encode four analogues of resistance genes of the receptor-like kinase family containing a leucine-rich repeat domain (LRR-RLKs). This work provides not only initial information for breeding aphid-resistant pepper varieties, but also forms the basis for future molecular analysis of gene(s) involved in aphid resistance.


A novel first aid stretcher for immobilization and transportation of spine injured patients.
Effective immobilization and transportation are vital to the life-saving acute medical care needed when treating critically injured people. However, the most common types of stretchers used today are wrought with problems that can lead to further medical complications, difficulty in employment and rescue, and ineffective transitions to hospital treatment. Here we report a novel first aid stretcher called the "emergency carpet", which solves these problems with a unique design for spine injured patients. Polyurethane composite material, obtained by a novel process of manually mixing isocyanate and additives, can be poured into a specially designed fabric bag and allowed to harden to form a rigid human-shaped stretcher. The effectiveness of the emergency carpet was examined in the pre-hospital management of victims with spinal fractures. Additionally, it was tested on flat ground and complex terrain as well as in the sea and air. We demonstrated that the emergency carpet can be assembled and solidified on the scene in 5 minutes, providing effective immobilization to the entire injured body. With the protection of the emergency carpet, none of the 20 patients, who were finally confirmed to have spinal column fracture or dislocation, had any neurological deterioration during transportation. Furthermore, the carpet can be handled and transported by multiple means under differing conditions, without compromising immobilization. Finally, the emergency carpet allows the critically injured patient to receive multiple examinations such as X-ray, CT, and MRI without being removed from the carpet. Our results demonstrate that the emergency carpet has ideal capabilities for immobilization, extrication, and transportation of the spine injured patients. Compared with other stretchers, it allows for better mobility, effective immobilization, remarkable conformity to the body, and various means for transportation. The emergency carpet is promising for its intrinsic advantages in the pre-hospital management of accident victims.


Current trends in youth suicide and firearms regulations.
Despite numerous prevention initiatives, suicide remains the second leading cause of death in youth aged 10-19. One of the major prevention strategies is the introduction of restrictive firearms regulations. For example, Bill C-17 was enacted in 1991 to promote safer handling and storage of firearms through mandatory safety courses for all new gun owners. Examining the suicide rates subsequent to Bill C-17 may shed light on the possible benefit of these regulations as a solution to this major public health issue. Therefore, this paper examines the trends in youth suicide from 1979-1999 and the association with changes in the firearms act in 1991. Age-specific suicide rates for youth between 15-19 years and rates by methods of suicide were calculated based on data from Statistics Canada for the years 1979-1999. Time series analyses were conducted. Although the overall rates did not change from 1979-1999 in youth aged 15-19, there was a substantial change in the methods used. In particular, the rates of suicide by firearms dropped from 60% to 22% while suicide due to hanging/suffocation increased from 20% to 60% in this age group over this period of time. These results suggest a possible association between changes in the firearms act in 1991 and the methods used by youth to complete suicide. However, the overall rates of suicides did not change over this same period. These trends underscore the need for broader prevention interventions that do not solely focus on methods of suicide but rather, their underlying causes.


Synthesis, in vitro antiviral evaluation, and stability studies of bis(S-acyl-2-thioethyl) ester derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as potential PMEA prodrugs with improved oral bioavailability.
A new series of hitherto unknown 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) phosphonodiester derivatives incorporating carboxyesterase-labile S-acyl-2-thioethyl (SATE) moieties as transient phosphonate-protecting groups was prepared in an attempt to increase the oral bioavailability of the antiviral agent PMEA. We report here a direct comparison of the in vitro anti-HIV and anti-HSV activities as well as the in vitro stability between the bis(SATE) derivatives and the already known PMEA prodrugs, namely, bis[(pivaloyloxy)methyl (POM)]- and bis[dithiodiethyl (DTE)]PMEA. All of the compounds tested showed an enhanced in vitro antiviral activity compared to the parent PMEA. The bis(POM)- and bis(tBu-SATE)PMEA derivatives were the most effective. However, striking differences between these two compounds were found during the stability studies. In particular the bis(tBu-SATE)PMEA was found to be more stable than bis(POM)PMEA in human gastric juice and human serum, suggesting it could be considered as a promising candidate for further in vivo development.


[Use of gammaphos for protecting the brain from delayed radiation damage].
The influence of a radioprotector, gammaphos, on the development of delayed vascular changes and necrosis in rat brain following local brain irradiation with 25 Gy was investigated. The radioprotective effect was manifested by both the morphometric parameters of vessels and the survival rate and relative number of animals with gross vascular abnormalities and brain necrosis. There was a causative relationship between the development of gross vascular abnormalities and the occurrence of brain necrosis after exposure to moderate radiation doses.


Site-specific alteration of murine hepatitis virus type 4 peplomer glycoprotein E2 results in reduced neurovirulence.
Strains of the murine coronavirus mouse hepatitis virus type 4 (MHV-4) which contained a mutation in the E2 peplomer glycoprotein were obtained by selection for resistance to neutralization by monoclonal antibodies. Characterization of six variants representing two independent epitopes on E2, E2B and E2C, by in vitro neutralization and antibody-binding assays demonstrated that selection for an alteration in epitope E2B also resulted in changes in epitope E2C and vice versa. We observed a mutation frequency of approximately 10(-4.3) to 10(-4.6), which is consistent with the expected occurrence of single point mutations. The variant virus strains were attenuated with respect to neurovirulence when compared with wild-type MHV-4. Mice normally develop encephalomyelitis and die after wild-type MHV-4 infection. Mice receiving 2- to 3-log-higher doses of the variant strains survived and developed demyelinating disease. As the disease progressed, evidence of remyelination and ongoing demyelination was observed up to 65 days after infection. Virus reisolated 15 days after infection retained the variant phenotype. The data indicate that the E2 glycoprotein plays a central role in determining the cellular tropism and virulence of MHV-4 in the mouse.


Effects of Three Different Frequencies of Aerobic Physical Activity on Heart and Kidney Tissues in Type 2 Diabetes-Induced Rats.
Exercise has many beneficial effects in the treatment and prevention of Type 2 Diabetes Mellitus (T2DM). The aim of this study was to evaluate the effect of physical activities with different frequencies performed within a total total duration of one week on the heart and kidney tissues and vascular endothelial growth factor (VEGF) expressions in experimental T2DM model. Rats (n: 30) were divided into sedentary control (SC), sedentary T2DM (SD), T2DM and continuous exercise (DEc, 30 min/day, 5 days/week), T2DM and short bouts exercise (DEsb, 3x10 min/day, 5 days/week), T2DM and weekend warrior exercise (DEww, 35+40 min/day, 2 days/week) groups. Rats were administered streptozotocin (65 mg/kg) and nicotinamide (110 mg/kg) through intraperitoneal route. After 6-weeks of swimming exercise (total duration 150 min/week), biochemical analyzes were performed to measure oral glucose tolerance test, insulin sensitivity and cytokines. Histopathological and immunohistochemical analyses [VEGF, capillary density, Transforming growth factor beta (TGF-β)] were performed in heart and kidney tissues. Compared with sedentary T2DM rats, significant improvements were observed in all exercise groups in terms of blood glucose level, insulin sensitivity, capillary density in heart tissue, VEGF expressions in tissues, TGF-β expressions in kidney tissue and all histopathological analysis (p<0.05). This study shows that physical activity at various frequencies may significantly ameliorate harmful effects of T2DM on heart and kidney tissue without significant differences between exercise frequencies, provided that the total duration of aerobic exercise remains the same (150 min/week).


The clinical efficacy of laminectomy fusion fixation and posterior single open-door laminoplasty in the treatment of multilevel cervical ossification of the posterior longitudinal ligament (OPLL): a retrospective study.
To compared the clinical efficacy of two surgical methods, posterior laminectomy fusion fixation, and posterior single open-door laminoplasty, in treating multilevel cervical ossification of the posterior longitudinal ligament (OPLL). The study retrospectively included 102 patients treated between December 2016 and December 2020. The patients were included into an observation group (56 cases) treated with total laminectomy and lateral screw fixation, and a control group (46 cases) treated with single open-door laminoplasty. After 24 months, both groups showed significant improvement in Japanese Orthopaedic Association (JOA) scores and Visual Analogue Scale (VAS) scores, indicating better clinical symptoms and functional recovery. There was no significant difference in preoperative JOA and VAS scores between the two groups (P > 0.05). At 24 months after surgery, there was no significant difference in JOA and VAS scores between the two groups (P > 0.05). However, the observation group had a significantly higher cervical curvature index (CCI) and lower range of motion (ROM) of the cervical spine compared to the control group (P < 0.05). The CCI in control group was lower than before surgery, while the CCI in observation group was higher than before surgery, and CCI in the control group was considerably lower than that in the observation group (P < 0.05). The complication rate was lower in the control group, with fewer cases of axial symptoms, fifth cervical nerve root palsy, and overall complications. The overall complication rate was 25.0% (14/56) in the observation group and 10.8% (5/46) in the control group (P < 0.05). Both posterior laminectomy fusion fixation and posterior single open-door laminoplasty yield positive outcomes in improving clinical neurological function, cervical curvature, range of motion of the cervical spine, and cervical sagittal balance. Although open-door laminoplasty is less effective than total laminectomy in maintaining CCI and sagittal balance, it excels in preserving cervical range of motion, less surgical trauma and complications. Thus, open-door laminoplasty may be a suitable first-choice treatment for multi-segmental cervical OPLL, especially for patients with lordotic cervical spine physiological curvature.


Placental efficiency and intrauterine resource allocation strategies in the common marmoset pregnancy.
Mothers and fetuses are expected to be in some degree of conflict over the allocation of maternal resources to fetal growth in the intrauterine environment. Variation in placental structure and function may be one way a fetus can communicate need and quality to its mother, potentially manipulating maternal investment in its favor. Whereas common marmosets typically produce twin litters, they regularly give birth to triplet litters in captivity. The addition of another fetus is a potential drain on maternal resource availability and thus a source of elevated conflict over resource allocation. Marmoset littermates share a single placental mass, so that differences in the ratio of fetal to placental weight across litter categories suggest the presence of differential intrauterine strategies of resource allocation. The fetal/placental weight ratio was calculated for 26 marmoset pregnancies, representing both twin and triplet litters, to test the hypothesis that triplet fetuses respond to intrauterine conflict by soliciting placental overgrowth as a means of accessing maternal resources. In fact, relative to fetal mass, the triplet marmoset placenta is significantly undergrown, with individual triplets associated with less placental mass than their twin counterparts, suggesting that the triplet placenta is relatively more efficient in its support of fetal growth. There still may be an important role for maternal-fetal conflict in the programming of placental structure and function. Placental adaptations that solicit potential increases of maternal investment may occur at the microscopic or metabolic level, and thus may not be reflected in the size of the placenta as a whole.


Prenatal diagnosis of femoral facial syndrome: Three case reports and literature review.
Facial femoral syndrome (FFS) is a rare congenital abnormality, also known as femoral hypoplasia-unusual facies syndrome, characterized by variable degrees of femoral hypoplasia, associated with specific facial features. Other organ malformations are sometimes present. Most cases are sporadic, but rare family observations suggest genetic origin. However, no chromosomal or genetic abnormalities have ever been incriminated. We conducted a comprehensive literature review and added three new unreported observations. Through these 92 cases, authors aimed to determine sonographic signs that should direct towards diagnosis, and discuss potential genetic etiology. Diagnosis was suspected prenatally in 27.2% of cases, and maternal diabetes was found in 42.4% of patients. When fetal karyotype was available, it was normal in 97.1% of cases, but genomic variations of unknown significance were discovered in all three cases in which array comparative genomic hybridization (CGH) techniques were applied. Femoral affection defining FFS was hypoplasia in 78.3% of cases, agenesis in 12%, and both in 9.8%. Affection was bilateral in 84.8% of cases. Retrognathia was present in 65.2% of cases, cleft lip and/or palate in 63%, and other organ malformations in 53.3%. Intellectual development was normal in 79.2% of cases. Better prenatal recognition of this pathology, notably frequently associated malformations, should lead to a more precise estimation of functional prognosis. It seems likely that today's tendency to systematically employ array-CGH and exome/genome sequencing methods to investigate malformative sequences will allow the identification of a causal genetic abnormality in the near future.


Desalkylgidazepam blood concentrations in 63 forensic investigation cases.
Desalkylgidazepam, also known as bromonordiazepam, is the latest designer benzodiazepine to appear in postmortem blood samples in British Columbia. Our laboratory was first alerted to the presence of desalkylgidazepam in seized drug samples in May 2022, and the analyte was added to an in-house library shortly thereafter. Previously acquired spectra from routine death investigation cases were reprocessed using the updated library with the first presumptive identification of desalkylgidazepam occurring in a sample received in April 2022. A standard addition method for the quantitation of desalkylgidazepam in blood samples (from femoral, iliac, jugular and subclavian veins) was validated and consequently used to confirm presence and concentrations of the drug in 63 cases, with an average concentration of 42.2 ± 44.0 ng/mL (median concentration: 24.5 ng/mL; range: 3.7-220.6 ng/mL). Similar to detections of other novel benzodiazepines, co-occurrence of desalkylgidazepam with opioids and/or stimulants was common. To our knowledge, this paper is the first to report desalkylgidazepam concentrations in postmortem blood samples.


The neurobiology of recovery memory.
The so-called recovery memory syndrome--reports by adults of recovered memories of childhood sexual abuse and trauma that were allegedly "repressed" for many years--has become an important issue in the field of mental health. In particular, there is debate about the credibility of recovered memories. The author describes findings in several fields of brain science about the way memory works and how memory is organized in the brain. These findings clarify aspects of normal memory function and the process of memory distortion, and they provide a neurobiological perspective from which to approach the topic of recovered memory.


The Evolution of Flavonoid Biosynthesis: A Bryophyte Perspective.
The flavonoid pathway is one of the best characterized specialized metabolite pathways of plants. In angiosperms, the flavonoids have varied roles in assisting with tolerance to abiotic stress and are also key for signaling to pollinators and seed dispersal agents. The pathway is thought to be specific to land plants and to have arisen during the period of land colonization around 550-470 million years ago. In this review we consider current knowledge of the flavonoid pathway in the bryophytes, consisting of the liverworts, hornworts, and mosses. The pathway is less characterized for bryophytes than angiosperms, and the first genetic and molecular studies on bryophytes are finding both commonalities and significant differences in flavonoid biosynthesis and pathway regulation between angiosperms and bryophytes. This includes biosynthetic pathway branches specific to each plant group and the apparent complete absence of flavonoids from the hornworts.


Tissue kallikrein is required for the cardioprotective effect of cyclosporin A in myocardial ischemia in the mouse.
Clinical and experimental studies suggest that pharmacological postconditioning with Cyclosporin A (CsA) reduces infarct size in cardiac ischemia and reperfusion. CsA interacts with Cyclophilin D (CypD) preventing opening of the mitochondrial permeability transition pore (mPTP). Tissue kallikrein (TK) and its products kinins are involved in cardioprotection in ischemia. CypD knockout mice are resistant to the cardioprotective effects of both CsA and kinins suggesting common mechanisms of action. Using TK gene knockout mice, we investigated whether the kallikrein-kinin system is involved in the cardioprotective effect of CsA. Homozygote and heterozygote TK deficient mice (TK(-/-), TK(+/-)) and wild type littermates (TK(+/+)) were subjected to cardiac ischemia-reperfusion with and without CsA postconditioning. CsA reduced infarct size in TK(+/+) mice but had no effect in TK(+/-) and TK(-/-) mice. Cardiac mitochondria isolated from TK(-/-) mice had indistinguishable basal oxidative phosphorylation and calcium retention capacity compared to TK(+/+) mice but were resistant to CsA inhibition of mPTP opening. TK activity was documented in mouse heart and rat cardiomyoblasts mitochondria. By proximity ligation assay TK was found in close proximity to the mitochondrial membrane proteins VDAC and Tom22, and CypD. Thus, partial or total deficiency in TK induces resistance to the infarct size reducing effect of CsA in cardiac ischemia in mice, suggesting that TK level is a critical factor for cardioprotection by CsA. TK is required for the mitochondrial action of CsA and may interact with CypD. Genetic variability in TK activity has been documented in man and may influence the cardioprotective effect of CsA.


Screening for the presence of FMR1 premutation alleles in women with parkinsonism.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, late-onset neurodegenerative disease that affects older carriers of premutation (CGG) repeat expansions of the fragile X mental retardation 1 (FMR1) gene. Clinical features include intention tremor, gait ataxia, memory loss, peripheral neuropathy, autonomic dysfunction, and parkinsonism. The presence of parkinsonism in FXTAS raises the possibility that some individuals who have Parkinson disease are actually carriers of a premutation FMR1 allele. To screen DNA samples from a large cohort of females with Parkinson disease for an excess of expanded alleles of the FMR1 gene. We screened a cohort of 595 women with parkinsonism, the largest screening of a parkinsonism-associated group to date, for the presence of an FMR1 premutation allele (55-200 CGG repeats). The screening protocol uses an enhanced polymerase chain reaction method capable of flagging any FMR1 expanded CGG repeat in women as well as in men. Diagnostic assessments were performed at an outpatient tertiary clinic (Parkinson Institute, Milan). Genotyping was conducted at the University of California, Davis. CGG repeat number and clinical/neuroimaging assessments of patients with Parkinson disease were conducted. Two premutation carriers were identified. Two individuals possessed an FMR1 allele in the premutation range (CGG repeats: 30 and 75; 30 and 115). This carrier frequency (2 of 595 [0.34%]) is not significantly different from estimates of the allele frequency among women in the general population (0.4%-0.8%). Clinical and radiologic features of these 2 patients were similar to those of the general Parkinson disease population; however, 1 patient (115 CGG repeats) had a family history of 2 sons with the fragile X syndrome. Screening of women within the parkinsonism clinical spectrum is unlikely to be productive in the absence of additional medical or family history suggestive of involvement of the FMR1 gene.


Epitaxially aligned submillimeter-scale silver nanoplates grown by simple vapor transport.
Epitaxially aligned large silver (Ag) nanoplate arrays with ultraclean surfaces are very attractive for novel plasmonic applications. Although solution-phase methods have been extensively employed to synthesize Ag nanoplates, these cannot be used to grow epitaxial large Ag nanoplates on substrates. Here we report a vapor-phase synthetic strategy to epitaxially grow submillimeter-scale Ag nanoplates on a variety of substrates. By simply transporting Ag vapor to the substrates at an optimal temperature (820 °C), we synthesize ∼100 μm-sized Ag nanoplates with atomically clean surfaces, which are three-dimensionally aligned on the substrates. We demonstrate that both the type of supported seed and their interfacial lattice matching with the substrates determine the epitaxial growth habit of the nanoplates, directing their crystallinity, shape, and orientation. (i) On r-cut sapphire substrates, twinned pentagonal nanoplates grow vertically from twinned triangular seeds through a seed → nanoplate process. (ii) On m-cut sapphire substrates, twinned trapezoidal Ag nanoplates grow slantingly from twinned decahedral seeds through a seed → NW → nanoplate process. (iii) Interestingly, twin-free single-crystalline trapezoidal Ag nanoplates grow from twin-free square pyramidal seeds on STO (001) substrates through a seed → NW → nanoplate process. The epitaxially aligned Ag nanoplate arrays could serve as a new platform for two-dimensional (2D) guiding of surface plasmons as well as for hierarchical 3D plasmonic nanoarchitecturing.


Surgical treatment of granulomatous mastitis associated with autoimmune response.
Granulomatous mastitis (GM) is a rare breast disease with unknown etiology. Clinical management strategies for GM include surgery, antibiotics, and steroid treatments. As patients with GM often respond to steroids, GM is thought to be an autoimmune disease. Here we describe a case of trauma-induced GM that presented as autoimmune disease but was successfully treated by surgery without steroids. The patient showed no sign of recurrence for 11 months. This case provides useful information on both the underlying mechanisms and clinical management of GM.


Pharmacokinetics of nebulized and subcutaneously implanted terbinafine in cottonmouths (Agkistrodon piscivorus).
Ophidiomyces ophiodiicola, the causative agent of snake fungal disease, is proposed as a serious threat to the conservation of several snake populations. The objective of this study was to determine the pharmacokinetic parameters of terbinafine administered through nebulization and a sustained subcutaneous implant as potential treatments of Ophidiomyces in reptiles. Seven adult cottonmouths (Agkistrodon piscivorus) were used in single-dose trials. Each snake was nebulized with terbinafine (2 mg/ml) for 30 min and had blood collected before nebulization and up to 12 hr after nebulization. Following a 5-month washout, the same snakes were administered a subcutaneous implant containing 24.5 mg terbinafine; blood was collected at baseline, 1 day postimplant placement, and then once weekly for 9 weeks. Plasma for both studies was analyzed by high-performance liquid chromatography. The mean plasma concentrations of nebulized terbinafine peaked between 0.5 and 4 hr. The subcutaneously implanted terbinafine reached therapeutic concentrations on day 1 and maintained therapeutic for over 6 weeks. These methods and doses are recommended as potential treatment options for snake fungal disease in reptiles.


Manipulating Internal and External Loads During Repeated Cycling Sprints: A Comparison of Continuous and Intermittent Blood Flow Restriction.
Mckee, JR, Girard, O, Peiffer, JJ, and Scott, BR. Manipulating internal and external loads during repeated cycling sprints: A comparison of continuous and intermittent blood flow restriction. J Strength Cond Res 38(1): 47-54, 2024-This study examined the impact of blood flow restriction (BFR) application method (continuous vs. intermittent) during repeated-sprint exercise (RSE) on performance, physiological, and perceptual responses. Twelve adult male semi-professional Australian football players completed 4 RSE sessions (3 × [5 × 5-second maximal sprints:25-second passive recovery], 3-minute rest between the sets) with BFR applied continuously (C-BFR; excluding interset rest periods), intermittently during only sprints (I-BFR WORK ), or intraset rest periods (I-BFR REST ) or not at all (Non-BFR). An alpha level of p < 0.05 was used to determine significance. Mean power output was greater for Non-BFR ( p < 0.001, dz = 1.58 ), I-BFR WORK ( p = 0.002, dz = 0.63 ), and I-BFR REST ( p = 0.003, dz = 0.69 ) than for C-BFR and for Non-BFR ( p = 0.043, dz = 0.55 ) compared with I-BFR REST . Blood lactate concentration ( p = 0.166) did not differ between the conditions. Mean oxygen consumption was higher during Non-BFR ( p < 0.001, dz = 1.29 and 2.31; respectively) and I-BFR WORK ( p < 0.001, dz = 0.74 and 1.63; respectively) than during I-BFR REST and C-BFR and for I-BFR REST ( p = 0.002, dz = 0.57) compared with C-BFR. Ratings of perceived exertion were greater for I-BFR REST ( p = 0.042, dz = 0.51) and C-BFR ( p = 0.011, dz = 0.90) than for Non-BFR and during C-BFR ( p = 0.023, dz = 0.54) compared with I-BFR WORK . Applying C-BFR or I-BFR REST reduced mechanical output and cardiorespiratory demands of RSE and were perceived as more difficult. Practitioners should be aware that BFR application method influences internal and external demands during RSE.


Therapeutic exercise in cancer cachexia.
This review takes into account experimental and clinical evidence to provide an overview of the rationale for the use of exercise in cancer cachexia, its clinical application, and future developments. Studies targeting cachectic patients have demonstrated that even in advanced disease peripheral muscle has the capacity to respond to exercise training. Effects of exercise include enhancing muscle protein synthesis, attenuating the catabolic effects of cachexia, and modulating levels of inflammation. Nonetheless, there are challenges in applying therapeutic exercise, particularly once cachexia is established, and not all patients are able or willing to undertake programs currently being offered. Strategies to make exercise a more accessible therapy are required and could include offering it earlier in the course of the disease, at lower intensities, and in various forms, including novel approaches. In conclusion, the use of therapeutic exercise has a sound rationale, even in patients with advanced disease and cachexia, and has the potential to help maintain or slow the loss of physical function. Because of practical issues with its application, further study is required to examine if the benefits achieved in small studies can be translated to a wider clinical population.


The many faced symbiotic snakelocks anemone (Anemonia viridis, Anthozoa): host and symbiont genetic differentiation among colour morphs.
How can we explain morphological variations in a holobiont? The genetic determinism of phenotypes is not always obvious and could be circumstantial in complex organisms. In symbiotic cnidarians, it is known that morphology or colour can misrepresent a complex genetic and symbiotic diversity. Anemonia viridis is a symbiotic sea anemone from temperate seas. This species displays different colour morphs based on pigment content and lives in a wide geographical range. Here, we investigated whether colour morph differentiation correlated with host genetic diversity or associated symbiotic genetic diversity by using RAD sequencing and symbiotic dinoflagellate typing of 140 sea anemones from the English Channel and the Mediterranean Sea. We did not observe genetic differentiation among colour morphs of A. viridis at the animal host or symbiont level, rejecting the hypothesis that A. viridis colour morphs correspond to species level differences. Interestingly, we however identified at least four independent animal host genetic lineages in A. viridis that differed in their associated symbiont populations. In conclusion, although the functional role of the different morphotypes of A. viridis remains to be determined, our approach provides new insights on the existence of cryptic species within A. viridis.


Hypersensitivity Reaction Following Administration of Low-Dose Oral Vancomycin for the Treatment of Clostridium difficile in a Patient With Normal Renal Function.
Systemic absorption of oral vancomycin for the treatment of Clostridium difficile is thought to be trivial in patients without risk factors for increased systemic absorption and is often overlooked in clinical practice. A 51-year-old male elicits a suspected immunoglobulin E-mediated hypersensitivity following administration of low-dose oral vancomycin for the treatment of severe C difficile. The patient had normal renal function and was administered low doses of the medication, however, had a medical history significant for diverticulitis. Applying the Naranjo adverse drug reaction probability scale, a score of 5 was obtained, indicating a probable association between the administration of oral vancomycin and the hypersensitivity reaction. This case demonstrates that hypersensitivity reactions following low-dose oral vancomycin administration in patients with severe C difficile are possible, despite having normal renal function. Other risk factors for systemic absorption of oral vancomycin need to be evaluated in the literature, including severity of disease and underlying gastrointestinal processes.


Acrylamide determination during an industrial roasting process of coffee and the influence of asparagine and low molecular weight sugars.
The formation and partial degradation of acrylamide (AA), asparagine and low molecular weight sugars were evaluated during an industrial coffee roasting process, in which the temperature increased from 90° to about 215 °C. Arabica and Robusta varieties were roasted individually. AA content reached the maximum value at 10 min, corresponding to a temperature of 175-177 °C (1045 ± 28 and 795 ± 25 µg kg-1 for Arabica and Robusta, respectively). Successively, AA content decreased very quickly and at 14 min (203-205 °C) its concentration was lower than the benchmark level of 400 µg kg-1 for roast coffee set by the EU Commission Regulation (2017/2158). In the final product, AA content was close to 300 µg kg-1. Asparagine quickly decreased; contrary, the concentration of fructose and glucose increased reaching their maximum value at 12 min. Then, a quick degradation occurred; their increase could be mainly due to the hydrolysis of sucrose, which decreased in the same period.


[The use of a plasma scalpel during thoracoscopy for the treatment of traumatic and spontaneous pneumothorax].
The authors suggest performing thoracoscopic coagulation of pleuropulmonary defects with a plasma stream (VSVU-160 apparatus) in patients with traumatic and spontaneous pneumothorax. A special nozzle and a manipulation trocar were designed for this purpose. Such combined thoracoscopy was used successfully in 31 patients with open and closed chest injury with rupture of the subpleural bullae. The manipulation makes it possible to reduce the number of emergency thoracotomies undertaken for hemo- and aerostatic indications.


An Evolutionary Insertion in the Mxra8 Receptor-Binding Site Confers Resistance to Alphavirus Infection and Pathogenesis.
Alphaviruses are emerging, mosquito-transmitted RNA viruses with poorly understood cellular tropism and species selectivity. Mxra8 is a receptor for multiple alphaviruses including chikungunya virus (CHIKV). We discovered that while expression of mouse, rat, chimpanzee, dog, horse, goat, sheep, and human Mxra8 enables alphavirus infection in cell culture, cattle Mxra8 does not. Cattle Mxra8 encodes a 15-amino acid insertion in its ectodomain that prevents Mxra8 binding to CHIKV. Identical insertions are present in zebu, yak, and the extinct auroch. As other Bovinae lineages contain related Mxra8 sequences, this insertion likely occurred at least 5 million years ago. Removing the Mxra8 insertion in Bovinae enhances alphavirus binding and infection, while introducing the insertion into mouse Mxra8 blocks CHIKV binding, prevents infection by multiple alphaviruses in cells, and mitigates CHIKV-induced pathogenesis in mice. Our studies on how this insertion provides resistance to CHIKV infection could facilitate countermeasures that disrupt Mxra8 interactions with alphaviruses.


Alterations in the metabolism of Pseudosuccinea columella (Mollusca: Gastropoda) caused by Heterorhabditis bacteriophora HP88 (Rhabditida: Heterorhabditidae).
The gastropod Pseudosuccinea columella participates in the dissemination of Fasciola hepatica in the environment, acting as the main intermediate host of this parasite in Brazil. The present study sought to elucidate the possible pathogenic effects of the entomopathogenic nematode (EPN) Heterorhabditis bacteriophora on P. columella, by evaluating the influence of infection on alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as the concentrations of total protein, uric acid, and urea in the snail's hemolymph. For this, the snails were exposed to EPNs for 24 and 48 h, and for each exposure time, 20 snails were dissected after 7, 14 and 21 days for hemolymph collection. The primary findings suggest a significant proteolysis alongside elevated levels of uric acid and urea in P. columella infected individuals. These findings reveal that H. bacteriophora HP88 infection induced serious changes in the snail's metabolism, triggering important deleterious effects.


Analysis of components in a cardiogenic hypertensive chemoreflex.
A cardiogenic hypertensive chemoreflex was studied in 38 anesthetized and three unanesthetized dogs. Serotonin (100 mug/ml) injected into either the left atrium or small brancehes of the proximal left coronary artery produced a maximal response, with 96 +/- 18 mm Hg increment in mean aortic pressure within 6 +/- 2 seconds, lasting about 1 min; a later phase of the same hypertension lasted 9 +/- 5 minutes more and could partially be produced with serotonin injected into the thoracic aorta. Injections into the distal left coronary artery produced only the Bezold-Jarisch reflex. Concomitant with the immediate hypertension there were vagal and sympathetic efferent effects in both the sinus node and the atrioventricular (A-V) junction. Either of these effects could be selectively eliminated and the other augmented by direct local perfusion with an appropriate cholinergic (atropine 10 mug/ml) or adrenergic beta-receptor (propranolol 10 mug/ml) blocking agent. Bilateral vagotomy markedly attenuated but did not eliminate the acute hypertension, but it abolished both chronotropic and dromotropic effects. Phentolamine (2 mg/min i.v.) markedly diminished the hypertensive response. Guanethidine or reserpine pretreatment markedly diminished the hypertensive response; reserpine eliminated the electrophsiologic effects but guanethidine did not. Infiltration of serotonin around the main left coronary partially reproduced the reflex, but similar infiltration of xylocaine hydrochloride blocked the reflex. Serial section histologic studies of the region around the main left coronary atery in seven dog hearts and nine human hearts demonstrated the presence of a small structure resembling a chemoreceptor; its blood supply originated from the left coronary artery. Some possible clinical implications are discussed.


Characterization of tracked radiofrequency ablation in phantom.
In radiofrequency ablation (RFA), successful therapy requires accurate, image-guided placement of the ablation device in a location selected by a predictive treatment plan. Current planning methods rely on geometric models of ablations that are not sensitive to underlying physical processes in RFA. Implementing plans based on computational models of RFA with image-guided techniques, however, has not been well characterized. To study the use of computational models of RFA in planning needle placement, this work compared ablations performed with an optically tracked RFA device with corresponding models of the ablations. The calibration of the tracked device allowed the positions of distal features of the device, particularly the tips of the needle electrodes, to be determined to within 1.4 +/- 0.6 mm of uncertainty. Ablations were then performed using the tracked device in a phantom system based on an agarose-albumin mixture. Images of the sliced phantom obtained from the ablation experiments were then compared with the predictions of a bioheat transfer model of RFA, which used the positional data of the tracked device obtained during ablation. The model was demonstrated to predict 90% of imaged pixels classified as being ablated. The discrepancies between model predictions and observations were analyzed and attributed to needle tracking inaccuracy as well as to uncertainties in model parameters. The results suggest the feasibility of using finite element modeling to plan ablations with predictable outcomes when implemented using tracked RFA.


Retrospective diagnosis of feline GM2 gangliosidosis variant 0 (Sandhoff-like disease) in Japan: possible spread of the mutant allele in the Japanese domestic cat population.
GM2 gangliosidosis variant 0 (human Sandhoff disease) is a lysosomal storage disease caused by simultaneous deficiencies of acid beta-hexosaminidase (Hex) A and Hex B due to an abnormality of beta-subunit, a common component in these enzyme molecules, which is coded by the HEXB gene. In the present study, a retrospective diagnosis was performed in 2 previous suspected cases of feline Sandhoff-like disease using a DNA test to detect the causative mutation identified previously in 4 cats in 2 other families of Japanese domestic cats. Enzymic analysis was also performed using stored leukocytes and plasma collected from the subject families in order to investigate the usefulness of enzymic diagnosis and genotyping of carriers. The DNA test suggested that the 2 cases were homozygous recessive for the mutation. Consequently, 6 cats homozygous for the same mutation have been found in 4 separate locations of Japan, suggesting that this mutant allele may be spread widely in the Japanese domestic cat populations. In enzymic analysis, Hex A and Hex B activities in leukocytes and plasma measured using 4-methylumbelliferyl N-acetyl-beta-D-glucosaminide as a substrate were negligible in affected cats, compared with those in normal and carrier cats. However, there was a wide overlap in enzyme activity between normal and carrier cats. Therefore, it was concluded that enzymic analysis is useful for diagnosis of affected cats, but is not acceptable for genotyping of carriers.


A domesticated Harbinger transposase forms a complex with HDA6 and promotes histone H3 deacetylation at genes but not TEs in Arabidopsis.
In eukaryotes, histone acetylation is a major modification on histone N-terminal tails that is tightly connected to transcriptional activation. HDA6 is a histone deacetylase involved in the transcriptional regulation of genes and transposable elements (TEs) in Arabidopsis thaliana. HDA6 has been shown to participate in several complexes in plants, including a conserved SIN3 complex. Here, we uncover a novel protein complex containing HDA6, several Harbinger transposon-derived proteins (HHP1, SANT1, SANT2, SANT3, and SANT4), and MBD domain-containing proteins (MBD1, MBD2, and MBD4). We show that mutations of all four SANT genes in the sant-null mutant cause increased expression of the flowering repressors FLC, MAF4, and MAF5, resulting in a late flowering phenotype. Transcriptome deep sequencing reveals that while the SANT proteins and HDA6 regulate the expression of largely overlapping sets of genes, TE silencing is unaffected in sant-null mutants. Our global histone H3 acetylation profiling shows that SANT proteins and HDA6 modulate gene expression through deacetylation. Collectively, our findings suggest that Harbinger transposon-derived SANT domain-containing proteins are required for histone deacetylation and flowering time control in plants.


Enhanced cellulase production from Trichoderma reesei Rut-C30 by engineering with an artificial zinc finger protein library.
Trichoderma reesei Rut-C30 is a well-known cellulase producer, and improvement of its cellulase production is of great interest. An artificial zinc finger protein (AZFP) library is constructed for expression in T. reesei Rut-C30, and a mutant strain T. reesei U3 is selected based on its enhanced cellulase production. The U3 mutant shows a 55% rise in filter paper activity and 8.1-fold increased β-glucosidase activity, when compared to the native strain T. reesei Rut-C30. It is demonstrated that enhanced β-glucosidase activity was due to elevated transcription level of β-glucosidase gene in the U3 mutant. Moreover, significant elevation in transcription levels of several putative Azfp-U3 target genes is detected in the U3 mutant, including genes encoding hypothetical transcription factors and a putative glycoside hydrolase. Furthermore, U3 cellulase shows 115% higher glucose yield from pretreated corn stover, when compared to the cellulase of T. reesei Rut-C30. These results demonstrate that AZFP can be used to improve cellulase production in T. reesei Rut-C30. Our current work offers the establishment of an alternative strategy to develop fungal cell factories for improved production of high value industrial products.


Oxidation Mechanism of Si1-xGex Nanowires with Au Catalyst Tip as a Function of Ge Content.
Si1-xGex nanowires (NWs) (0.22 ≤ x ≤ 0.78) were synthesized using a vapor-liquid-solid procedure with a Au catalyst. We measured the intrinsic physical, chemical, and electrical properties of the oxidized Si1-xGex NWs using several techniques, including transmission electron microscopy, X-ray photoemission spectroscopy, and optical pump-THz probe spectroscopy. We suggest two distinct oxidation mechanisms depending on the Ge content in the Si1-xGex NWs: (i) when the Ge content is around 0.22, a Au catalytic effect brings about oxidation in both the axial and lateral directions; and (ii) when the Ge content is greater than 0.22, the Au tip is detached from the NW body and does not act as a catalyst, which is a result of the high degree of Ge-atom participation in the oxidation process. Additionally, we measured the photoconductivity decay time distribution for the Si1-xGex NWs before and after oxidation process; the decay time is significantly shortened in oxidized Si1-xGex NWs (0.22 < x), whereas it is maintained for Si-rich Si1-xGex NWs (x ≈ 0.22) as compared to the as-grown Si1-xGex NWs. It indicates that the number of defect states is generated with the formation of defective Ge oxide at the oxide-shell-layer/Si1-xGex-core-NW interface.


How to assess frailty and the need for care? Report from the Study of Health and Drugs in the Elderly (SHADES) in community dwellings in Sweden.
Knowledge about the need for care of elderly individuals in community dwellings and the factors affecting their needs and support is limited. The aim of this study was to characterize the frailty of a population of elderly individuals living in community dwellings in Sweden in relation to co-morbidity, use of drugs, and risk of severe conditions such as malnutrition, pressure ulcers, and falls. In 2008, 315 elderly individuals living in community dwellings were interviewed and examined as part of the SHADES-study. The elderly demonstrated co-morbidity (a mean of three diseases) and polypharmacy (an average of seven drugs). More than half the sample was at risk for malnutrition, one third was at risk for developing pressure ulcers, and nearly all (93%) had an increased risk of falling and a great majority had cognitive problems. Age, pulse pressure, body mass index, and specific items from the modified Norton scale (MNS), the Downton fall risk index (DFRI), and the mini nutritional assessment (MNA-SF) were related to different outcomes, defining the need for care and frailty. Based on the results of this study, we suggest a single set of items useful for understanding the need for care and to improve individual based care in community dwellings.


Promotion of hydroxyapatite-associated, stem cell-based bone regeneration by CCN2.
Multiple roles have been already recognized for CCN2 in cartilage development and regeneration. However, the effects of CCN2 on bone regeneration remain to be elucidated. In this study, the utility of CCN2 on bone regeneration was examined in vitro and in vivo in combination with hydroxyapatite (HAp) as a scaffold. Human bone marrow stromal cells (hBMSCs) were isolated from human iliac bone marrow aspirates of healthy donors and expanded, and the effects of CCN2 on their proliferation and migration were examined in vitro. The proliferation of hBMSCs on a plastic or HAp plate was significantly enhanced by CCN2. Moreover, the migration of hBMSCs also dramatically increased by CCN2. Interestingly, a C-terminal signal modular fragment of CCN2 (CT-module) also enhanced the cell proliferation and migration as efficiently as the full-length CCN2. Next, in order to estimate the effect of CCN2 on the migration and survival of hBMSCs and bone formation inside the HAp scaffold in vivo, two experiments were performed. First, the porous HAp carrier was cultured with hBMSCs for a week, and the cell-scaffold hybrid was transplanted with or without CCN2 subcutaneously into immunocompromised mice. CCN2 accelerated the hBMSC-like cell migration and survival inside the porous HAp within 4 weeks after transplantation. Second, the porous HAp carrier with or without CCN2 was directly implanted into bone defects within a rabbit mandible, and bone regeneration inside was evaluated. As a result, CCN2 efficiently induced the cell invasion and bone formation inside the porous HAp scaffold. These findings suggest that CCN2 and its CT-module fragment could be useful for regeneration and reconstruction of large-scale bone defects.


Ape1 regulates WNT/β-catenin signaling through its redox functional domain in pancreatic cancer cells.
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1, Ape1) is a multifunctional protein that is upregulated in human pancreatic cancer. Ape1 redox domain plays an essential role in regulating the effects of reactive oxygen species (ROS) generated during physiological metabolism and pathological stress. In the present study, we explored whether Ape1 and ROS affect WNT/β-catenin signaling. We used E3330, a small molecule inhibitor of the redox activity of Ape1, and a siRNA approach to knock down Ape1, in two human pancreatic cancer cell lines. Inhibition of Ape1 resulted in growth suppression of pancreatic cancer cells, increased ROS levels, upregulation of β-catenin and c-myc and downregulation of cyclin D1. Consistent with these data, overexpression of Ape1 in pancreatic cancer cells reduced ROS and c-myc levels and increased cyclin D1 levels. Moreover, treatment of pancreatic cancer cells with H2O2 to induce oxidative stress resulted in upregulated ROS levels, decreased Ape1 at both the mRNA and protein level, and alterations in WNT/β-catenin pathway components. Finally, treatment of pancreatic cancer cells with the WNT/β-catenin inhibitor IWR-1 resulted in growth inhibition, which was greatly enhanced when combined with E3330 treatment. In summary, our results demonstrate that ROS is an important intracellular messenger that can modulate WNT/β‑catenin signaling. The present study provides interesting new insight into crosstalk between the redox function of Ape1 and WNT/β-catenin signaling in cancer cells. Furthermore, our data show that the combination of Ape1 and WNT inhibitors enhanced the inhibition of pancreatic cell proliferation. These results provide a promising novel therapeutic strategy for treating pancreatic cancer in future.


The solution structure and activity of caerin 1.1, an antimicrobial peptide from the Australian green tree frog, Litoria splendida.
Caerin 1.1 is one of the major antimicrobial peptides isolated from the skin of the Australian green tree frog, Litoria splendida. Two-dimensional 1H-1H and 1H-13C NMR spectroscopy in trifluoroethanol/H2O (50:50, by vol.) have been used to assign the 1H and 13C-NMR spectra of this 25-amino-acid peptide. From an examination of these data, and using distance geometry and molecular dynamics calculations, the solution conformation of caerin 1.1 has been determined. The peptide adopts two well-defined helices from Leu2 to Lys11 and from Val17 to His24 separated by a region of less-defined helicity and greater flexibility. Overall, the peptide has a distinct amphipathic charge distribution. The solution structure of caerin 1.1 is compared with activity data against a variety of micro-organisms for the parent peptide and some naturally occurring and synthetic variants of caerin 1.1. The structural and activity data are consistent with caerin 1.1 interacting with membranes in a similar manner to other antimicrobial peptides, i.e. via a carpet-like mechanism whereby the individual peptides aggregate in a helical manner and orient themselves parallel to the membrane in a sheet-like arrangement [Shai, Y. (1995) Trends Biochem. Sci. 20, 460-464].


Clinical utility of venoarterial-extracorporeal membrane oxygenation (VA-ECMO) in patients with drug-induced cardiogenic shock: a retrospective study of the Extracorporeal Life Support Organizations' ECMO case registry.
Background: Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) is increasingly utilized to treat severe or refractory drug-induced cardiovascular shock. There is limited evidence regarding VA-ECMO's clinical utility in poisoning. Therefore, we investigated the clinical benefit of VA-ECMO use in drug-induced cardiovascular shock using the Extracorporeal Life Support Organization (ELSO)'s ECMO case registry.Methods: The ELSO registry was systematically searched retrospectively, using ICD-9/10 codes for poisoning-related cases from January 1, 2003 to July 30, 2018. All adult cases (age ≥ 18 years) that received VA-ECMO for cardiac support were included. Cardiogenic shock was defined as systolic blood pressure (SBP) <90 mmHg, mean arterial pressure (MAP) <65 mmHg, or requiring infusion of ≥2 vasopressor agents. Study outcomes included survival to discharge (i.e., from the ECMO center), changes in metabolic (acid/base), hemodynamic and ventilatory status, and complications related to ECMO support. Demographic and clinical characteristics of pre-ECMO and 24-h after VA-ECMO cannulation were compared between survivors vs. non-survivors.Results: A total of 113 cases were identified from the ELSO registry; 9 cases were excluded because cardiogenic shock was not related to poisoning, leaving 104 cases for analysis. The median age was 34 years and 53.5% (n = 54) were male. Cardiovascular agents were involved in 47.1% (n = 49) of the cases followed by opioids (n = 9, 6.7%); 34 cases experienced pre-ECMO cardiac arrest. About 92.4% of the cases (n = 85) received vasopressor infusion for hemodynamic support, most frequently norepinephrine (83.7%). Median duration of VA-ECMO was 68 h (interquartile range [IQR]: 48, 113 h); 52.9% (n = 55) of the cases survived to discharge. VA-ECMO significantly improved hemodynamics (MAP, SBP, and DBP), acidemia/acidosis (pH, HCO3 level) and ventilatory parameters (pO2, SpO2, and SvO2). Non-survivors showed persistent acidemia/acidosis at 24-h after VA-ECMO cannulation compared to survivors. Renal replacement therapy (50.9%) and arrhythmia (26.3%) were the most frequently reported complications.Conclusions: VA-ECMO improved hemodynamic and metabolic parameters in patients with drug-induced cardiogenic shock (DCS).