Mimicking biological cation-transport based on sphere-surface supramolecular chemistry: simultaneous interaction of porous capsules with molecular plugs and passing cations.
Spherical capsules of the type [{(Mo)Mo(5)}(12){Mo(2)(ligand)}(30)](n-) exhibiting 20 {Mo(9)O(9)} pores with crown ether functions allowed us to perform a sophisticated study of the title phenomenon based on synthetic work as well as NMR spectroscopy. The pores of the host system interact in solution specifically with guests that can be noncovalently bonded, such as formamidinium and acetamidinium cations, while having different affinities to the pores. The exchange between the guest species present in solution and in the pores was investigated, including, besides the extreme scenarios of complete pore closing and complete opening, that of stepwise pore plugging. Because of this option it was possible to model for the first time passive transmembrane cation transport based on gated pores/channels. These have the appropriate dimensions and can even adopt different structure flexibilities in response to different cations. The present investigation is based on related syntheses as well as on numerous detailed (7)Li NMR studies of Li(+) transport/exchange equilibria in dependence of the pore environment/guest situations. One compound containing capsules with sulfate ligands (2) could be obtained in which all the pores are plugged with formamidinium cations and another corresponding one was obtained with additionally encapsulated Ca(2+) ions (3); these were taken up after temporary release of some of the formamidinium plugs/guests upon short heating of the related solution.


An Emerging Role for Chloroplasts in Disease and Defense.
Chloroplasts are key players in plant immune signaling, contributing to not only de novo synthesis of defensive phytohormones but also the generation of reactive oxygen and nitrogen species following activation of pattern recognition receptors or resistance (R) proteins. The local hypersensitive response (HR) elicited by R proteins is underpinned by chloroplast-generated reactive oxygen species. HR-induced lipid peroxidation generates important chloroplast-derived signaling lipids essential to the establishment of systemic immunity. As a consequence of this pivotal role in immunity, pathogens deploy effector complements that directly or indirectly target chloroplasts to attenuate chloroplast immunity (CI). Our review summarizes the current knowledge of CI signaling and highlights common pathogen chloroplast targets and virulence strategies. We address emerging insights into chloroplast retrograde signaling in immune responses and gaps in our knowledge, including the importance of understanding chloroplast heterogeneity and chloroplast involvement in intraorganellular interactions in host immunity.


Trends in postoperative infection rates and their relationship to glycosylated hemoglobin levels in diabetic patients undergoing foot and ankle surgery.
The association of hyperglycemia with postoperative infectious complications after foot and ankle surgery has been well studied. However, many surgeons in their current practice use the somewhat arbitrary cutoff of 7% glycosylated hemoglobin (HbA1c) as the level above which surgery is considered unsafe and conducive to complications. Our goal in the present study was to assess the relationship between the HbA1c levels and the rate of postoperative infection to begin to determine whether 7% is a suitable cutoff or whether this level needs to be reevaluated. Furthermore, we were interested in the general trends relating to the infection rates and preoperative HbA1c levels. Our preliminary, subjective, analysis has indicated that infection rates increase steadily as the HbA1c increases toward 7.3%, increase rapidly at an HbA1c of 7.3% to 9.8%, and then level off. Additional study is warranted to better understand the role played by other covariates in determining the infection rate and to investigate whether patient selection has influenced the appearance of decreased infection rates at high HbA1c levels. Additional study could also assess similar relationships for other types of complication, such as nonunion, and perhaps examine different foot and ankle procedures in isolation.


The production of anti-IgG2a autoantibody in the 129/Sv mouse: onset in the lymph nodes draining the intestinal tract and prevention by neonatal thymectomy.
The histological distribution of anti-IgG-secreting cells was studied by measuring the amount of anti-IgG autoantibodies produced in vitro by cells isolated from various lymphoid organs. Before 20 wk, the production of anti-IgG autoantibody in 129/Sv mice from our Institute predominated in the mesenteric and caudal lymph nodes, which both drain the intestinal tract. After 20 wk, the production extended to the spleen and bone marrow. At that time no production was detected in the mediastinal, lumbar, and inguinal lymph nodes. A similar distribution of anti-IgG-secreting cells was observed in 25-wk-old 129/J mice from the Jackson Laboratory. These data indicate that anti-IgG autoimmunity in the 129 primarily results from a local immune response, probably induced by a specific stimulus of intestinal origin. Neonatal thymectomy prevented the production of anti-IgG, demonstrating that the mesenteric anti-IgG production did not result from the direct stimulation of B lymphocytes by endotoxin-like polyclonal activators. It was found that the anti-IgG produced in vitro had the same narrow specificity against IgG2a as its serum counterpart, indicating that this specificity resulted from the selective stimulation of anti-IgG2a-secreting cells rather than from in vivo consumption of anti-IgG antibodies recognizing other IgG subclasses.


Usefulness of monocyte to HDL-cholesterol ratio to predict high SYNTAX score in patients with stable coronary artery disease.
We aimed to investigate whether baseline monocyte to high-density lipoprotein cholesterol ratio (MHR), an easily available inflammatory and oxidative stress marker, is associated with SYNTAX score. In this cross-sectional study, n = 1229 consecutive patients with coronary artery disease were classified into two groups, low SYNTAX score (≤22) and high SYNTAX score (≥23). MHRs were significantly higher in patients with high SYNTAX score (p < 0.05). In multivariate regression analysis, MHR remained as independent predictor of high SYNTAX score together with C-reactive protein (CRP), hypertension and diabetes mellitus. In correlation analysis, MHR showed significant positive correlations with SYNTAX score (r = 0.371, p < 0.001) and CRP level (r = 0.336, p < 0.001). This study suggests MHR is independently associated with burden of coronary atherosclerosis.


Differential expression of PDZ domain-containing proteins in human diseases - challenging topics and novel issues.
The general features of the PDZ domain structure and functions have been extensively studied during the last decade. PDZ domains are generally present in proteins that are involved in multiple interactions to assemble functional protein complexes that control key cellular processes. One of the best characterized functions of PDZ domain-containing proteins is control of epithelial cell polarity and cell-cell contacts. In the present review, we summarize the current knowledge on regulation of expression of certain PDZ polarity proteins localized at the intercellular junctions. In addition, we provide a critical overview of recent findings regarding the role of these proteins during development of human diseases. Complete understanding of these issues is valuable for the design of novel therapeutic intervention for common pathologies, such as cancer.


Comparative studies on speciation: 30 years since Coyne and Orr.
Understanding the processes of population divergence and speciation remains a core question in evolutionary biology. For nearly a hundred years evolutionary geneticists have characterized reproductive isolation (RI) mechanisms and specific barriers to gene flow required for species formation. The seminal work of Coyne and Orr provided the first comprehensive comparative analysis of speciation. By combining phylogenetic hypotheses and species range data with estimates of genetic divergence and multiple mechanisms of RI across Drosophila, Coyne and Orr's influential meta-analyses answered fundamental questions and motivated new analyses that continue to push the field forward today. Now 30 years later, we revisit the five questions addressed by Coyne and Orr, identifying results that remain well supported and others that seem less robust with new data. We then consider the future of speciation research, with emphasis on areas where novel methods and data motivate potential progress. While the literature remains biased towards Drosophila and other model systems, we are enthusiastic about the future of the field.


Combined intravitreal ranibizumab and verteporfin photodynamic therapy versus ranibizumab alone for the treatment of age-related macular degeneration.
To compare same-day combined therapy of photodynamic therapy with verteporfin (PDT-V) and intravitreal ranibizumab versus monotherapy with ranibizumab for the treatment of choroidal neovascularization. IN THIS PROSPECTIVE STUDY, THE TOTAL NUMBER OF EYES WAS RANDOMIZED INTO TWO GROUPS: in the first, treatment consisted of a combined therapy of PDT-V and ranibizumab 0.5 mg on the same day; in the second, ranibizumab 0.5 mg in 3 monthly injections. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) on optical coherence tomography (OCT) were recorded before and 6 months after treatment. A total of 47 eyes of 47 subjects were enrolled in the study. In the combined-therapy group (group 1), the mean baseline BCVA ± standard deviation (SD) was 32.65 ± 11.09 letters (Snellen equivalent, 20/59); in the ranibizumab-alone group (group 2), 29.13 ± 9.03 letters (20/70). At 6 months' follow-up, in group 1 the mean baseline BCVA was 39.06 ± 10.12 letters (20/42); in group 2, 33.87 ± 12.06 letters (20/57). Improvement was significant in both group 1 (P = 0.03) and group 2 (P = 0.002). In group 1, the mean CMT at baseline ± SD was 315 ± 95.49 μm; in group 2, 306.33 ± 71.61 μm. At 6 months' follow-up, in group 1 it was 202 ± 52.02 μm; in group 2, 226 ± 65.58 μm. Reduction was significant in both group 1 (P = 0.0007) and group 2 (P = 0.00001). After 6-months, the rate of retreated eyes was 29.4% in group 1 and 43.3% in group 2. The need for retreatment did not depend on the treatment protocol (P = 0.34). From a functional and anatomic point of view, the two treatments showed equivalent efficacy, with fewer retreatments in group 1. No serious adverse events, such as retinal detachment, endophthalmitis, or ocular hypertension occurred in either group.


Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae.
VPS34 gene function is required for the efficient localization of a variety of vacuolar proteins. We have cloned and sequenced the wild-type VPS34 gene in order to gain a better understanding of the role of its protein product in this intracellular sorting pathway. Interestingly, disruption of the VPS34 locus resulted in a temperature-sensitive growth defect, indicating that the VPS34 gene is essential for vegetative growth only at elevated growth temperatures. As with the original vps34 alleles, vps34 null mutants exhibited severe vacuolar protein sorting defects and possessed a morphologically normal vacuolar structure. The VPS34 gene DNA sequence identifies an open reading frame that could encode a hydrophilic protein of 875 amino acids. The predicted protein sequence lacks any apparent signal sequence or membrane-spanning domains, suggesting that Vps34p does not enter the secretory pathway. Results from immunoprecipitation experiments with antiserum prepared against a TrpE-Vps34 fusion protein were consistent with this prediction: a rare, unglycosylated protein of approximately 95,000 Da was detected in extracts of wild-type Saccharomyces cerevisiae cells. Cell fractionation studies indicated that a significant portion of the Vps34p is found associated with a particulate fraction of yeast cells. This particulate Vps34p was readily solubilized by treatment with 2 M urea but not with Triton X-100, suggesting that the presence of Vps34p in this pelletable structure is mediated by protein-protein interactions. vp34 mutant cells also exhibited a defect in the normal partitioning of the vacuolar compartment between mother and daughter cells during cell division. In more than 80% of the delta vps34 dividing cells examined, no vacuolar structures were observed in the newly emerging bud, whereas in wild-type dividing cells, more than 95% of the buds had a detectable vacuolar compartment. Our results suggest that the Vps34p may act as a component of a relatively large intracellular structure that functions to facilitate specific steps of the vacuolar protein delivery and inheritance pathways.


The class I HDAC inhibitor Romidepsin targets inflammatory breast cancer tumor emboli and synergizes with paclitaxel to inhibit metastasis.
Inflammatory breast cancer (IBC) is the most metastatic variant of locally advanced breast cancer. IBC has distinctive characteristics including invasion of tumor emboli into the skin and rapid disease progression. Given our previous studies suggesting that HDAC inhibitors have promise in targeting IBC, the present study revealed that the class I HDAC inhibitor Romidepsin (FK-288, Istodax; Celgene Corporation, Summit, NJ) potently induced destruction of IBC tumor emboli and lymphatic vascular architecture. associated with inhibition of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha, (HIF1alpha) proteins in the Mary-X pre-clinical model of IBC. Romidepsin treatment induced clinically relevant biomarkers in including induction of acetylated Histone 3 (Ac-H3) proteins, apoptosis, and increased p21WAF1/CIP1. Romidepsin, alone and synergistically when combined with Paclitaxel, effectively eliminated both primary tumors and metastatic lesions at multiple sites formed by the SUM149 IBC cell line. This is the first report of the ability of an HDAC inhibitor to eradicate IBC tumor emboli, to destroy the integrity of lymphatic vessel architecture and to target metastasis. Furthermore, Romidepsin, in combination with a taxane, warrants evaluation as a therapeutic strategy that may effectively target the skin involvement and rapid metastasis that are hallmarks of IBC.


Population Dynamics of Dactylella oviparasitica and Heterodera schachtii: Toward a Decision Model for Sugar Beet Planting.
A series of experiments were performed to examine the population dynamics of the sugarbeet cyst nematode, Heterodera schachtii, and the nematophagus fungus Dactylella oviparasitica. After two nematode generations, the population densities of H. schachtii were measured in relation to various initial infestation densities of both D. oviparasitica and H. schachtii. In general, higher initial population densities of D. oviparasitica were associated with lower final population densities of H. schachtii. Regression models showed that the initial densities of D. oviparasitica were only significant when predicting the final densities of H. schachtii J2 and eggs as well as fungal egg parasitism, while the initial densities of J2 were significant for all final H. schachtii population density measurements. We also showed that the densities of H. schachtii-associated D. oviparasitica fluctuate greatly, with rRNA gene numbers going from zero in most field-soil-collected cysts to an average of 4.24 x 10(8) in mature females isolated directly from root surfaces. Finally, phylogenetic analysis of rRNA genes suggested that D. oviparasitica belongs to a clade of nematophagous fungi that includes Arkansas Fungus strain L (ARF-L) and that these fungi are widely distributed. We anticipate that these findings will provide foundational data facilitating the development of more effective decision models for sugar beet planting.


When to inspect? Recurrent inspection decisions in a simulated risky environment.
Participants scheduled inspections to detect costly events for which they were repeatedly at constant risk (probability of event onset) within a computerized environment. They were responsive to risk variations, conveyed either in advance or by experience with inspection outcomes, although experiencing unannounced increases in risk affected inspections more than experiencing unannounced decreases. Participants responded to variations in cost (time varying or fixed) when the effects were made perceptually salient. Compared with a normative model (R. L. Klatzky, D. M. Messick, & J. Loftus, 1992), some conditions showed near-optimal inspecting or had flat payoff functions that tolerated observed departures from optimal performance. Costly departures occurred particularly when combined cost and risk levels caused optimal responses to be extreme (always or never inspect). Results assess people's processing of relevant variables and indicate circumstances in which they may set substantially nonoptimal inspection schedules.


Optimizing the balance between heterologous acetate- and CO2-reduction pathways in anaerobic cultures of Saccharomyces cerevisiae strains engineered for low-glycerol production.
In anaerobic Saccharomyces cerevisiae cultures, NADH (reduced form of nicotinamide adenine dinucleotide)-cofactor balancing by glycerol formation constrains ethanol yields. Introduction of an acetate-to-ethanol reduction pathway based on heterologous acetylating acetaldehyde dehydrogenase (A-ALD) can replace glycerol formation as 'redox-sink' and improve ethanol yields in acetate-containing media. Acetate concentrations in feedstock for first-generation bioethanol production are, however, insufficient to completely replace glycerol formation. An alternative glycerol-reduction strategy bypasses the oxidative reaction in glycolysis by introducing phosphoribulokinase (PRK) and ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO). For optimal performance in industrial settings, yeast strains should ideally first fully convert acetate and, subsequently, continue low-glycerol fermentation via the PRK-RuBisCO pathway. However, anaerobic batch cultures of a strain carrying both pathways showed inferior acetate reduction relative to a strain expressing only the A-ALD pathway. Complete A-ALD-mediated acetate reduction by a dual-pathway strain, grown anaerobically on 50 g L-1 glucose and 5 mmol L-1 acetate, was achieved upon reducing PRK abundance by a C-terminal extension of its amino acid sequence. Yields of glycerol and ethanol on glucose were 55% lower and 6% higher, respectively, than those of a nonengineered reference strain. The negative impact of the PRK-RuBisCO pathway on acetate reduction was attributed to sensitivity of the reversible A-ALD reaction to intracellular acetaldehyde concentrations.


Clinical and epidemiologic features of Coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009.
Isolates of Coxsackievirus A6 (Cox A6) is increasing clinically in 2009 in Taiwan but detailed clinical features of Cox A6 infections in children have not been reported. This study is to define clinical manifestations and laboratory findings of Cox A6 infection in children. From January 2004 to December 2009, a total of 4,664 children with enterovirus infections, based on throat virus culture, were treated in Chang Gung Children's hospital. Two hundred and ninety-six (6.3%) patients positive for Cox A6 infection were included in this study. One hundred and forty-one (47.6%) inpatients were further analyzed for clinical presentations, laboratory findings, and clinical diagnoses. There were two peaks of Cox A6 infection in 2007 and 2009 during the study period, especially during the warm season. The proportion of Cox A6 among total enterovirus isolates was 15.5% in 2007 and up to 22.2% in 2009. The mean age of inpatients was 2.42 ± 0.14 years. The mean hospitalization duration was 4.21 ± 0.11 days. The most common symptoms were fever (100%), oral ulcers (90.8%), and decreased oral intake (89.4%). The mean duration of fever was 2.78 ± 1 days (range, 1-7 days). Seventy-seven (54.6%) patients had fever more than 3 days. The mean leukocyte count was 14,850/mm(3), and 63 (45%) patients had leukocytosis (>15,000/mm(3)). The mean serum C-reactive protein (CRP) level was 44.1 ± 3.3 mg/L (normal, <10 mg/L) and 62 (44%) had a CRP level >40 mg/L. One hundred and eight (76.6%) inpatients were diagnosed as herpangina and 18 (12.8%) hand-foot-mouth disease. Three patients had complications, including aseptic meningitis in one and encephalitis in two. All 141 inpatients recovered uneventfully. Cox A6 is among the major serotypes of enteroviruses in Taiwan and most cases presented as herpangina and hand-foot-mouth disease. Nearly half of the cases may have leukocytosis and elevated CRP levels. Outcomes are usually good.


Phase I and pharmacokinetic study of prinomastat, a matrix metalloprotease inhibitor.
Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics. Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy. The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2-3 arthralgias and myalgias were noted 2-3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K(i) for MMPs 2 and 9 were achieved at all of the dose levels. Doses of 5-10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10-100-fold greater than the K(i) (in vitro inhibition constant) for the targeted MMPs (2 and 9).


Parenting practices, mental health, and electronic cigarette use among U.S. young adolescents: A longitudinal panel analysis, 2013-2018.
This study examined prospective association of parenting practices related to tobacco use with adolescent e-cigarette use and the moderating role of mental health among U.S. young adolescents. We study used multi-wave longitudinal data (2013-2018) drawn from the Population Assessment of Tobacco and Health Study. A total of 5114 young adolescents (12-14 years) who were not lost to follow-ups across four waves (Wave 1-4) comprised the study sample. Weighted logistic regression models along with generalized linear mixed modeling assessed the within-subject associations of parenting practices related to tobacco use (tobacco availability at parent/guardian's home, past-year parent talk about tobacco use, and rules about non-combustible tobacco use at home) with adolescent current e-cigarette use. Prevalence of having home rules about non-combustible tobacco use increased (74.5%-80.2%) and that of parent talk about tobacco use decreased (52.0%-33.9%) over time while tobacco availability at home did not show a specific trend. Tobacco availability at home was associated with increased odds of adolescent e-cigarette use (adjusted odd ratio[OR] = 2.25, 95% confidence interval[CI] = 1.72-2.95), and having home rules about non-combustible tobacco use was linked to decreased likelihood of e-cigarette use (adjusted OR = 0.72, 95% CI = 0.55-0.92). The magnitude of negative association between having rules about non-combustible tobacco and adolescent e-cigarette use was stronger among adolescents with internalizing problems but weaker among those with externalizing problems. Our findings highlight the important role of home-based interventions in discouraging young adolescents from e-cigarette use. Parents/guardians should consider adolescents' mental health to provide more efficient home- and/or clinical-based e-cigarette use prevention.


Lymphadenectomy for low-risk endometrial cancer based on preoperative and intraoperative assessments.
The aim of this study was to ascertain whether lymphadenectomy is necessary when endometrial cancer is considered low risk based on preoperative and intraoperative assessments. Between 2000 and 2004, a total of 122 patients with low-risk endometrial cancer who underwent preoperative endometrial sampling and magnetic resonance imaging (MRI) were treated surgically. All 122 patients were considered eligible for the study if they fulfilled the following criteria: (a) grade 1 or 2 endometrioid corpus cancer by endometrial sampling, (b) no lymphadenopathy by MRI, (c) myometrial invasion of 50% or less by MRI, and (d) no intraoperative evidence of macroscopic extrauterine spread. We divided the 122 patients into 2 groups (the total abdominal hysterectomy and bilateral salpingo-oophorectomy [TH/bilateral salpingo-oophorectomy] with lymphadenectomy [THND group, n = 64] and the TH/bilateral salpingo-oophorectomy without lymphadenectomy [TH group, n = 58]). The concordance rate between preoperative and postoperative grades was 92.6% (113/122, kappa = 0.805). Evaluation of the depth of myometrial invasion with MRI had an accuracy of 95.1% (116/122) for ruling out deep myometrial invasion. In the THND group, the operative time, the hospital stay, the estimated blood loss during surgery, and the incidence of perioperative complications were significantly higher than those in the TH group. The 5-year progression-free survival rates were similar (96.9% in the THND group and 98.3% in the TH group). The present findings suggest that MRI and office endometrial sampling may accurately categorize patients into low- or high-risk groups. Lymphadenectomy should be limited to patients with high-risk endometrial cancer.


Absence of MHC-II expression by lymph node stromal cells results in autoimmunity.
How lymph node stromal cells (LNSCs) shape peripheral T-cell responses remains unclear. We have previously demonstrated that murine LNSCs, lymphatic endothelial cells (LECs), blood endothelial cells (BECs), and fibroblastic reticular cells (FRCs) use the IFN-γ-inducible promoter IV (pIV) of the MHC class II (MHCII) transactivator CIITA to express MHCII. Here, we show that aging mice (>1 yr old) in which MHCII is abrogated in LNSCs by the selective deletion of pIV exhibit a significant T-cell dysregulation in LNs, including defective Treg and increased effector CD4+ and CD8+ T-cell frequencies, resulting in enhanced peripheral organ T-cell infiltration and autoantibody production. The proliferation of LN-Tregs interacting with LECs increases following MHCII up-regulation by LECs upon aging or after exposure to IFN-γ, this effect being abolished in mice in which LECs lack MHCII. Overall, our work underpins the importance of LNSCs, particularly LECs, in supporting Tregs and T-cell tolerance.


Testing whether genetic variation explains correlation of quantitative measures of gene expression, and application to genetic network analysis.
Genetic networks for gene expression data are often built by graphical models, which in turn are built from pair-wise correlations of gene expression levels. A key feature of building graphical models is the evaluation of conditional independence of two traits, given other traits. When conditional independence can be assumed, the traits that are conditioned on are considered to 'explain' the correlation of a pair of traits, allowing efficient building and interpretation of a network. Overlaying genetic polymorphisms, such as single nucleotide polymorphisms (SNPs), on quantitative measures of gene expression provides a much richer set of data to build a genetic network, because it is possible to evaluate whether sets of SNPs 'explain' the correlation of gene expression levels. However, there is strong evidence that gene expression levels are controlled by multiple interacting genes, suggesting that it will be difficult to reduce the partial correlation completely to zero. Ignoring the fact that some sets of SNPs can explain at least part of the correlation between gene expression levels, if not all, might result in missing important clues on the genetic control of gene expression. To enrich the assessment of the causes of correlation between gene expression levels, we develop methods to evaluate whether a set of covariates (e.g. SNPs, or even a set of quantitative expression transcripts) explains at least some of the correlation of gene expression levels. These methods can be used to assist the interpretation of regulation of gene expression and the construction of gene regulatory networks.


Genome-Wide Analysis Reveals the Role of Mediator Complex in the Soybean-Phytophthora sojae Interaction.
The mediator complex is an essential link between transcription factors and RNA polymerase II, and mainly functions in the transduction of diverse signals to genes involved in different pathways. Limited information is available on the role of soybean mediator subunits in growth and development, and their participation in defense response regulation. Here, we performed genome-wide identification of the 95 soybean mediator subunits, which were unevenly localized on the 20 chromosomes and only segmental duplication events were detected. We focused on GmMED16-1, which is highly expressed in the roots, for further functional analysis. Transcription of GmMED16-1 was induced in response to Phytophthora sojae infection. Agrobacterium rhizogenes mediated soybean hairy root transformation was performed for the silencing of the GmMED16-1 gene. Silencing of GmMED16-1 led to an enhanced susceptibility phenotype and increased accumulation of P. sojae biomass in hairy roots of transformants. The transcript levels of NPR1, PR1a, and PR5 in the salicylic acid defense pathway in roots of GmMED16-1-silenced transformants were lower than those of empty-vector transformants. The results provide evidence that GmMED16-1 may participate in the soybean-P. sojae interaction via a salicylic acid-dependent process.


Effects of carperitide on the long-term prognosis of patients with acute decompensated chronic heart failure: the PROTECT multicenter randomized controlled study.
Carperitide is used to treat acute decompensated heart failure (ADHF), but its effects on long-term prognosis have not been studied. A multicenter randomized controlled study of 49 patients with ADHF was performed to clarify the drug's effects on long-term prognosis. Low-dose carperitide (0.01-0.05 microg x kg(-1 ) x min(-1)) was infused for 72 h as the initial treatment (n=26), whereas in the control group (n=23), standard medical treatment other than carperitide was given without limitation. Anti-aldosterone drugs were prohibited in both groups. During carperitide infusion, significant increases of the atrial natriuretic peptide and cyclic GMP levels and a significant decrease in the heart-type fatty acid-binding protein/serum creatinine ratio were observed, suggesting inhibition of myocyte cell membrane damage. On the other hand, no significant differences in the plasma brain natriuretic peptide, troponin T, and creatinine levels were noted in either group. During 18-month follow-up, significant reductions of death and rehospitalization occurred in the carperitide vs control group (11.5% vs 34.8%; p=0.0359). Cox regression analysis revealed that randomization to carperitide (p=0.020), pretreatment systolic blood pressure >or=140 mmHg (p=0.043), and beta-blocker therapy (p=0.016) were independent predictors for freedom from cardiac events. Acute-phase low-dose carperitide infusion improved the long-term prognosis of patients with ADHF.


Generating the orbital angular momentum of radio frequency signals using optical-true-time-delay unit based on optical spectrum processor.
A system for generating radio frequency signals with orbital angular momentum (OAM) is proposed and certificated for the first time, which employs an array of multiple optical-true-time-delay elements and circular antennas array (CAAs). A constructive Fourier series theory about CAAs collectively forming an OAM radio beam is demonstrated. An optical spectrum processor offers the four lines high-resolution time delay by adding a series of linear optical phase shifts. The OAM radio beam with topological charge L=1 is produced and measured successfully.


Associations between the ultrasound features of invasive breast cancer and breast cancer specific survival.
To assess whether ultrasound features of breast cancer are associated with breast cancer specific survival (BCSS). Within a single breast service, data was collected prospectively (April 2010-April 2012) from 319 consecutive women (mean age 63 years) with 335 ultrasound-visible invasive breast cancers. Ultrasound features were evaluated retrospectively from the recorded images according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon by a radiologist blinded to outcomes. Survival and cause of death were ascertained from local and national sources. Kaplan-Meier survival curves were generated, and statistical significance tested using the log-rank test. Mean follow-up in those alive was 80.9 months. Thirty breast cancer deaths and 45 non-breast cancer deaths occurred. Five-year BCSS in the presence of distal acoustic enhancement was 76% compared to 88%, 96%, and 100% for those with distal shadowing, no distal effect or combined effect respectively (p<0.0002). Patients with sonographic skin involvement had 73% 5-year BCSS compared to 92% for no skin involvement (p<0.0001). Focal oedema was associated with 56% 5-year BCSS compared to 89% for those without (p=0.0002). A significant association was demonstrated between ultrasound tumour size and BCSS (p<0.0001). At multivariate analysis, skin changes, distal enhancement, and focal oedema maintained prognostic significance. Distal enhancement, focal oedema, and skin involvement have strong associations with breast cancer death. These factors could be taken into account, along with lesion size and other commonly used preoperative prognostic features, when considering management of women with breast cancer.


Predictive performance of international COVID-19 mortality forecasting models.
Forecasts and alternative scenarios of COVID-19 mortality have been critical inputs for pandemic response efforts, and decision-makers need information about predictive performance. We screen n = 386 public COVID-19 forecasting models, identifying n = 7 that are global in scope and provide public, date-versioned forecasts. We examine their predictive performance for mortality by weeks of extrapolation, world region, and estimation month. We additionally assess prediction of the timing of peak daily mortality. Globally, models released in October show a median absolute percent error (MAPE) of 7 to 13% at six weeks, reflecting surprisingly good performance despite the complexities of modelling human behavioural responses and government interventions. Median absolute error for peak timing increased from 8 days at one week of forecasting to 29 days at eight weeks and is similar for first and subsequent peaks. The framework and public codebase ( https://github.com/pyliu47/covidcompare ) can be used to compare predictions and evaluate predictive performance going forward.


Stellar production rates of carbon and its abundance in the universe.
The bulk of the carbon in our universe is produced in the triple-alpha process in helium-burning red giant stars. We calculated the change of the triple-alpha reaction rate in a microscopic 12-nucleon model of the (12)C nucleus and looked for the effects of minimal variations of the strengths of the underlying interactions. Stellar model calculations were performed with the alternative reaction rates. Here, we show that outside a narrow window of 0.5 and 4% of the values of the strong and Coulomb forces, respectively, the stellar production of carbon or oxygen is reduced by factors of 30 to 1000.


Preterm birth.
Preterm birth occurs in about 5% to 10% of all births in resource-rich countries, but in recent years the incidence seems to have increased in some countries, particularly in the USA. We found little reliable evidence for incidence in resource-poor countries. The rate in northwestern Ethiopia has been reported to vary from 11% to 22%, depending on the age group of mothers studied, and is highest in teenage mothers. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in women at high risk of preterm delivery? What are the effects of interventions to improve neonatal outcome after preterm rupture of membranes? What are the effects of treatments to stop contractions in preterm labour? What are the effects of elective compared with selective caesarean delivery for women in preterm labour? What are the effects of interventions to improve neonatal outcome in preterm delivery? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 58 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amnioinfusion for preterm rupture of membranes, antenatal corticosteroids, antibiotic treatment, bed rest, beta-mimetics, calcium channel blockers, elective caesarean, enhanced antenatal care programmes, magnesium sulphate, oxytocin receptor antagonists (atosiban), progesterone, prophylactic cervical cerclage, prostaglandin inhibitors (e.g., indometacin), selective caesarean, and thyrotropin-releasing hormone (TRH) (plus corticosteroids).


Real-time noise removal for line-scanning hyperspectral devices using a minimum noise fraction-based approach.
Processing line-by-line and in real-time can be convenient for some applications of line-scanning hyperspectral imaging technology. Some types of processing, like inverse modeling and spectral analysis, can be sensitive to noise. The MNF (minimum noise fraction) transform provides suitable denoising performance, but requires full image availability for the estimation of image and noise statistics. In this work, a modified algorithm is proposed. Incrementally-updated statistics enables the algorithm to denoise the image line-by-line. The denoising performance has been compared to conventional MNF and found to be equal. With a satisfying denoising performance and real-time implementation, the developed algorithm can denoise line-scanned hyperspectral images in real-time. The elimination of waiting time before denoised data are available is an important step towards real-time visualization of processed hyperspectral data. The source code can be found at http://www.github.com/ntnu-bioopt/mnf. This includes an implementation of conventional MNF denoising.


Validation and evaluation of clinical prediction systems for first and repeated transarterial chemoembolization in unresectable hepatocellular carcinoma: A Chinese multicenter retrospective study.
The treatment outcome of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) varies greatly due to the clinical heterogeneity of the patients. Therefore, several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE (re-TACE). To investigate the correlations between prognostic systems and radiological response, compare the predictive abilities, and integrate them in sequence for outcome prediction. This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016. The Hepatoma Arterial-embolization Prognostic (HAP) score system and its modified versions (mHAP, mHAP2 and mHAP3), as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival (OS) prediction for first TACE. The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART (assessment for re-treatment with TACE) and ABCR (alpha-fetoprotein, Barcelona Clinic Liver Cancer, Child-Pugh and Response) systems for post re-TACE survival (PRTS). All the prognostic systems were correlated with radiological response achieved by first TACE, and the six-and-twelve criteria exhibited the highest correlation (Spearman R = 0.39, P = 0.026) and consistency (Kappa = 0.14, P = 0.019), with optimal performance by area under the receiver operating characteristic curve of 0.71 [95% confidence interval (CI): 0.68-0.74]. With regard to the prediction of OS, the mHAP3 system identified patients with a favorable outcome with the highest concordance (C)-index of 0.60 (95%CI: 0.57-0.62) and the best area under the receiver operating characteristic curve at any time point during follow-up; whereas, PRTS was well-predicted by the ABCR system with a C-index of 0.61 (95%CI: 0.59-0.63), rather than ART. Finally, combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo, compared with non-candidates with a median PRTS of 20.0 mo (log-rank test P < 0.001). Radiological response to TACE is closely associated with tumor burden, but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.


A genome-wide association study (GWAS) for bronchopulmonary dysplasia.
Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD. The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip. Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative. We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.


Social status differences regulate the serotonergic system of a cichlid fish, Astatotilapia burtoni.
Serotonin (5-HT) inhibits aggression and modulates aspects of sexual behaviour in many species, but the mechanisms responsible are not well understood. Here, we exploited the social dominance hierarchy of Astatotilapia burtoni to understand the role of the serotonergic system in long-term maintenance of social status. We identified three populations of 5-HT cells in dorsal and ventral periventricular pretectal nuclei (PPd, PPv), the nucleus of the paraventricular organ (PVO) and raphe. Dominant males had more 5-HT cells than subordinates in the raphe, but the size of these cells did not differ between social groups. Subordinates had higher serotonergic turnover in the raphe and preoptic area (POA), a nucleus essential for hypothalamic-pituitary-gonadal (HPG) axis function. The relative abundance of mRNAs for 5-HT receptor (5-HTR) subtypes 1A and 2A (htr1a, htr2a) was higher in subordinates, a difference restricted to the telencephalon. Because social status is tightly linked to reproductive capacity, we asked whether serotonin turnover and the expression of its receptors correlated with testes size and circulating levels of 11-ketotestosterone (11-KT). We found negative correlations between both raphe and POA serotonin turnover and testes size, as well as between htr1a mRNA levels and circulating 11-KT. Thus, increased serotonin turnover in non-aggressive males is restricted to specific brain nuclei and is associated with increased expression of 5-HTR subtypes 1A and 2A exclusively in the telencephalon.


The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders.
Hereditary motor and sensory neuropathy type 2C (HMSN2C, Charcot-Marie-Tooth 2C [CMT2C]) is an autosomal dominant motor and sensory neuropathy involving limb, diaphragm, vocal cord, and intercostal muscles. To identify the chromosome localization for this disorder in one large American family of English and Scottish ethnicity. Variable clinical severity led the authors to combine several approaches to accurately identify affected patients. Genome-wide two-point linkage analysis, high-definition mapping, and multipoint and recombinant haplotype analyses were performed. Mutation analysis of the triplet repeat region of ataxin-2 was also carried out. The initial genome-wide scan identified a region at 12q24, and fine mapping provided a maximal lod score of 4.73 (D12S1645 and D12S1583 at theta = 0.01 and 0, respectively). With multipoint analysis, a higher lod score of 5.17 was obtained and localized to the same region at 119.0 cM. Haplotype analysis narrowed the region to approximately 5.0 cM between D12S1646,D12S1330 and D12S105,D12S1339 (12q23.3-24.21). Ataxin-2, the gene responsible for spinocerebellar ataxia type 2 (SCA2), localizes to this region, but no triplet repeat expansion or point mutations within the repeat were found. The gene for HMSN2C maps to 12q23-24. This region is associated with SCA2, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Further studies are needed to demonstrate the specific gene alteration and its relationship with nearby genes.


Psychoacoustic consequences of compression in the peripheral auditory system.
Input-output functions on the basilar membrane of the cochlea show a strong compressive nonlinearity at midrange levels for frequencies close to the characteristic frequency of a given place. This article shows how many different phenomena can be explained as consequences of this nonlinearity, including the "excess" masking produced when 2 nonsimultaneous maskers are combined, the nonlinear growth of forward masking with masker level, the influence of component phase on the effectiveness of complex forward maskers, changes in the ability to detect increments and decrements with level, temporal integration, and the influence of component phase and level on the perception of vowellike sounds. Cochlear hearing loss causes basilar-membrane responses to become more linear. This can account for loudness recruitment, linear additivity of nonsimultaneous masking, linear growth of forward masking, reduced temporal resolution for sounds with fluctuating envelopes, and reduced temporal integration.


Prominent plasmacytosis following intravenous immunoglobulin correlates with clinical improvement in Guillain-Barré syndrome.
High doses of pooled polyclonal IgG are commonly used to treat numerous autoimmune diseases. Their mode of action nevertheless remains only partially explained. At the same time, until now, no early biological marker has been able to predict their efficacy. In a first pilot retrospective analysis, we reviewed white blood cell counts and blood smears in consecutive patients with autoimmune disease (n = 202) and non-autoimmune disease (n = 104). Autoimmune patients received either intravenous immunoglobulin (IVIg, n = 103), plasma exchange (n = 78) or no specific treatment (n = 21). We then prospectively monitored consecutive autoimmune patients with IVIg injection (n = 67), or without any specific treatment (n = 10) using the same routine laboratory tests, as well as flow cytometry. Both retrospective and prospective analyses identified large plasma-cell mobilization exclusively in IVIg-treated autoimmune patients 7 days after initiation of treatment. The majority of IVIg-mobilized plasma cells were immature HLA-DR(high)/CD138(low)/CXCR4(low) plasma cells expressing intracellular immunoglobulin G which were neither IVIg- nor human IgG-specific. Importantly, we found a strong negative correlation between the absolute number of IVIg-mobilized plasma cells and time to improve neurological function in both retrospective and prospective studies of Guillain-Barré syndrome (GBS), (r = -0.52, p = 0.0031, n = 30, r = -0.47, p = 0.0028, n = 40, respectively). IVIg promotes immature plasma-cell mobilization in patients with GBS, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis and inflammatory myopathy. Prominent day 7 plasma-cell mobilization is a favourable prognostic marker in patients with GBS receiving IVIg treatment.


The role and place of medicinal plants in the strategies for disease prevention.
Medicinal plants have been used in healthcare since time immemorial. Studies have been carried out globally to verify their efficacy and some of the findings have led to the production of plant-based medicines. The global market value of medicinal plant products exceeds $100 billion per annum. This paper discusses the role, contributions and usefulness of medicinal plants in tackling the diseases of public health importance, with particular emphasis on the current strategic approaches to disease prevention. A comparison is drawn between the 'whole population' and 'high-risk' strategies. The usefulness of the common-factor approach as a method of engaging other health promoters in propagating the ideals of medicinal plants is highlighted. The place of medicinal plants in preventing common diseases is further examined under the five core principles of the Primary Health Care (PHC) approach. Medicinal plants play vital roles in disease prevention and their promotion and use fit into all existing prevention strategies. However, conscious efforts need to be made to properly identify, recognise and position medicinal plants in the design and implementation of these strategies. These approaches present interesting and emerging perspectives in the field of medicinal plants. Recommendations are proposed for strategising the future role and place for medicinal plants in disease prevention.


The enhancing effects of testosterone in exposure treatment for social anxiety disorder: a randomized proof-of-concept trial.
Individuals with a social anxiety disorder (SAD) show hypofunctioning of the hypothalamus-pituitary-gonadal (HPG) axis, which is linked to social fear and avoidance behavior. As testosterone administration has been shown to facilitate social-approach behavior in this population, it may enhance the effectiveness of exposure treatment. In this proof-of-concept study, we performed a randomized clinical assay in which 55 women diagnosed with SAD received two exposure therapy sessions. Session 1 was supplemented with either testosterone (0.50 mg) or placebo. Next, transfer effects of testosterone augmentation on within-session subjective fear responses and SAD symptom severity were assessed during a second, unenhanced exposure session (session 2) and at a 1-month follow-up, respectively. The participants having received testosterone showed a more reactive fear pattern, with higher peaks and steeper reductions in fear levels in session 2. Post-hoc exploration of moderating effects of endogenous testosterone levels, revealed that this pattern was specific for women with high basal testosterone, both in the augmented and in the transfer session. In contrast, the participants with low endogenous testosterone showed reduced peak fear levels throughout session 1, again with transfer to the unenhanced session. Testosterone did not significantly affect self-reported anxiety. The effects of testosterone supplementation on fear levels show transfer to non-enhanced exposure, with effects being modulated by endogenous testosterone. These first preliminary results indicate that testosterone may act on important fear mechanisms during exposure, providing the empirical groundwork for further exploration of multi-session testosterone-enhanced exposure treatment for SAD.


[Surgical treatment of benign tracheoesophageal fistula and bronchoesophageal fistula in the adults].
This article deals with experiences of surgical treatment of benign tracheoesophageal fistula and bronchoesophageal fistula in seven adults. Among them 2 cases were congenital, 2 cases were infective and 3 cases were traumatic. There were 5 males and 2 females. Their average age ranged from 24 to 53 years. The modes of operation were as follows: (1) resection of fistula, and repairing of leak in 3 cases; (2) pneumonectomy and repairing of leak in 2 cases; (3) esophagectomy through right thoracotomy and cervical reconstruction of the retrosternal esophagogastrostomy was performed in one case; (4) repairing of leak with pedicled esophagus wall in one case. Follow-up shows that the surgical treatment gives satisfactory results in these patients.


Borna disease: association with a maturation defect in the cellular immune response.
Borna disease virus (BDV) is a negative-strand RNA virus which produces persistent infection in a variety of experimental animals. In the rat, the presence or absence of clinical signs of Borna disease, a characteristic, biphasic neurobehavioral illness, depends on host-related factors. A window of opportunity exists after birth wherein inoculation with BDV produces a persistently infected rat without signs of Borna disease or encephalitis (persistent, tolerant infection-newborn [PTI-NB] rat). Although immunopathological destruction of the nervous system does not occur in the PTI-NB rat, significant alterations in the development of the nervous system were noted, including site-specific lysis of neurons. Unlike the case with other pharmacologically produced, persistent, tolerant BDV infections, adoptive transfer of spleen cells from BDV-infected rats did not produce disease in the PTI-NB rats. PTI-NB rats developed Borna disease after being connected by parabiosis to rats with Borna disease. Bone marrow transplantation experiments revealed that bone marrow cells from PTI-NB rats produced Borna disease in lethally irradiated, BDV-infected recipient rats. Bone marrow from PTI-NB rats contained a complement of inflammatory cells capable of inducing Borna disease. Thus, the loss of BDV-specific cellular immunity appeared to occur after the release of cells from the bone marrow.


Distribution of murine adipose-derived mesenchymal stem cells in vivo following transplantation in developing mice.
Systemic delivery of mesenchymal stem cells (MSCs) or stromal cells in vivo is attractive because it offers means of disseminating therapeutic cells to various tissues and organs in vivo. In the present study, we investigated the distribution and engraftment of the murine adipose-derived mesenchymal stem cells (ADSCs) without exposure to or exposed to bone microenvironment or transforming growth factor-beta1 (TGF-beta1) prior to transplantation into developing mice. The ADSCs harvested from the murine inguinal fat pad exhibited potential for differentiation toward osteogenic and adipogenic cell lineages in vitro. Fourteen days after systemic transplantation of the ADSCs marked with enhanced green fluorescent protein (EGFP) into developing mice, minimal donor GFP(+) cells were detected in the skeletal tissues in a limited number of the recipient mice. Exposure of the ADSCs to bone microenvironment for 7 or 14 days prior to transplantation into developing mice enhanced their migration and survival in the bones of the recipient mice. Exposure of ADSCs to TGF-beta1 prior to systemic transplantation exerted similar effects on cell migration and engraftment in various tissues, including the bones of the recipient developing mice. At 28 days following systemic transplantation, the ADSCs exposed to bone microenvironment were restricted mostly to the skeletal tissues of the recipient mice. Donor cells retrieved from the bones of the recipient mice at 28 days following cell transplantation expressed the differentiation markers Runx2 and Osterix (Osx). These data suggest that exposure of ADSCs to bone microenvironment or to TGF-beta1 prior to transplantation enhances their survival in the skeletal tissues following transplantation.


N-acetylcysteine prevents the development of gastritis induced by Helicobacter pylori infection.
Helicobacter pylori (H. pylori) is a human gastric pathogen, causing various gastric diseases ranging from gastritis to gastric adenocarcinoma. It has been reported that combining N-acetylcysteine (NAC) with conventional antibiotic therapy increases the success rate of H. pylori eradication. We evaluated the effect of NAC itself on the growth and colonization of H. pylori, and development of gastritis, using in vitro liquid culture system and in vivo animal models. H. pylori growth was evaluated in broth culture containing NAC. The H. pylori load and histopathological scores of stomachs were measured in Mongolian gerbils infected with H. pylori strain 7.13, and fed with NAC-containing diet. In liquid culture, NAC inhibited H. pylori growth in a concentration-dependent manner. In the animal model, 3-day administration of NAC after 1 week from infection reduced the H. pylori load; 6-week administration of NAC after 1 week from infection prevented the development of gastritis and reduced H. pylori colonization. However, no reduction in the bacterial load or degree of gastritis was observed with a 6-week administration of NAC following 6-week infection period. Our results indicate that NAC may exert a beneficial effect on reduction of bacterial colonization, and prevents the development of severe inflammation, in people with initial asymptomatic or mild H. pylori infection.


Adaptive value of sex in microbial pathogens.
Explaining the adaptive value of sex is one of the great outstanding problems in biology. The challenge comes from the difficulty in identifying the benefits provided by sex, which must outweigh the substantial costs of sex. Here, we consider the adaptive value of sex in viruses, bacteria and fungi, and particularly the information available on the adaptive role of sex in pathogenic microorganisms. Our general theme is that the varied aspects of sex in pathogens illustrate the varied issues surrounding the evolution of sex generally. These include, the benefits of sex (in the short- and long-term), as well as the costs of sex (both to the host and to the pathogen). For the benefits of sex (that is, its adaptive value), we consider three hypotheses: (i) sex provides for effective and efficient recombinational repair of DNA damages, (ii) sex provides DNA for food, and (iii) sex produces variation and reduces genetic associations among alleles under selection. Although the evolution of sex in microbial pathogens illustrates these general issues, our paper is not a general review of theories for the evolution of sex in all organisms. Rather, we focus on the adaptive value of sex in microbial pathogens and conclude that in terms of short-term benefits, the DNA repair hypothesis has the most support and is the most generally applicable hypothesis in this group. In particular, recombinational repair of DNA damages may substantially benefit pathogens when challenged by the oxidative defenses of the host. However, in the long-term, sex may help get rid of mutations, increase the rate of adaptation of the population, and, in pathogens, may infrequently create new infective strains. An additional general issue about sex illustrated by pathogens is that some of the most interesting consequences of sex are not necessarily the reasons for which sex evolved. For example, antibiotic resistance may be transferred by bacterial sex, but this transfer is probably not the reason sex evolved in bacteria.


Investigation of mucosal immunisation in pulmonary clearance of Moraxella (Branhamella) catarrhalis.
Moraxella (Branhamella) catarrhalis is a common cause of otitis media in children and respiratory infection in adults with chronic obstructive pulmonary disease. To identify immune responses that may facilitate the development of a mucosal vaccine, a mouse model to study pulmonary responses was established. Regimes involving intra-Peyer's patch, intratracheal and intranasal routes of immunisation with killed M. catarrhalis were investigated. A mucosal immunisation regime of a primary intra-Peyer's patch immunisation with an intratracheal boost resulted in significantly enhanced pulmonary clearance of bacteria compared to controls following an intratracheal challenge with live bacteria. Additional intratracheal boosts did not induce further enhancement of clearance. Intra-Peyer's patch immunisation alone, intratracheal and intranasal immunisations did not induce enhanced clearance. The levels of specific IgG and IgA in serum and bronchoalveolar lavage fluid correlated with pulmonary clearance. The present study showed that mucosal immunisation induced enhanced pulmonary clearance of M. catarrhalis following live bacterial challenge. This mucosal immunisation model has demonstrated that a mucosal vaccine, particularly an oral vaccine, would be feasible.


The heart and tuberous sclerosis. An echocardiographic and electrocardiographic study.
Cross sectional echocardiography, 12 lead electrocardiography, and 24 hour ambulatory electrocardiography were performed in eleven patients with tuberous sclerosis. Echocardiography showed single or multiple intramyocardial masses, most commonly in the ventricular septum, suggestive of rhabdomyomata in seven of the eleven cases. One patient with a normal echocardiogram showed ventricular pre-excitation on electrocardiography, with tachycardias of 180 beats per minute on ambulatory monitoring. Sinus bradycardia, sinus tachycardia, and supraventricular tachycardia were also seen, but their importance is uncertain. Echocardiography and electrocardiography should be routinely performed in the assessment of patients with tuberous sclerosis and ambulatory electrocardiography should be considered in those with seizures that respond poorly to anticonvulsants.


Parotid sialolithiasis in a two-year-old boy.
Sialolithiasis is caused by the obstruction of a salivary gland or its excretory duct by the formation of calcareous concretions or sialoliths; this results in salivary ectasia and provokes subsequent dilation of the salivary gland. Sialolithiasis is relatively common, accounting for 30% of salivary diseases; however, it is rarely observed in childhood. This case report describes a 2-year-old male patient who complained of a painful swelling over the right cheek, and presented with palpable stones and pus discharge from the orifice of the right Stensen's duct. Computerized tomography of the neck confirmed the diagnosis, and the patient received intravenous empiric antibiotics combined with intraoral sialolithotomy. We also provide a review of the spectrum of concepts regarding the pathogenesis, diagnosis, and treatment of sialolithiasis.


A compilation of North American tree provenance trials and relevant historical climate data for seven species.
Tree provenance trials consist of a variety of seed sources (or provenances) planted at several test sites across the range of a species. The resulting plantations are typically measured periodically to investigate provenance performance in relation to abiotic conditions, particularly climate. These trials are expensive and time consuming to establish, but are an important resource for seed transfer systems, which aim to match planting sites with well-adapted (climatically suitable) seed sources. Provenance trial measurements may be underutilized because the data are scattered across publications, conference proceedings, and university theses. Here we document an effort to collect available provenance trial measurements and associated climate data for seven eastern North American tree species (Pinus strobus, Pinus banksiana, Picea glauca, Picea mariana, Quercus rubra, Larix laricina, Betula alleghaniensis). The resulting datasets included a total of 773 provenances and 62 test sites, with 65 historical climate variables appended to each location. We hope this data will support forest managers in making seed transfer decisions, particularly in an era of rapid climate change.


Identification of transcribed sequences in Arabidopsis thaliana by using high-resolution genome tiling arrays.
Using a maskless photolithography method, we produced DNA oligonucleotide microarrays with probe sequences tiled throughout the genome of the plant Arabidopsis thaliana. RNA expression was determined for the complete nuclear, mitochondrial, and chloroplast genomes by tiling 5 million 36-mer probes. These probes were hybridized to labeled mRNA isolated from liquid grown T87 cells, an undifferentiated Arabidopsis cell culture line. Transcripts were detected from at least 60% of the nearly 26,330 annotated genes, which included 151 predicted genes that were not identified previously by a similar genome-wide hybridization study on four different cell lines. In comparison with previously published results with 25-mer tiling arrays produced by chromium masking-based photolithography technique, 36-mer oligonucleotide probes were found to be more useful in identifying intron-exon boundaries. Using two-dimensional HPLC tandem mass spectrometry, a small-scale proteomic analysis was performed with the same cells. A large amount of strongly hybridizing RNA was found in regions "antisense" to known genes. Similarity of antisense activities between the 25-mer and 36-mer data sets suggests that it is a reproducible and inherent property of the experiments. Transcription activities were also detected for many of the intergenic regions and the small RNAs, including tRNA, small nuclear RNA, small nucleolar RNA, and microRNA. Expression of tRNAs correlates with genome-wide amino acid usage.


Analysis of creatine and creatinine in urine by capillary electrophoresis.
Creatine is found in the urine of subjects ingesting creatine monohydrate as an ergogenic aid. Creatinine, the catabolic breakdown product of creatine, is a major constituent of normal urine. It is of interest to follow the excretion of creatine and creatinine in urine as a function of time after creatine ingestion. In this study, creatine and creatinine were analyzed in urine by capillary electrophoresis. The optimization of the method was discussed, with the best results being obtained using a 30 mM phosphate-150 mM sodium dodecyl sulfate buffer at pH 6, with the detector set at 214 nm and an applied voltage of 15 kV across a 45 cm capillary. Verification of the method was provided by HPLC analysis and spiking. The application of the method was demonstrated by analysis of creatine and creatinine in urine samples collected in a 24-h period following creatine ingestion.


The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain.
Simple low molecular weight (MW) chelates of Gd(3+) such as those currently used in clinical MRI are considered too insensitive for most molecular imaging applications. Here, we evaluated the detection limit (DL) of a molecularly targeted low MW Gd(3+)-based T(1) agent in a model where the receptor concentration was precisely known. The data demonstrate that receptors clustered together to form a microdomain of high local concentration can be imaged successfully even when the bulk concentration of the receptor is quite low. A GdDO3A-peptide identified by phage display to target the anti-FLAG antibody was synthesized, purified and characterized. T(1-)weighted MR images were compared with the agent bound to antibody in bulk solution and with the agent bound to the antibody localized on agarose beads. Fluorescence competition binding assays show that the agent has a high binding affinity (K(D)=150 nM) for the antibody, while the fully bound relaxivity of the GdDO3A-peptide/anti-FLAG antibody in solution was a relatively modest 17 mM(-1) s(-1). The agent/antibody complex was MR silent at concentrations below approximately 9 microM but was detectable down to 4 microM bulk concentrations when presented to antibody clustered together on the surface of agarose beads. These results provided an estimate of the DLs for other T(1)-based agents with higher fully bound relaxivities or multimeric structures bound to clustered receptor molecules. The results demonstrate that the sensitivity of molecularly targeted contrast agents depends on the local microdomain concentration of the target protein and the molecular relaxivity of the bound complex. A model is presented, which predicts that for a molecularly targeted agent consisting of a single Gd(3+) complex with bound relaxivity of 100 mM(-1) s(-1) or, more reasonably, four tethered Gd(3+) complexes each having a bound relaxivity of 25 mM(-1) s(-1), the DL of a protein microdomain is approximately 690 nM at 9.4 T. These experimental and extrapolated DLs are both well below current literature estimates and suggests that detection of low MW molecularly targeted T(1) agents is not an unrealistic goal.


Inferior turbinate arterial supply: histologic analysis and clinical implications.
To study the arterial architecture of the normal inferior turbinate. A prospective, nonrandomized, histologic study. Fourteen samples were removed at autopsy and during septoplasty operations, processed in the usual manner, stained with hematoxylin-eosin, and investigated microscopically. The analysis included data on the number, location within or outside the bone, the mean area, wall thickness, and distance the arteries traverse from the point of entrance into the bone to the point of exit into the soft tissue. One to three arteries enter the inferior turbinate posteriorly. In 7 of 14 inferior turbinates (50%), the arteries lie within the bone and in 2 (14%) within the soft tissue, and in 5 (36%), a mixed pattern was observed. The arteries run along a mean of 1.2 +/- 0.49 cm before piercing the bone into the soft tissue and split off to one to six branches. The mean area and the mean wall thickness of the arteries at the entrance into the bone posteriorly were significantly greater than that of the arteries emerging from the bone and entering the soft tissue anteriorly (0.099 +/- 0.056 mm2 vs 0.051 +/- 0.022 mm2 [p < .01] and 0.116 +/- 0.042 mm vs 0.083 +/- 0.031 mm [p < .05], respectively). The inferior mucosal layer lacks major arteries. Given the data presented here, the excision of the inferior mucosal layer and the anterior portion of the inferior turbinate bone distal to the point of arterial exit constitute a relatively low risk for postoperative arterial bleeding.


Computer-based first-principles kinetic Monte Carlo simulation of polyethylene glycol degradation in aqueous phase UV/H2O2 advanced oxidation process.
We have developed a computer-based first-principles kinetic Monte Carlo (CF-KMC) model to predict degradation mechanisms and fates of intermediates and byproducts produced from the degradation of polyethylene glycol (PEG) in the presence of hydrogen peroxide (UV/H2O2). The CF-KMC model is composed of a reaction pathway generator, a reaction rate constant estimator, and a KMC solver. The KMC solver is able to solve the predicted pathways successfully without solving ordinary differential equations. The predicted time-dependent profiles of averaged molecular weight, and polydispersitivity index (i.e., the ratio of the weight-averaged molecular weight to the number-averaged molecular weight) for the PEG degradation were validated with experimental observations. These predictions are consistent with the experimental data. The model provided detailed and quantitative insights into the time evolutions of molecular weight distribution and concentration profiles of low molecular weight products and functional groups. Our approach may be useful to predict the fates of degradation products for a wide range of complicated organic contaminants.


Access to antenatal blood pressure measurement in Malawi: Findings from a national census of health facilities.
To identify service side factors associated with access to antenatal blood pressure measurement at health facilities in Malawi. Secondary data analysis of 1499 observations of antenatal consultations undertaken in the Service Provision Assessment survey 2013-14, a census of all formal health facilities in the country. Differentials in access to antenatal blood pressure measurements by client age or educational status and provider gender or in-service training did not reach statistical significance although clinically important effects cannot be excluded. There was substantial variation among districts, ranging from 14% to 100% of observed consultations. Facilities in the Central and Southern regions had lower odds of providing blood pressure measurement relative to the Northern region (OR 0.17, 95% CI 0.03 to 0.30 and 0.11, 95% 0.04 to 0.31 respectively). Facilities affiliated to the Christian Health Association of Malawi and facilities under private management had higher odds of provision relative to government facilities (OR 3.24, 95% CI 1.71 to 6.11 and 5.77, 95% CI 1.87 to 17.79 respectively). Where observed consultations included taking the client's weight and measuring the symphysis-fundus height, the odds of blood pressure measurement were significantly increased (OR 6.4, 95% CI 3.32 to 12.34 and 1.71, 95% CI 1.01 to 2.88 respectively). An indicator for effective coverage, the proportion of antenatal visits that included blood pressure measurement, recorded in health passports examined at the time of admission for delivery, should be tested for incorporation into the District Health Information System to enable tracking of quality improvement in antenatal care. Further research is needed to elucidate the reasons for the variations identified here.


Domino liver transplants: where do we stand after a quarter-century? A US national analysis.
Domino liver transplantation (DLT) utilizes a phenotypically normal explant from select recipients as a donor graft in another patient. The procedure is not widely employed and remains restricted to a small number of centers. The purpose of this study was to assess the national profile of DLT in the United States (US) and evaluate current survival outcomes. The United Network for Organ Sharing (UNOS) database was queried for all liver transplants (LT) between 1996 and 2020. Outcomes of interest were long-term graft and patient survival. Of 181,976 LTs performed nationally during the study period, 185 (0.1%) were DLTs. Amyloidosis and maple syrup urine disease (MSUD) accounted for 83% of dominoed allografts. Out of 210 explants with amyloidosis, 103 (49%) were dominoed into secondary recipients. Only 50 (22%) of all MSUD explants (n = 227) were dominoed. Graft survival was 79%, 73% and 53% at 3-, 5- and 10-years, respectively, for DLT recipients. Overall patient survival was 83%, 76% and 57% at 3-, 5- and 10-years. Despite excellent long-term survival outcomes, DLT allografts comprise a very small percentage of the liver donor pool. A large proportion of potential DLTs may be unconscionably excluded despite shortages in deceased donor organs.


FNAC: its role, limitations and perspective in the preoperative diagnosis of breast cancer.
Fine-needle aspiration cytology (FNAC) was first described and performed in 1930. Thirty years later, it gained acceptance first in Europe and about a decade later in North America. The method is generally considered as a rapid, reliable, safe diagnostic tool to distinguish non-neoplastic from neoplastic breast lesions. In developed countries, in the last 20 years, mammographic screening programmes, which have been used extensively, are designed to detect the earliest possible breast cancer. The FNAC report is extremely important because it gives the necessary information for the management of patients, in order to proceed with more invasive diagnostic methods or surgical treatment, and to decide what kind of operation to perform. In the preoperative phase, FNAC has taken a fundamental role of both palpable and nonpalpable lesions, using ultrasound or stereotactic guidance. New developed techniques, breast biopsy instrumentation (ABBI) and mammotome have the advantage of complete removal of breast lesions, but this is not possible in all the examined cases. In developing countries, economical restrictions, low budget for health care and screening programmes put the patients at a disadvantage because of the high cost of sophisticated diagnostic methods, thus we recommend that FNAC be used as a routine diagnostic method because of its low cost compared with the others and this policy maximizes the availability of health care to women with breast cancer. We conclude that FNAC plays an important and essential role in the management of patients with breast lesions and also offers a great potential for prediction of patient outcome, disease response to therapy and assessment of risk of developing breast cancer. The reliability and efficiency of the method depends on the quality of the samples and the experience of the medical staff that performs the aspiration.


First results of a randomized clinical trial of fast neutrons compared with X or gamma rays in treatment of advanced tumours of the head and neck. Report to the Medical Research Council.
Results of the first randomized clinical trial to compare the effects of fast neutrons and those of x or gamma rays (photons) in treating patients with advanced tumours of the head and neck are reported. In 37 out of 52 patients treated with neutrons and 16 out of 50 treated with photons the local tumour completely regressed; the tumour later recurred in nine of the 16 photon patients but in none of the 37 neutron patients. The advantages to the neutron-treated patients were seen in tumours of well and poorly differentiated histology and in each site. Complications after treatment did not differ significantly between the groups. Despite these substantial differences in local control of the tumour there were no significant differences in mortality between the series. A detailed study of the effective doses and the response of tumours and normal tissue in each series indicated that the improved results from neutron therapy were due to differences in the biological quality of the beam and not to the rather higher average effective dose in the neutron series. To assess the long-term effects of neutron treatment patients in earlier stages of disease and with smaller tumours should be included in the next phase of the trial.


An analysis of US Africa command area of operations military medical transportations, 2008-2018.
With personnel scattered throughout a continent 3 times larger than the United States, a lack of mature medical facilities necessitates a significant transportation network for medical evacuation in US Africa Command (AFRICOM). We describe medical evacuations analyzed from the US Air Force Transportation Command Regulating and Command & Control Evacuation System (TRAC2ES). We performed a retrospective review of all TRAC2ES medical records for medical evacuations from the AFRICOM theater of operations conducted between January 1, 2008 and December 31, 2018. We abstracted free text data entry in TRAC2ES for diagnostic and therapeutic interventions performed prior to the patient movement request. During this time, there were 963 cases recorded in TRAC2ES originating within AFRICOM. 961 records were complete for analysis. Most patients were male (82%) and military personnel (92%). Most transports originated in Djibouti (72%), and Germany (93%) was the most common destination. Medical evacuations were largely routine (66%), and routine evacuations were proportionally highest amongst US military personnel compared to all other groups. A small portion of patients were evacuated for battle injuries (4%), compared to non-battle injury (33%) and disease (63%). Within disease, the largest proportion of patient complaints centered on gastrointestinal symptoms (13%), behavioral health (11%) and chest pain (8%). Prior to evacuation, only 55% of patients were document as receiving any medication. Pain control was documented in 21% of cases, most commonly being NSAIDs (7%). Extremely low numbers of battle injuries highlight the unique nature of AFRICOM operations compared to areas with more intense combat operations. Limitations of the dataset highlight the need for a data collection mandate within AFRICOM as within other areas for optimization and performance improvement.


The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.
Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform 'go-no-go' decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.


Product Development Partnerships: Case studies of a new mechanism for health technology innovation.
There is a continuing need for new health technologies to address the disease burdens of developing countries. In the last decade Product Development Partnerships (PDP) have emerged that are making important contributions to the development of these technologies. PDPs are a form of public private partnerships that focus on health technology development. PDPs reflect the current phase in the history of health technology development: the Era of Partnerships, in which the public and private sectors have found productive ways to collaborate. Successful innovation depends on addressing six determinants of innovation. We examine four case studies of PDPs and show how they have addressed the six determinants to achieve success.


TL1A both promotes and protects from renal inflammation and injury.
Death receptor 3 (DR3), a member of the TNF receptor (TNFR) superfamily, is induced in human renal tubular epithelial cells (TEC) in response to injury. This study examined the expression and actions of TL1A, the principal ligand for DR3. In histologically normal tissue from biopsy or nephrectomy specimens of renal allografts, TL1A mRNA and protein were expressed in vascular endothelial cells but not in TEC. In specimens of acute or antibody-mediated allograft rejection, vascular endothelial cells and infiltrating leukocytes expressed increased TL1A mRNA and protein, but TEC expressed TL1A protein without mRNA, consistent with uptake of exogenous ligand. Addition of TL1A to organ cultures of human or mouse kidney caused activation of NF-kappaB, expression of TNFR2, activation of caspase-3, and apoptosis in TEC. Inhibition of NF-kappaB activation increased TL1A-mediated caspase-3 activation and apoptosis of TEC, but it did not reduce the induction of TNFR2. In organ culture of DR3-deficient mouse kidneys, addition of TL1A induced TNFR2 but did not activate NF-kappaB and did not increase apoptosis of TEC. These data suggest that TL1A may contribute to renal inflammation and injury through DR3-mediated activation of NF-kappaB and caspase-3, respectively, but that an unidentified receptor may mediate the NF-kappaB-independent induction of TNFR2 in TEC.


A detailed kinetic analysis of rhodium-catalyzed alkyne hydrogenation.
Continuous monitoring using electrospray ionisation mass spectrometry (ESI-MS) shows that Wilkinson's catalyst hydrogenates a charge-tagged alkyne to the corresponding alkene, and at only a marginally slower rate, to the alkane. No rhodium-containing intermediates were observed during the reaction, consistent with the established mechanism which points at the initial dissociation of triphenylphosphine from Rh(PPh₃)₃Cl as being the key step in the reaction. A numerical model was constructed that the closely matched the experimental data, and correctly predicted the response of the reaction to the addition of excess PPh₃.


Internal organization of medial rectus and inferior rectus muscle neurons in the C group of the oculomotor nucleus in monkey.
Mammalian extraocular muscles contain singly innervated twitch muscle fibers (SIF) and multiply innervated nontwitch muscle fibers (MIF). In monkey, MIF motoneurons lie around the periphery of oculomotor nuclei and have premotor inputs different from those of the motoneurons inside the nuclei. The most prominent MIF motoneuron group is the C group, which innervates the medial rectus (MR) and inferior rectus (IR) muscle. To explore the organization of both cell groups within the C group, we performed small injections of choleratoxin subunit B into the myotendinous junction of MR or IR in monkeys. In three animals the IR and MR myotendinous junction of one eye was injected simultaneously with different tracers (choleratoxin subunit B and wheat germ agglutinin). This revealed that both muscles were supplied by two different, nonoverlapping populations in the C group. The IR neurons lie adjacent to the dorsomedial border of the oculomotor nucleus, whereas MR neurons are located farther medially. A striking feature was the differing pattern of dendrite distribution of both cell groups. Whereas the dendrites of IR neurons spread into the supraoculomotor area bilaterally, those of the MR neurons were restricted to the ipsilateral side and sent a focused bundle dorsally to the preganglionic neurons of the Edinger-Westphal nucleus, which are involved in the "near response." In conclusion, MR and IR are innervated by independent neuron populations from the C group. Their dendritic branching pattern within the supraoculomotor area indicates a participation in the near response providing vergence but also reflects their differing functional roles.


Biodegradation kinetics of 1,4-benzoquinone in batch and continuous systems.
Combining chemical and biological treatments is a potentially economic approach to remove high concentration of recalcitrant compounds from wastewaters. In the present study, the biodegradation of 1,4-benzoquinone, an intermediate compound formed during phenol oxidation by chlorine dioxide, was investigated using Pseudomonas putida (ATCC 17484) in batch and continuous bioreactors. Batch experiments were conducted to determine the effects of 1,4-benzoquinone concentration and temperature on the microbial activity and biodegradation kinetics. Using the generated data, the maximum specific growth rate and biodegradation rate were determined as 0.94 h(-1) and 6.71 mg of 1,4-benzoquinone l(-1) h(-1). Biodegradation in a continuous bioreactor indicated a linear relationship between substrate loading and biodegradation rates prior to wash out of the cells, with a maximum biodegradation rate of 246 mg l(-1) h(-1) observed at a loading rate of 275 mg l(-1) h(-1) (residence time: 1.82 h). Biokinetic parameters were also determined using the steady state substrate and biomass concentrations at various dilution rates and compared to those obtained in batch cultures.


Differential regulation of cytoskeletal gene expression in hamster facial motoneurons: effects of axotomy and testosterone treatment.
We have previously demonstrated that systemic administration of testosterone increases the rate of axonal regeneration following facial nerve crush in adult male hamsters. In the present study, the molecular mechanisms by which androgens could enhance axonal regeneration were examined at a cellular level. Specifically, the following question was addressed using quantitative in situ hybridization with cDNA probes complementary to betaII, and alpha1 tubulin mRNAs: Does exogenous testosterone augment axotomy-induced changes in tubulin mRNA expression in hamster facial motoneurons (FMN)? Castrated adult male hamsters were subjected to right facial nerve severance, with the left side serving as internal control. One-half of the animals received testosterone replacement in the form of subcutaneously implanted silastic capsules containing crystalline testosterone propionate, and the other half were implanted with blank capsules immediately following the axotomy. Postoperative survival times from 2-14 days were examined. Axotomy alone resulted in a significant increase in the levels of both betaII and alpha1 tubulin mRNAs in facial motor neurons between 2-14 days after injury. Administration of testosterone selectively augmented the axotomy-induced increases in betaII-tubulin, but not alpha1 tubulin, mRNA, levels at 7 and 14 days post axotomy. These results demonstrating an effect of testosterone in altering the neuronal cytoskeletal response to axotomy suggest that testosterone may enhance the regenerative properties of motor neurons via molecular mechanisms that involve selective alterations of the neuronal cytoskeleton.


A missing link in the sea urchin embryo gene regulatory network: hesC and the double-negative specification of micromeres.
Specification of sea urchin embryo micromeres occurs early in cleavage, with the establishment of a well defined regulatory state. The architecture of the gene regulatory network controlling the specification process indicates that transcription of the initial tier of control genes depends on a double-negative gate. A gene encoding a transcriptional repressor, pmar1, is activated specifically in micromeres, where it represses transcription of a second repressor that is otherwise active globally. Thus, the micromere-specific control genes, which are the target of the second repressor, are expressed exclusively in this lineage. The double-negative specification gate was logically required from the results of numerous prior experiments, but the identity of the gene encoding the second repressor remained elusive. Here we show that hesC is this gene, and we demonstrate experimentally all of its predicted functions, including global repression of micromere-specific regulatory genes. As logically required, blockade of hesC mRNA translation and global overexpression of pmar1 mRNA have the same effect, which is to cause all of the cells of the embryo to express micromere-specific genes.


Recent developments in the management of postmenopausal osteoporosis with bisphosphonates: enhanced efficacy by enhanced compliance.
Bisphosphonates are the current mainstay of treatment for postmenopausal osteoporosis. Although daily oral dosing is effective, it is associated with poor compliance, partly because of the pre and postdose fasting and posture requirements. This negatively impacts treatment outcomes, leading to a reduced clinical benefit. Improved, yet still suboptimal adherence has been noticed with less frequent bisphosphonate dosing e.g. once-weekly and once-monthly oral regimens. The recently approved quarterly intravenous (i.v.) injection regimen of ibandronate and yearly i.v. infusion of zoledronic acid are attractive options in the management of postmenopausal osteoporosis. These regimens may assure quarterly and year long compliance.


Evaluation of Injectable Naloxone-Releasing Hydrogels.
The opioid epidemic in the United States is a serious public health crisis affecting over 1.7 million Americans. In the last two decades, almost 450 000 people have died from an opioid overdose, with nearly 20% of these deaths occurring in 2017 and 2018 alone. During an overdose, overstimulation of the μ-opioid receptor leads to severe and potentially fatal respiratory depression. Naloxone is a competitive μ-opioid-receptor antagonist that is widely used to displace opioids and rescue from an overdose. Here, we describe the development of a slow-release, subcutaneous naloxone formulation for potential management of opioid overdose, chronic pain, and opioid-induced constipation. Naloxone is loaded into self-assembling peptide hydrogels for controlled drug release. The mechanical, chemical, and structural properties of the nanofibrous hydrogel enable subcutaneous administration and slow, diffusion-based release kinetics of naloxone over 30 days in vitro. The naloxone hydrogel scaffold showed cytocompatibility and did not alter the β-sheet secondary structure or thixotropic properties characteristic of self-assembling peptide hydrogels. Our results show that this biocompatible and injectable self-assembling peptide hydrogel may be useful as a vehicle for tunable, sustained release of therapeutic naloxone. This therapy may be particularly suited for preventing renarcotization in patients who refuse additional medical assistance following an overdose.


GDNF and its receptors in the regulation of the ureteric branching.
Recent transgenic and organ culture experiments have inevitably shown that glial cell line-derived neurotrophic factor (GDNF) is a mesenchyme-derived signal for ureteric budding and branching. The signalling receptor complex for GDNF includes a dimer of Ret receptor tyrosine kinase and two molecules of GDNF family receptor alpha1. Alpha-receptors are not only needed for the ligand binding and Ret activation, but they might mediate signals without Ret. While GDNF is clearly required for ureteric branching, tissue recombination studies have shown that it is not sufficient for the completion of ureteric morphogenesis, and other signalling molecules are needed. Different experimental models have resulted in somewhat contradictory results on their molecular identity, but transforming growth factor-beta1, -beta2, fibroblast growth factor-7 and hepatocyte growth factor form, obviously among others, a redundant set of growth factors in ureteric differentiation. Three other members of the GDNF family, neurturin, artemin and persephin, are also expressed in the developing kidney, and at least neurturin and persephin promote ureteric branching in vitro, but their true in vivo roles are still unclear.


Motoric characteristics of representational gestures produced by young children in a naming task.
This study explores the form of representational gestures produced by forty-five hearing children (age range 2 ; 0-3 ; 1) asked to label pictures in words. Five pictures depicting objects and five pictures depicting actions which elicited more representational gestures were chosen for more detailed analysis. The range of gestures produced for each item varied from 3 to 27 for a total of 128 gestures. Gestures have been analyzed with the same parameters used to describe signs produced by deaf children: handshape, location and movement. Results show that gestures for a given picture exhibit similarities in many of the parameters across children. Some motor characteristics found in the production of hearing toddlers' gestures are similar to those described for early signs. Implications of this similarity between gestural and signed linguistic representations in young children are discussed.


Antibacterial drug shortages from 2001 to 2013: implications for clinical practice.
Previous studies have described drug shortages; however, there has been no comprehensive evaluation focusing on US antibacterial shortages. Drug shortage data from the University of Utah Drug Information Service database were analyzed, with a focus on antibacterial agents from 2001 to 2013. We used descriptive statistics to describe trends in drug shortages, analyze drug classes commonly affected, and investigate whether drugs experienced multiple periods of shortages. One hundred forty-eight antibacterial drugs were on shortage over the 13-year study period, with 26 drugs still active on shortage as of December 2013. The median number of new shortages per year was 10 (interquartile range [IQR], 7). The number of drugs on shortage increased at a rate of 0.35 additional drugs every month (95% confidence interval, .22-.49) from July 2007 to December 2013 (P < .001). The median shortage duration was 188 days (IQR, 366.5). Twenty-two percent of drugs experienced multiple shortage periods. There were a substantial number of drug shortages from 2001 to 2013, with a dramatic rise in shortages since 2007. Shortages of agents used to treat multidrug-resistant infections are of concern due to continued transmission and limited treatment options.