A randomized comparison of ketorolac tromethamine and morphine for postoperative analgesia in critically ill children.
To evaluate the efficacy of a single dose of ketorolac compared with morphine for the relief of pain in children, and to determine the safety of ketorolac. Tertiary pediatric intensive care unit in a university-affiliated hospital. Prospective, randomized, double-blind, parallel, single-dose, positive control study. Children admitted to the intensive care unit with postoperative pain. Patients received a single dose of either morphine or ketorolac as the first postoperative analgesic when the pain score indicated significant pain. Blood pressure, heart rate, and urine output were recorded, as well as blood urea nitrogen, creatinine, bleeding time, hematuria or proteinuria, and aspartate aminotransferase. Side effects such as nausea and vomiting were noted. Morphine was used for rescue treatment if the patient continued to have significant pain > or =30 mins after study drug administration. Of the 102 children studied, 48 received morphine and 54 received ketorolac. The percentage of patients reporting pain relief in the first and second hours after drug administration was not different between groups. Likewise, the proportion of patients who met the criteria for pain relief during the entire evaluation period was not different between groups. There was a trend toward fewer patients who received ketorolac requiring remedication in the first 4 hrs compared with those who received morphine, but this trend did not reach statistical significance. More patients in the morphine group failed to achieve pain relief at any time after the dose compared with those who received ketorolac. There were no differences between the two groups in physiologic or laboratory variables. Vomiting was more common in patients who received ketorolac. Ketorolac is comparable to morphine in relief of postoperative pain in children. A single dose of ketorolac does not result in abnormal postoperative bleeding or alter renal function. However, ketorolac may cause nausea and vomiting in some patients.


Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia.
The general anesthetic gas xenon is neuroprotective and is undergoing clinical trials as a treatment for ischemic brain injury. A small number of molecular targets for xenon have been identified, the N-methyl-D-aspartate (NMDA) receptor, the two-pore-domain potassium channel TREK-1, and the adenosine triphosphate-sensitive potassium channel (KATP). However, which of these targets are relevant to acute xenon neuroprotection is not known. Xenon inhibits NMDA receptors by competing with glycine at the glycine-binding site. We test the hypothesis that inhibition of the NMDA receptor at the glycine site underlies xenon neuroprotection against hypoxia-ischemia. We use an in vitro model of hypoxia-ischemia to investigate the mechanism of xenon neuroprotection. Organotypic hippocampal brain slices from mice are subjected to oxygen-glucose deprivation, and injury is quantified by propidium iodide fluorescence. We show that 50% atm xenon is neuroprotective against hypoxia-ischemia when applied immediately after injury or after a delay of 3 h after injury. To validate our method, we show that neuroprotection by gavestinel is abolished when glycine is added, confirming that NMDA receptor glycine site antagonism underlies gavestinel neuroprotection. We then show that adding glycine abolishes the neuroprotective effect of xenon, consistent with competitive inhibition at the NMDA receptor glycine site mediating xenon neuroprotection. We show that xenon neuroprotection against hypoxia- ischemia can be reversed by increasing the glycine concentration. This is consistent with competitive inhibition by xenon at the NMDA receptor glycine site, playing a significant role in xenon neuroprotection. This finding may have important implications for xenon's clinical use as an anesthetic and neuroprotectant.


Weaning from mechanical ventilation: a cross-sectional study of reference values and the discriminative validity of aging.
[Purpose] To evaluate pre-extubation variables and check the discriminative validity of age as well as its correlation with weaning failure in elderly patients. [Subjects and Methods] Two hundred thirty-nine consecutive patients (48% female) who were on mechanical ventilation and had undergone orotracheal intubation were divided into four subgroups according to their age: <59 years, 60-69 years, 70-79 years, and >80 years old. The expiratory volume (VE), respiratory frequency (f), tidal volume (VT), and respiratory frequency/tidal volume ratio (f/VT) were used to examine differences in weaning parameters between the four subgroups, and age was correlated with weaning failure. [Results] The rate of weaning failure was 27.8% in patients aged >80 years and 22.1% in patients aged <60 years old. Elderly patients presented higher f/VT and f values and lower VT values. The areas under the receiver operating characteristic curves for f/VT ratio were smaller than those published previously. [Conclusion] Our results indicate that aging influences weaning criteria without causing an increase in weaning failure.


Zidovudine induced pure red cell aplasia: a case report.
Zidovudine, a Nucleoside Reverse Transcriptase Inhibitor (NRTI) is one of the earliest antiretroviral agents used as a combination in the Highly Active Antiretroviral Therapy (HAART) for the treatment of HIV infection. Its use is however not without adverse effect particularly bone marrow aplasia leading to varying degrees of cytopenias predominantly anaemia. This calls for adequate evaluation and monitoring of patients on this drug. Its major side effect of anaemia limits its use in some patients. We report a case of Zidovudine induced anaemia and bone marrow aplasia in a patient infected with HIV. The Hospital case note of a 27 year old widow with HIV infection and anaemia, who has been on HAART (Zidovudine, Lamivudine and Nevirapine) for one year, was reviewed. She presented with severe anaemia (PCV of 0.05), White cell and platelet counts were within normal limits and reticulocyte count of 0.001%. Bone marrow aspiration and biopsy were diagnostic of pure red cell aplasia on a background hypocellular marrow. She was transfused with four (4) units of packed cells and Zidovudine was replaced with Stavudine. She made remarkable improvement and remains transfusion independent afterwards. Zidovudine is well a known cause of anaemia and thus should be used with caution in the initiation of antiretroviral therapy.


Low blood pressure during pregnancy and poor perinatal outcomes: an obstetric paradox.
Low blood pressure during pregnancy has been associated with poor perinatal outcomes. However, whether this association is causal or is due to confounding has never been carefully assessed. The authors used data from the Collaborative Perinatal Project, a large prospective cohort study in 12 hospitals in the United States from 1959 to 1966. A total of 28,095 subjects were included. At first glance, it appeared that the lower the baseline blood pressure during pregnancy, the higher the incidence of very premature birth (<34 weeks) and severe small for gestational age (<5th percentile) in a consistent dose-response pattern. However, women with low blood pressure were generally younger, shorter, lighter, leaner, poorer, and more often a minority, and they gained less weight. After the authors controlled for these factors, low blood pressure was not associated with preterm birth (adjusted relative risks ranging from 0.86 to 0.93, p > 0.05) or small for gestational age (relative risks ranging from 0.45 to 2.0). Therefore, the association between low blood pressure during pregnancy and poor perinatal outcomes is largely due to confounding by other risk factors. Low blood pressure by itself does not increase risk of poor perinatal outcomes at a population level. However, this conclusion may not apply to individual patients who also have a compromised plasma volume expansion or pathologic homeostasis.


Characterization of Spetex-1, a new component of satellite fibrils associated with outer dense fibers in the middle piece of rodent sperm flagella.
Spetex-1, which has been isolated by differential display as a haploid spermatid-specific gene, encodes a protein with two coiled-coil motifs located in the middle piece of flagella in rodent spermatozoa. The middle piece of flagella is composed of axoneme and peri-axonemal elements including outer dense fibers (ODFs) and satellite fibrils. Pre-embedding immunoelectron microscopy clearly demonstrated that Spetex-1 is located at satellite fibrils associated with ODFs in the middle piece of flagella of rat spermatozoa. Extraction of Spetex-1 from spermatozoa by SDS or urea required dithiothreitol, suggesting crosslinking by disulfide bond is involved in the assembly of satellite fibrils containing Spetex-1. We identified putative Spetex-1 orthologs in many animal species, and both cysteine residues and coiled-coil motifs were well conserved in mammalian orthologs of Spetex-1. When Spetex-1 was co-transfected into COS-7 cells with myc-tagged Tektin4, another filamentous protein associated with ODFs, the two molecules were co-localized in various sizes of aggregates in the cells. These data suggested that Spetex-1, a new component of satellite fibrils, might be involved in the structural stability of the sperm flagellar middle piece and functions in co-operation with Tektin4.


Elucidation of the effects of the CYP1A2 deficiency polymorphism in the metabolism of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1h)-one (YM-64227), a phosphodiesterase type 4 inhibitor, and its metabolites in dogs.
The canine CYP1A2 1117 C>T single nucleotide polymorphism is responsible for a substantial portion of the interindividual variability seen in the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227). The purpose of this study is to investigate the contribution of CYP1A2 to the metabolism of YM-64227 and its five metabolites (MM-1 to MM-5), as well as to determine the interindividual variability between the pharmacokinetic profiles of the compounds with respect to the CYP1A2 deficiency polymorphism. alpha-Naphthoflavone and anti-CYP1A1/2 antibody inhibited the metabolic activities at which MM-2 and MM-3 were formed from YM-64227 in C/C- and C/T-type microsomes. In T/T type, the rate of MM-2 and MM-3 formation was lower, and alpha-naphthoflavone and anti-CYP1A1/2 antibody were shown to have no effect. A positive correlation between the overall metabolism of YM-64227 and phenacetin O-deethylation, a CYP1A2 activity marker, was observed in all the genotypes. The in vitro metabolic clearances in the T/T type of MM-1, MM-3, MM-4, and MM-5 were less than 50% lower than those in the C/C type. The anti-CYP1A1/2 antibody inhibited the metabolism of MM-1, MM-3, MM-4, and MM-5 in the C/C and C/T types. These results suggest that the formation of MM-2 and MM-3 from YM-64227 is catalyzed by CYP1A2, and that CYP1A2 contributes mainly to the subsequent metabolism of the primary metabolites of YM-64227, with the exception of MM-2. It is possible that the interindividual variability of YM-64227 with respect to the CYP1A2 deficiency polymorphism is caused by a decrease in the metabolic activities of both the unchanged drug and its metabolites.


Meta-analysis of the effectiveness of prophylactic antibiotics in the prevention of postoperative complications after tension-free hernioplasty.
Previous reviews of the effectiveness of antibiotic prophylaxis for elective inguinal hernia repair were not conclusive owing to the limited number of patients enrolled in randomized controlled trials (RCTs). However, since new RCTs involving patients undergoing tention-free hernioplasty have been published in recent years, we performed a new meta-analysis to evaluate the effectiveness of antibiotic prophylaxisin the prevention of postoperative complications after this procedure. We performed a meta-analysis of RCTs studying the use of antibiotic prophylaxis to prevent postoperative complications in patients undergoing tension-free hernioplasty. We included 6 RCTs conducted around the world in our analysis. Compared with the control condition, antibiotic prophylaxis was associated with a lower incidence of incision infection (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.26-0.77, p = 0.004). There were no significant differences in risk for incision hematoma (OR 1.57, 95% CI 0.60-4.10, p = 0.35), respiratory infection (OR 1.00, 95% CI 0.17-5.79, p > 0.99) or urinary tract infection (OR 1.81, 95% CI 0.38-8.52, p = 0.45) between the 2 conditions. Antibiotic prophylaxis use in patients undergoing tension-free hernioplasty decreases the rate of incision infection by 55%.


The Prevalence of Multiple Comorbidities in Stroke Survivors in Rural Appalachia and the Clinical Care Implications.
The majority of studies on multimorbidity have been in aging populations and there is a paucity of data on individuals following stroke. In order to better understand the overall complexity of the stroke population in rural Kentucky, we examined the prevalence of multimorbidity that impact the overall long-term health and health care for these individuals. A secondary analysis examined whether there are gender or age differences in this stroke population related to the prevalence of multimorbidity. A total of 5325 individuals, 18 years of age and older, seen at an academic medical center for the primary diagnosis of acute ischemic stroke or transient ischemic attack between the years of 2010-2017 were identified using the Kentucky Appalachian Stroke Registry. Descriptive analysis was used to report the prevalence of each comorbidity in the rural population by age group, gender, and level of multimorbidity by looking at concurrent frequencies. Overall, hypertension, dyslipidemia, tobacco use, diabetes, and obesity were the comorbidities with the highest prevalence in our population irrespective of gender. Over 78% (n = 4153) of the individuals had 3 or more comorbidities while 61% (n = 3285) had at least 3 out of the top 5 comorbidities (hypertension, hyperlipidemia, tobacco, obesity, diabetes). With respect to age, 15% (n = 795) of the sample was under the age of 50, while 32% (n = 1704) were between the age of 50 and 64 and 53% (n = 2826) of the sample were 65 years or older. The results of this study indicate the majority of individuals affected by stroke in rural Appalachia Kentucky have multimorbidity. In addition, almost half of these individuals are having their strokes at a younger age, which will require a shift in the focus for therapeutic interventions (eg, reintegration into the workforce versus just community reintegration).


Large-area synthesis of high-quality beta-MnO(2) nanowires and the mechanism of formation through a facile mineralization process.
High-quality large-area beta-MnO(2) nanowires can be easily synthesized using KNO(3) as the mineralizing agent in a process of mineralization from Mn(NO(3))(2) aqueous solution. The morphological evolution of the beta-MnO(2) nanowires and the influences of mineralizing agents and their concentrations on the morphology of the final products were investigated in detail. KNO(3) was the best mineralizing agent among KNO(3), NaNO(3), KCl, and NaCl. More interestingly, when the concentration of the mineralizing agent KNO(3) was not saturated, only irregular short faceted nanorods, instead of nanowires, can be observed. Finally, the formation mechanism is discussed.


Frontal White Matter Hyperintensities Effect on Default Mode Network Connectivity in Acute Mild Traumatic Brain Injury.
The functional connectivity of the brain depends not only on the structural integrity of the cortex but also on the white matter pathways between cortical areas. White matter hyperintensities (WMH), caused by chronic hypoperfusion in the white matter, play a role in the outcome of traumatic brain injury (TBI) and other neurodegenerative disorders. Herein, we investigate how the location and volume of WMH affect the default-mode network (DMN) connectivity in acute mild TBI (mTBI) patients. Forty-six patients with acute mTBI and 46 matched healthy controls were enrolled in the study. All participants underwent T2-weighted fluid-attenuated inversion recovery magnetic resonance imaging (MRI), resting-state functional MRI (fMRI),and neuropsychological assessments. The volume and location of WMH were recorded. The relationships between the WMH volume and clinical assessments were evaluated using Spearman's correlation. Patients with higher frontal lobe WMH volume had more severe post-concussion symptoms and poorer information processing speed. Moreover, these patients had significantly lower functional connectivity in the right middle temporal gyrus, left middle frontal gyrus, right superior frontal gyrus, and left anterior cingulate cortex, compared with patients with low frontal lobe WMH volume. Compared to the controls, the patients with high frontal WMH volume exhibited significantly lower functional connectivity in the right inferior temporal gyrus, left anterior cingulate cortex, and right superior frontal gyrus. These findings suggest that frontal lobe WMH volume may modulate the functional connectivity within the DMN. Therefore, the WMH volume in specific regions of the brain, particularly the frontal and parietal lobes, may accelerate the process of aging and cognitive impairment may be a useful biomarker for the diagnosis and prognosis of acute mTBI.


[Transgenerational genomic instability in children of liquidators of the accident at the ChNPP (cytogenetic and immunogenetic characteristics)].
A complex of cytogenetic and of immunogenetic study of the state of the lymphocyte genomes in the liquidators of the ChNPP accident and their unirradiated children has been carried out for the first time. Increased frequencies of the chromosome aberrations, of gene mutations (TCR mutations) and of predictors of apoptosis (cells with CD95+ immunophenotype) have been revealed in both generations. The analysis of correlations between the parameters under study has demonstrated distinctive features characteristic of induction of genomic instability in the organism of unirradiated children as compared to their fathers--liquidators directly exposed to radiation. Individual variability of genome destabilization were observed by all criteria used and manifested themselves in the diverse spectrum of transgenerational mutational effects and in different levels of their expression. The results obtained demonstrate the necessity of integral evaluation of the state of the genome using several genetic criteria to reveal transgenerational genomic instability in children of a special category--the offsprings of irradiated parents.


Modeling HIV quasispecies evolutionary dynamics.
During the HIV infection several quasispecies of the virus arise, which are able to use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are starting large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains. We present a model of HIV early infection which describes the dynamics of R5 quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the following findings: after superinfection (multiple infections at different times) or coinfection (simultaneous infection by different strains), quasispecies dynamics has time scales of several months and becomes even slower at low number of CD4+ T cells. Phylogenetic inference of chemokine receptors suggests that viral mutational pathway may generate a large variety of R5 variants able to interact with chemokine receptors different from CXCR4. The decrease of CD4+ T cells, during AIDS late stage, can be described taking into account the X4-related Tumor Necrosis Factor dynamics. The results of this study bridge the gap between the within-patient and the inter-patients (i.e. world-wide) evolutionary processes during HIV infection and may represent a framework relevant for modeling vaccination and therapy.


Mitochondrial dysfunction triggers a catabolic response in chondrocytes via ROS-mediated activation of the JNK/AP1 pathway.
Mitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of the catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we showed that mitochondrial membrane potential was lower in OA cartilage, and that this was associated with increased production of mitochondrial superoxide and catabolic genes [interleukin 6 (IL-6), COX-2 (also known as PTGS2), MMP-3, -9, -13 and ADAMTS5]. Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using carbonyl cyanide 3-chlorophenylhydrazone increased mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3, -9, -13 and ADAMTS5, and cartilage matrix degradation. Mitochondrial dysfunction-induced expression of catabolic genes was dependent on the JNK (herein referring to the JNK family)/activator protein 1 (AP1) pathway but not the NFκB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO, or pharmacological inhibition of JNK or cFos and cJun, blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1-mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.This article has an associated First Person interview with the first author of the paper.


Antimicrobial treatments to control Listeria monocytogenes in queso fresco.
Queso fresco, is a Hispanic non-fermented cheese highly susceptible to contamination with L. monocytogenes. This research was aimed to determine the effect of GRAS antimicrobial ingredients to control L. monocytogenes. Antimicrobials included caprylic acid (CA), Nisaplin® (N, 2.5% nisin), a mixture of sodium lactate and sodium diacetate (SL/SD), Lactococcus lactis sbp. lactis DPC 3147, monolaurin, and lactic acid (LA). Batches of queso fresco curds were inoculated with 104 CFU/g and stored at 4 °C for three weeks. During storage the count of L. monocytogenes reached 7 to 8 Log CFU/g in control samples. Most individual antimicrobial treatments resulted in less than 1 Log CFU/g reductions in final counts, with the exception of N (0.5 g/kg) and CA (2.9 g/kg) that caused more than 3 and 5 Log CFU/g differences with controls, respectively. Mixtures of ingredients were more effective in inhibiting L. monocytogenes growth, and treatments with N and CA consistently delivered 6 Log CFU/g less counts than controls. Supplementation of 12 g/kg LA to treatments with SL/SD (3%/0.22%) caused differences of more than 4 Log CFU/g in final Listeria populations. Samples treated with the binary mixtures of N and CA (0.5 and 0.7 g/kg, respectively) were evaluated in a consumer panel (n = 67). Panelists slightly preferred control and commercial over treated samples, but all samples were in average rated between "slightly liking" and "moderately liking." These experiments indicated that combined use of antimicrobial ingredients may be an effective way to control the population of Listeria monocytogenes in queso fresco.


Tumor necrosis factor {alpha} reversibly disrupts the blood-testis barrier and impairs Sertoli-germ cell adhesion in the seminiferous epithelium of adult rat testes.
The timely restructuring of the blood-testis barrier (BTB) that facilitates the migration of preleptotene and leptotene spermatocytes from the basal to the adluminal compartment in the seminiferous epithelium of adult rat testes, which occurs at late stage VII through early stage VIII of the epithelial cycle, is a crucial cellular event of spermatogenesis. However, the regulation of BTB dynamics at the biochemical level remains elusive. In this study, tumor necrosis factor alpha (TNFalpha), a secretory product of Sertoli and germ cells in rat testes, was shown to affect junction dynamics in vivo. Following an acute administration of recombinant TNFalpha directly to adult rat testes in vivo at 0.5 and 2 mug/testis (with a body weight ~300 g), this treatment significantly and transiently disrupted the BTB. It also transiently inhibited the steady-state protein levels of occludin, zonula occludens-1, and N-cadherin, but not junction adhesion molecule-A, alpha-, and beta-catenin in testes at the BTB site as illustrated by immunoblottings, immunohistochemistry, electron microscopy, and fluorescent microscopy. This transient disruption of the BTB integrity induced by TNFalpha treatment was further demonstrated by a functional test to assess the passage of a fluorescent dye (e.g. fluorescein-5-isothiocyanate) from the systemic circulation to the adluminal compartment. Additionally, both the phosphorylated-Ser/Thr protein kinase activated by MAP kinase kinase (p-p38) and phosphorylated-externally regulated kinase (p-ERK) mitogen -activated protein kinase-signaling pathways were transiently activated. Collectively, these data coupled with the recently published in vitro studies have illustrated that the BTB is likely utilizing a novel mechanism in which localized production of TNFalpha by Sertoli and germ cells into the microenvironment at the basal compartment facilitates the timely restructuring ('opening'?) of the BTB during spermatogenesis to facilitate germ cell migration.


Scanning electron microscopic observation on the equatorial region of the rat intrafusal muscle fibres, especially on the subsarcolemmal sarcoplasmic reticulum.
We examined intracellular structures in the equatorial region of the muscle spindles of rat soleus muscles by scanning electron microscopy, paying particular attention to the ultrastructure of the sarcoplasmic reticulum (SR) beneath the sarcolemma. The subsarcolemmal SR was more developed in nuclear chain fibres than in nuclear bag fibres as was reported in the sleeve and extracapsular regions. In addition, the subsarcolemmal SR of the chain fibre formed a fenestrated sheet, whereas that of the bag fibre organized a layer of fenestrated bands beneath the sarcolemma where the sensory nerve endings are associated. No T-tubules were discerned in the subsarcolemmal SR of both fibres, which may be concerned with the little contraction of the equatorial region.


The mechanical and biological properties of demineralised cortical bone allografts in animals.
We studied the calcium content and mechanical strength of cortical bone from rats and dogs after different periods of demineralisation, showing that the rate of demineralisation differed considerably between the species. Specimens from the rat were further treated by chemical extraction and autolysis and tested for osteoinductive properties. We showed that partially demineralised cortical bone retained adequate mechanical strength, while retaining the biological effects of completely demineralised bone. This shows that it is possible to prepare allografts which have adequate mechanical strength and still retain osteo-inductive properties.


Quality assessment of localization technique performance in small volume in vivo 1H MR spectroscopy.
A new phantom and evaluation method for experimental evaluation of 1H-magnetic resonance spectroscopy single volume localization techniques regarding signal contamination (C), defined as the part of the signal originating outside the volume of interest, is presented. The quality assessment method is based on a spherical phantom with an oil/water interface in order to reduce susceptibility effects, and applied for stimulated-echo acquisition method (STEAM) and spin-echo (SE) sequences, echo times of 270, 135, and 10 ms, and cubic volumes of interest (VOI) of 1(3), 1.5(3), 2(3), 2.5(3), and 3(3) cm3. To be able to mimic measurements of the contamination in three dimensions the physical gradients representing the three orthogonal directions for slice selection were shifted in the pulse sequences. Contamination values in one dimension differed between 6.5% and 8.4% in SE sequences, and between 0.7% and 13.8% in STEAM sequences. In STEAM sequences a decrease of C with increasing VOI size was observed while SE sequences showed comparable C values for the different VOI sizes tested. The total contamination in three dimensions were 19% and 18% in SE and STEAM sequences with a TE of 270 ms, and 7% in a STEAM sequence with a TE of 10 ms, respectively. The presented evaluation method is easily applied to the new phantom and showed high reproducibility.


Association between epicardial fat thickness and cognitive function in elderly. A preliminary study.
Recent studies suggested that the visceral fat could exert a predictive role in the pathogenesis of dementia. The aims of the present study were to evaluate: i) possible differences between groups with different epicardial adipose tissue (EAT) thickness on the included variables; ii) the possible predictive role of the EAT levels on cognitive functioning. 65 community-dwelling subjects were enrolled and divided into two groups: EAT < 7 mm (n = 36); EAT > 7 mm (n = 29). The metabolic profile was assessed through the evaluation of the biochemical parameters whereas the EAT thickness was measured through the transthoracic echocardiography. The Mini Mental State Examination (MMSE) was also administered. The two EAT groups reported several significant differences, included on the MMSE scores. The multiple linear regression analysis showed that the EAT thickness levels and the hypertension had a predictive effect on the MMSE scores. These preliminary findings support the association between EAT thickness levels and cognitive impairment.


Preparation Mechanism and Properties of Orthoboric Acid Nanowires with Honeycomb-Like Structure.
Orthoboric acid (H₃BO₃) nanowires with honeycomb-like structure are successfully synthesized on boron nitride (BN) substrate using Fe powder as a catalyst. The formation of the nanowires is a two-step process (solid-liquid-solid growth mechanism), including the formation of B2O3 and its reaction with water to form H₃BO₃. The fundamental properties of H₃BO₃ nanowires, including their morphology, crystal structure, optical properties, thermal stability, and electrochemical properties, were systematically studied in order to expand their application fields. When innovatively investigated as anode materials for lithium ion batteries, the nanowires show a high discharge specific capacity of 243 mA h g-1 in the first cycle at a current density of 100 mA g-1. Further modification is essential for improving its cycling stability, such as surface coating and doping ions. Orthoboric acid nanowires with high first discharge capacity are believed to have great prospects for the development of novel anode materials for lithium ion batteries.


Parent training and social skills training for children with attention-deficit hyperactivity disorder: how can they be combined for greater effectiveness?
Attention-deficit hyperactive disorder (ADHD) is a chronic and treatment-refractory syndrome affecting academic, social and emotional adjustment in children. Stimulant medication is the treatment of choice and is often paired with psychosocial treatment. However, no single treatment modality alleviates the symptoms or improves the negative peer status of these children in their social ecology over the long term. This article reviews two psychosocial treatments used for ADHD, parent training and social skills training and suggests ways that these two components may be combined for greater effectiveness by encouraging the parent to: 1. learn more about the importance of developing social competence and positive peer status; 2. use incidental teaching and self-evaluation strategies; 3. become strategic organizers of the child's social life; and 4. become case managers to facilitate more consistency between the significant adults in the child's social environment.


Transparent Blend of Poly(Methylmethacrylate)/Cellulose Acetate Butyrate for the Protection from Ultraviolet.
The use of transparent polymers as an alternative to glass has become widespread. However, the direct exposure of these materials to climatic conditions of sunlight and heat decrease the lifetime cost of these products. The aim of this study was to minimize the harm caused by ultraviolet (UV) radiation exposure to transparent poly(methylmethacrylate) (PMMA), which usually leads to changes in the physical and chemical properties of these materials and reduced performance. This was achieved using environmentally friendly cellulose acetate butyrate (CAB). The optical, morphological, and thermal properties of CAB blended with transparent PMMA was studied using UV-VIS spectrophotometry, scanning electron microscopy, X-ray diffraction, dynamic mechanical analysis, and thermal gravimetric analysis. The results show that CAB was able to reduce the effects of UV radiation by making PMMA more transparent to UV light, thereby preventing the negative effects of trapped radiation within the compositional structure, while maintaining the amorphous structure of the blend. The results also show that CAB blended with PMMA led to some properties commensurate with the requirements of research in terms of a slight increase in the value of the modulus and the glass transition temperature for the PMMA/CAB blend.


Are cutaneous melanomas of specified thickness showing deeper levels of invasion at diagnosis?
Secular trends in Clark level were investigated by Breslow category for 8,432 invasive cutaneous melanomas diagnosed in South Australia in 1980-2000. More recently diagnosed lesions were found to have deeper levels. After adjusting for age at diagnosis, tumour site, histology, and thickness measured in half millimetres, the relative odds (95% confidence limits) of penetration to the reticular dermis or subcutaneous fat were 1.99 (1.59, 2.50) for the 1987-93 diagnostic period, and 2.82 (2.25, 3.54) for 1994-2000, when compared with 1980-86. After adjusting for melanoma thickness, the secular trends for deeper lesions applied to a broad cross-section of socio-demographic sub-groups, tumour sites, and histological types. While this similarity in trend would be consistent with a measurement effect, a real change cannot be ruled out and increased emphasis on earlier detection may be warranted. The prognostic implications of changes in inter-relationships between measures of thickness and level require periodic re-evaluation.


Recognition of multiple tachyarrhythmias by rate-independent means using a small microcomputer.
New implantable devices are now available that can offer different therapies for different arrhythmias but they need a method of discriminating between these rhythms. Heart rate analysis is predominantly used to discern between sinus rhythm (SR) and pathological tachycardias but this may be of limited value when the rates of the rhythms are similar. An enhanced form of Gradient Pattern Detection (GPD) has been developed using an 8-bit microcomputer that can distinguish between SR and up to three other arrhythmias in real time. This is a method based on electrogram morphology where each rhythm's specific electrogram is classified by a sequence of gradient 'zones'. The microprocessor of the computer is of similar processing power to ones used in current pacemakers. Five patients with multiple arrhythmias were studied. Four had ventricular tachycardia (VT) and one had three conduction patterns during supraventricular tachycardia (SVT). Bipolar endocardial right ventricular electrograms were recorded during SR and tachycardia in all patients. The computer would first 'learn' about each different rhythm by a semi-automatic means. Once all the rhythms were learned the program would enter the GPD analysis phase. The computer would output a series of real-time rhythm specific marker codes onto a chart recorder as it recognized each rhythm. Sixteen different arrhythmias (13 VT, 3 SVT) were examined for this study. All rhythms (including SR) were distinguished from each other except in the case of one patient with six VTs where two VTs had identical shapes and therefore could not be detected apart. The method would be a useful addition to heart rate analysis for future generations of microprocessor assisted pacemakers.


RNN- and LSTM-Based Soft Sensors Transferability for an Industrial Process.
The design and application of Soft Sensors (SSs) in the process industry is a growing research field, which needs to mediate problems of model accuracy with data availability and computational complexity. Black-box machine learning (ML) methods are often used as an efficient tool to implement SSs. Many efforts are, however, required to properly select input variables, model class, model order and the needed hyperparameters. The aim of this work was to investigate the possibility to transfer the knowledge acquired in the design of a SS for a given process to a similar one. This has been approached as a transfer learning problem from a source to a target domain. The implementation of a transfer learning procedure allows to considerably reduce the computational time dedicated to the SS design procedure, leaving out many of the required phases. Two transfer learning methods have been proposed, evaluating their suitability to design SSs based on nonlinear dynamical models. Recurrent neural structures have been used to implement the SSs. In detail, recurrent neural networks and long short-term memory architectures have been compared in regard to their transferability. An industrial case of study has been considered, to evaluate the performance of the proposed procedures and the best compromise between SS performance and computational effort in transferring the model. The problem of labeled data scarcity in the target domain has been also discussed. The obtained results demonstrate the suitability of the proposed transfer learning methods in the design of nonlinear dynamical models for industrial systems.


Placenta increta occurring in a blighted ovum.
We present a rare case of placenta increta, confirmed postoperatively by pathologic analysis, occurring before 20 weeks' gestation in a blighted ovum. Hysterectomy was necessary for control of hemorrhage.


Synthesis of N-allylideneamines and their use for the double nucleophilic addition of ketene silyl (thio)acetals and trimethylsilyl cyanide.
N-Allylideneamines 1a, b were prepared from acrolein and diphenylethyl or trityl amine in the presence of Ti(OEt)4. Double nucleophilic addition of various ketene silyl (thio)acetals and trimethylsilyl cyanide to these imines proceeded efficiently to give, after workup with TFA, homoglutamic acid derivatives 3 and valerolactam 5.


Predictive Value of Class III D Cytological Diagnosis (Munich II, Low and Moderate Dysplasia) and Additional High-risk HPV Testing.
The validity of cytological diagnostic procedures for the detection of pre- and early cervical cancer stages is limited due to biological conditions, the uncertainty of cell sampling, and the subjective nature of microscopic assessment. Particularly in class III D cases (Munich II) this can lead to a stigmatization of patients and uncertainty with regard to further clinical follow-up and therapy. Prior to carrying out additional investigations such as high-risk HPV testing or the examination of biomarkers, the positive predictive values of patients with a class III D cytological diagnosis need to be assessed in routine practice. To this end, all relevant data from patients from our practice classed as class III D (pap smears) between 2002 and 2008 (n = 1190; 38.2 % histological diagnosis = therapeutic endpoint) and their current HPV status were recorded. Cytology, histology, persistence, age and follow-up were recorded. The database was used for comparative statistical analysis. Overall, the positive predictive value of conventional pap smear for CIN 2+ was calculated to be 32.3 % (mean follow-up: 39.7 months). The following values were calculated for high-risk HPV testing: sensitivity 94.8 %, specificity 39 %, positive predictive value 42.8 %, negative predictive value 94 %. The additional information obtained from high-risk HPV testing resulted in a significantly better positive predictive value only in patients older than 40 years. However, there was no evidence for an individual risk stratification approach which would reduce uncertainty in the management of III D patients.


[Complication of tracheal intubation: severe cervical cellulitis].
A 40-year-old man, victim of a traffic accident has been hospitalized for a severe head trauma. His trachea has been intubated under general anaesthesia with an 8.0 mm ID tube (Vygon). The cerebral scan revealed a surgical subdural haematoma. In the postoperative period, the patient was admitted in surgical intensive care, under sedation and mechanically ventilation. At day 12 the patient developed a cervical cellulitis complicated of a septic shock. The cervical scan showed an important dilatation of the trachea in the site of the tube cuff. The surgical exploration discovered a complete destruction of the anterior face of de trachea on several centimetres of height. The patient died 24 hours later by multiple organ failure.


A prospective trial of intravenous streptokinase in acute myocardial infarction (I.S.A.M.). Mortality, morbidity, and infarct size at 21 days.
Within six hours after the onset of symptoms of myocardial infarction, we randomly assigned 1741 patients up to 75 years of age to a one-hour intravenous infusion of 1.5 million IU of streptokinase or placebo. At 21 days mortality was 6.3 percent in the streptokinase group and 7.1 percent in the placebo group. Of those treated within three hours of the onset of symptoms, 5.2 percent died in the streptokinase group (n = 477), as compared with 6.5 percent in the placebo group (n = 463). These differences were not significant. The time to peak serum levels of creatine kinase of myocardial origin (CK-MB) after the onset of symptoms was significantly shorter (13.9 vs. 19.2 hours), and the integrated area under the CK-MB curve (CK-MB infarct size) was significantly smaller, in the streptokinase group (P less than 0.02). Angiograms obtained in 848 patients three to four weeks after infarction revealed that the streptokinase group had higher global ejection fractions (56.8 vs. 53.9 percent, P less than 0.005) and regional ejection fractions (all patients in group, P less than 0.005; patients with anterior or inferior infarctions, P less than 0.05). We conclude that beginning intravenous streptokinase infusion early after the onset of myocardial infarction limits the size of the infarct regardless of its localization. There was, however, only a trend toward reduced mortality at 21 days.


Escherichia coli strains (ndk) lacking nucleoside diphosphate kinase are powerful mutators for base substitutions and frameshifts in mismatch-repair-deficient strains.
Nucleoside diphosphate (NDP) kinase is one of the enzymes that maintains triphosphate pools. Escherichia coli strains (ndk) lacking this enzyme have been shown to be modest base substitution mutators, and two members of the human family of NDP kinases act as tumor suppressors. We show here that in E. coli strains lacking NDP kinase high levels of mispairs are generated, but most of these are corrected by the mismatch-repair system. Double mutants that are ndk mutS, lacking both the NDP kinase and mismatch repair, have levels of base substitutions 15-fold higher and levels of certain frameshifts up to 10-fold higher than those of the respective mutations in mutS strains that are NDP kinase proficient. A sequence analysis of the specificity of base substitution mutations generated in ndk and ndk mutS backgrounds as well as other experiments suggests that NDP kinase deficiency stimulates polymerase errors that lead to A:T --> G:C transitions and that the editing capacity of cells may be affected, leading to additional uncorrected mispairs and to A:T --> T:A transversions.


[Significance of P504s in distinction between solid pseudopapillary tumor of pancreas and pancreatic neuroendocrine tumors].
To study the significance of P504s in differential diagnosis between solid pseudopapillary tumor of the pancreas (SPTP) and pancreatic neuroendocrine tumors (PanNET). Forty-three patients with SPTP and 41 patients with PanNET encountered during the period from 2007 to 2014 were recruited. Immunohistochemical study for vimentin, CD10, chromogranin A, synaptophysin, beta-catenin, CD99 and P504s in SPTP and PanNET was performed. The diagnostic value of P504s in differentiating SPTP from PanNET was analyzed. Immunohistochemical study showed that vimentin, CD10, chromogranin A, synaptophysin and CD99 were expressed both in SPTP and PanNET. All cases of SPTP showed granular cytoplasmic expression of P504s, whereas those of PanNET were negative. P504s is a sensitive and useful marker for SPTP and can be used in the distinction between SPTP and PanNET.


Identification and characterization of the erect-pose panicle gene EP conferring high grain yield in rice (Oryza sativa L.).
The breeding of japonica varieties with erect-pose panicle (EP) has recently progressed in the northern part of China, because these varieties exhibit a far higher grain yield than the varieties with normal-pose panicle (NP). A genetic analysis using the F(2) population from the cross between Liaojing5, the first japonica EP variety in China, and the Japanese japonica NP variety Toyonishiki revealed that EP is governed by a single dominant gene EP. Based on previous studies, map-based cloning of EP locus was conducted using Liaojing5, Toyonishiki, their F(2) population, and a pair of near-isogenic lines for EP locus (ZF14 and WF14) derived from the cross between the two varieties; consequently, the STS marker H90 was found to completely cosegregate with panicle pose. The H90 is located in the coding sequence AK101247 in the database, and the AK101247 of Liaojing5 has a 12 bp sequence in exon 5 replaced with a 637 bp sequence of its wild type allele. It was therefore considered that the AK101247 encodes the protein of the wild type allele at EP locus, and that the sequence substitution in exon 5 of Liaojing5 is crucial for expression of the EP phenotype. The effects of EP gene on agronomic traits were investigated using two pairs of near-isogenic lines (ZF6 vs. WF6 and ZF14 vs. WF14) derived from the cross between the two varieties. Experimental results showed that EP gene markedly enhanced grain yield, chiefly by increasing number of secondary branches and number of grains on the secondary branch. EP gene also produced a remarkable increase in grain density.


Biopolymeric modification of superoxide dismutase (mPEG-SOD) to prevent muscular ischemia-reperfusion damage.
The efficacy of preventing ischemia-reperfusion damage by employing native or modified (mPEG-SOD) superoxide dismutase in an experimental animal model of acute ischemia of the left hindlimb was tested. Four hours and thirty minutes complete warm ischemia was induced in the left hindlimb of 43 Wistar rats, by clamping the femoral artery and monitoring its efficacy with Laser Doppler flowmetry. After ten days, a significative difference (p = 0.004) of the survival leg rate was found in the group treated with mPEG-SOD (86.6%) compared with the control group (30%). Histomorphological and ultrastructural analysis were performed at different time intervals confirming what the clinical course had already pointed out. These results show that SOD in its modified form, despite the lower dosage, can provide good protection against ischemia/reperfusion injury of muscles.


Talipes equinovarus: two case reports and literature review.
Clubfoot, or talipes equinovarus, was introduced into the medical literature by Hippocrates in 400 B.C. The clubfoot deformity is a pathologic condition consisting of inversion and adduction of the forefoot, equinus of the ankle, and inversion of the heel. The condition has also been described as a congenital subluxation of the talocalcaneonavicular joints. This manuscript will review the literature with respect to history, incidence, etiology, anatomy, classification, radiology, and treatment. Two case reports are also presented.


Evidence that tamoxifen preserves bone density in late postmenopausal women with breast cancer.
Tamoxifen, which is used for treating breast cancer, exhibits estrogenic and antiestrogenic characteristics, depending on the tissue. In the human breast it acts as an antiestrogen, whereas estrogenic effects have been reported on endometrium and bone. The purpose of this study was to determine whether tamoxifen (TAM) prevents bone loss in elderly, postmenopausal women. Bone mineral density of the lumbar spine (SBD) was measured in elderly women (at least 10 years after menopause) 5 years after stage I or II breast cancer (n = 111). The results showed that SBD in untreated patients (n = 74) was significantly lower (p < 0.05) than SBD in patients (n = 37) treated with TAM over 5 years. In a subgroup of patients (n = 24) with positive estrogen receptor status, changes in SBD 12 months after discontinuation of 5-year TAM therapy were measured and compared with the changes of extended TAM treatment over a sixth year. Twelve months after withdrawal of 5-year TAM medication (n = 11) bone density decreased significantly (- 4.8+/-2.5%; p > 0.05), whereas in the group of women (n = 13) receiving extended TAM medication (20 mg) for an additional 12 months, SBD ( + 1.9+/-3.5 %) was maintained during the observation period, and was significantly higher when compared with the group of untreated patients (p <0.05). We conclude that tamoxifen has a preventive effect on trabecular bone loss at the lumbar spine, when compared to age-matched data and to untreated women with breast cancer in the late menopause. Our data give evidence of benefits to bone density provided by prolonged administration in patients after breast cancer and at risk of osteoporosis.


Human islets in mixed islet grafts protect mouse pancreatic beta-cells from alloxan toxicity.
We have previously shown that human beta-cells are resistant to the toxic effects of alloxan. In order to further clarify this characteristic of human islets, we investigated whether these cells might transfer their alloxan resistance to alloxan-sensitive rat or mouse islets. Islets from two species (human-mouse or rat-mouse) were mixed into one graft, which was implanted into the subcapsular kidney space of nude mice. Alloxan or saline was injected intravenously two weeks after implantation and one week thereafter the mice were killed. The number of grafted and endogenous beta-cells were evaluated by a semi-quantitative method after immunohistochemistry. Human islet production of the scavenging enzymes extracellular superoxide dismutase and plasma glutathione peroxidase were analyzed with ELISA-techniques, and mouse and human islet hydrogen peroxide breakdown activity were monitored with a horseradish peroxidase-dependent assay. Mouse beta-cells transplanted together with human islets were protected against alloxan cytotoxicity. Rat islets did not protect mouse beta-cells against alloxan, suggesting that the mixing procedure as such did not impose the protection. Production of extracellular superoxide dismutase and plasma glutathione peroxidase by human islets was very low. Moreover, H2O2 breakdown in vitro, did not differ between human and mouse islets. Alloxan-insensitive human islets protect mouse beta-cells against alloxan-induced lesions, suggesting that yet to be identified extracellular factors are involved in human islet resistance to alloxan toxicity.


Assessing whiplash recovery--the Whiplash Disability Questionnaire.
General practitioners often need to track outcomes of whiplash patients, and a disability questionnaire may be useful. Whiplash patients who attended primary care clinics in Edmonton, Canada were interviewed 3 months postcollision. Subjects were asked a global recovery question: "Do you feel you have recovered fully from your accident injuries?" Subjects then completed the Whiplash Disability Questionnaire (WDQ). A total of 131 subjects participated. Of these, 52 (39.7%) reported that they felt they had recovered. Those who reported complete recovery had a mean WDQ score of 2.5 and those who reported they had not recovered had a mean WDQ score of 29.9. All who responded "yes" to the recovery question had a WDQ score below 13, while all those responding "no" to the recovery question had a WDQ score of 13 or more. The WDQ as an outcome measure may be useful in clinical practice.


[Cavitary choroidal melanoma in a child].
Uveal melanoma is very rare in children, and in both adults and children it can in rare cases develop intralesional cavities resembling an intraocular cyst. The presence of a solid mass at the base and a thick wall surrounding the cavity can assist in differentiating cavitary melanoma from a benign cyst. We report the case of a 5-year-old girl who presented with a large intraocular pigmented mass in the left eye, showing multiple hollow cavities on ocular ultrasonography, CT scan, and MRI. The patient was treated by enucleation and the pathology confirmed the diagnosis of choroidal melanoma. FISH revealed no aberration in chromosome 3.


25-Hydroxyvitamin D in Canadian adults: biological, environmental, and behavioral correlates.
We assessed vitamin D status and its correlates in the population-based Canadian Multicentre Osteoporosis Study (CaMos). Results showed that serum 25-hydroxyvitamin D levels <75 nmol/L were common. Given Canada's high latitude, attention should be given to strategies for enhancing vitamin D status in the population. Inadequate vitamin D has been implicated as a risk factor for several clinical disorders. We assessed, in a Canadian cohort, vitamin D status and its correlates, based on serum 25-hydroxyvitamin D [25(OH)D], the best functional indicator of vitamin D status. We studied 577 men and 1,335 women 35+ years from seven cities across Canada in the randomly selected, population-based Canadian Multicentre Osteoporosis Study (CaMos). Participants completed a comprehensive questionnaire. Serum 25(OH)D was measured by immunoassay. Multivariate linear regression modeling assessed the association between 25(OH)D and determinants of vitamin D status. Participants (2.3%) were deficient in 25(OH)D (<27.5 nmol/L); a further 18.1% exhibited 25(OH)D insufficiency (27.5-50 nmol/L). Levels <75 nmol/L were evident in 57.5% of men and 60.7% of women and rose to 73.5% in spring (men) and 77.5% in winter (women); 25(OH)D <50 nmol/L was ≤10% year round for those supplementing with ≥400 IU vitamin D/day but was 43.9% among those not supplementing in winter and spring. The strongest predictors of reduced 25(OH)D for both men and women were winter and spring season, BMI ≥30, non-white ethnicity, and lower vitamin D supplementation and its modification by fall and winter. In this national Canadian cohort, vitamin D levels <75 nmol/L were common, particularly among non-white and obese individuals, and in winter and spring. Vitamin D intake through diet and supplementation and maintenance of normal weight are key modifiable factors for enhancing vitamin D status and thus potentially influencing susceptibility to common chronic diseases.


Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure.
The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the glycoprotein (spike). However, not all antigenic sites are targeted equally by antibodies, leading to complex immunodominance patterns. We used 3D computational models to estimate antibody pressure on the seasonal influenza H1N1 and SARS spikes. Analyzing publically available sequences, we show that antibody pressure, through the geometrical organization of spikes on the viral surface, shaped their mutability. Studying the mutability patterns of SARS-CoV-2 and the 2009 H1N1 pandemic spikes, we find that they are not predominantly shaped by antibody pressure. However, for SARS-CoV-2, we find that over time, it acquired mutations at antibody-accessible positions, which could indicate possible escape as define by our model. We offer a geometry-based approach to predict and rank the probability of surface resides of SARS-CoV-2 spike to acquire antibody escaping mutations.


Synthesis, antiviral activity, and mode of action of some 3-substituted 2,5,6-trichloroindole 2'- and 5'-deoxyribonucleosides.
A series of chlorinated indole nucleosides has been synthesized and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1) and for cytotoxicity. The 2'- and 5'-deoxy derivatives of the reported 3-formyl-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (FTCRI) and 3-cyano-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (CTCRI) were synthesized by either a modification of the appropriate 3-unsubstituted sugar-modified nucleoside analogues or by a glycosylation of 3-substituted heterocycles with a protected alpha-chlorosugar. The modifications were guided in part by structural similarity to the corresponding series of chlorinated benzimidazole ribonucleosides and the fact that 5'-deoxy analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) are very active against HCMV. The 5'-deoxy analogues of FTCRI and CTCRI were nearly as active as FTCRI and CTCRI, suggesting that the chlorinated benzimidazole nucleosides and the chlorinated indole nucleosides act in a similar manner. This hypothesis was supported by time-of-addition studies using FTCRI and by the resistance of TCRB-resistant strains of HCMV to four different 3-substituted indole ribonucleosides. The 2'-deoxy analogues of the trichlorinated indole nucleosides also had potent antiviral activity, in contrast to decreased activity and selectivity observed for 2'-deoxy TCRB compared to TCRB. In addition, 3-acetyl-2,5,6-trichloro-1-(2-deoxy-beta-d-ribofuranosyl)indole was also active and much less cytotoxic (HCMV IC50 = 0.30 microM, HFF CC50 >100 microM) than previous analogues. None of the analogues had significant activity against HSV-1.


Intravenous cidofovir for compassionate use in AIDS patients with cytomegalovirus retinitis. Spanish Cidofovir Study Group.
We report the compassionate use of intravenous cidofovir for the treatment of cytomegalovirus retinitis in 51 patients with AIDS who were receiving highly active antiretroviral therapy (HAART). After a median of 9 doses, 49 patients showed no retinitis activity. However, treatment was stopped in 17 patients because of adverse reactions and in 5 patients for other reasons. Two deaths were considered related to the drug. Iritis developed in 21 patients (41.2%), a frequency higher than that reported during the pre-HAART era. Patients with iritis had median CD4 cell counts-both at nadir and at the initiation of cidofovir therapy-approximately 3 times higher than those for patients without iritis (P=.003 and P=.05, respectively). Our study confirms the efficacy of cidofovir therapy for AIDS-associated cytomegalovirus retinitis. Our data suggest that the risk of iritis may be higher for patients with better immunological status, probably because of their enhanced ability to mount an inflammatory response.


Modified docetaxel, cisplatin and fluorouracil therapy as the first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck cancer: a retrospective study.
Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) therapy has been shown to be a well tolerated and highly effective regimen for metastatic gastric carcinoma. Herein we investigated the effectiveness of the mDCF combination as the first-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC). A total of 80 patients with recurrent/metastatic HNSCC who were treated with mDCF between 2009 and 2015 were enrolled into this study. All patients were treated in the first-line with 2-6 cycles of mDCF chemotherapy which consisted of docetaxel 60 mg/m2 intravenously (IV) on day 1, cisplatin 60 mg/m2 IV on day 1, and 5-fluorouracil 600 mg/m2 IV for 5 days of continuous infusion, with cycles repeated every 21 days. The most common grade 3-4 toxicities were neutropenia (22.5%), anemia (10%), thrombocytopenia (7.5%), nephrotoxicity (1.3%), hepatotoxicity (1.3%), and diarrhea (2.5%). Twelve patients (15%) experienced a febrile neutropenic episode. Dose modification was required in 22 (27.5%) of the patients due to drug toxicity. Complete response was achieved in 2.5% of all patients, while partial and stable responses were reported to be 43.8% and 25%, respectively, with a disease control rate of 71.3%. The median progression-free and overall survival was 7 (95% CI: 5.3-8.6) and 11.5 (95% CI: 9.4-13.7) months, respectively. The efficiency of the mDCF combination for induction chemotherapy has been well established previously. To our knowledge, this is one of the largest studies evaluating the survival and safety significance of mDCF chemotherapy as a first-line treatment in patients with recurrent/metastatic HNSCC.


Entropy and Fragility in Supercooling Liquids.
We review the Kauzmann paradox and what it implies about the configuration space energy hypersurface for "structural glassformers." With this background, we then show how the relaxation expression of Adam and Gibbs qualitatively accounts for most of the phenomenology of liquid and polymeric glassformers including the strong/fragile liquid pattern, and the behavior of non-ergodic systems. Extended temperature range relaxation studies are consistent with a relaxation time pre-exponent on the quasi-lattice vibration time scale. When this boundary condition is imposed on Vogel-Fulcher-Tammann fittings, correspondence of T0 with TK is found for liquids with Tg ranging over 1000 K. When it is imposed on the WLF equation C1 is obliged to become ~16, and the corresponding force-fitted C2 provides a measure of the polymer fragility which is generally not available from thermodynamic studies. Systems which exhibit discontinuous changes in configurational entropy on temperature increase, which include unfolding proteins, are briefly reviewed.


N-Acylethanolamine metabolism interacts with abscisic acid signaling in Arabidopsis thaliana seedlings.
N-Acylethanolamines (NAEs) are bioactive acylamides that are present in a wide range of organisms. In plants, NAEs are generally elevated in desiccated seeds, suggesting that they may play a role in seed physiology. NAE and abscisic acid (ABA) levels were depleted during seed germination, and both metabolites inhibited the growth of Arabidopsis thaliana seedlings within a similar developmental window. Combined application of low levels of ABA and NAE produced a more dramatic reduction in germination and growth than either compound alone. Transcript profiling and gene expression studies in NAE-treated seedlings revealed elevated transcripts for a number of ABA-responsive genes and genes typically enriched in desiccated seeds. The levels of ABI3 transcripts were inversely associated with NAE-modulated growth. Overexpression of the Arabidopsis NAE degrading enzyme fatty acid amide hydrolase resulted in seedlings that were hypersensitive to ABA, whereas the ABA-insensitive mutants, abi1-1, abi2-1, and abi3-1, exhibited reduced sensitivity to NAE. Collectively, our data indicate that an intact ABA signaling pathway is required for NAE action and that NAE may intersect the ABA pathway downstream from ABA. We propose that NAE metabolism interacts with ABA in the negative regulation of seedling development and that normal seedling establishment depends on the reduction of the endogenous levels of both metabolites.


A Journey in Science: "Not Lost in Translation".
Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by Tak Mak, PhD, Professor, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Princess Margaret Cancer Centre in Toronto. A visionary in the field of cancer, this is the story of Dr. Mak's scientific journey.


Reduced expression of reelin (RELN) gene is associated with high recurrence rate of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the world's top five causes of cancer-related deaths. Current treatments available ameliorate HCC; however, current therapy fails to completely treat and prevent HCC, as shown by its high recurrence rate. Recently developed genome-wide gene-expression profile analyses can now robustly detect many candidate genes that are modified by HCC. Here we attempt to identify novel genes displaying altered gene expression profiles when comparing healthy tissue with HCC by means of a double-combination array previously developed. Double-combination array analysis of gene expression profiles and single nucleotide polymorphism arrays were performed on each HCC tissue sample. Subsequently, samples from 48 HCC patients were subjected to quantitative real-time reverse transcription polymerase chain reaction and methylation-specific polymerase chain reaction. The reelin (RELN) gene was detected as a pertinent tumor suppressor gene by means of this method. Of the 48 clinical samples obtained, 34 (79.2%) displayed reduced RELN expression in tumor tissue, and the expression level of tumor tissues clearly reduced compared with that of corresponding normal tissues (P = 0.002). Eighteen (37.5%) of 48 tumor tissues were found to be hypermethylated on the RELN gene promoter. Moreover, analysis of clinical data revealed an inverse correlation between RELN expression and HCC recurrence. The present study indicates that our in-house double-combination array is an effective and convenient technique in detecting novel genes with altered expression in disease. We suggest RELN is a key regulatory gene associated with the recurrence of HCC.


Iopromide. A new non-ionic contrast medium.
The new non-ionic contrast agent, iopromide (Schering) is comparable in osmolality and viscosity to the other recently developed low osmolality media, ionic and non-ionic. Its chemotoxicity, as assessed by protein binding, enzyme inhibition and effects on the coagulation cascade is significantly less than that of the conventional media and very similar to that of another established new non-ionic agent, iopamidol (Niopam, Bracco/Merck).


Visual prosthetics 2006: assessment and expectations.
This report provides a brief overview of blinding eye diseases for which prosthetic vision may hold promise as a treatment modality, and of current and near-term technological approaches towards the creation of prosthetic interfaces with the remaining visual system. Principal anatomical, physiological, technological and functional obstacles and possible solutions are outlined, and references are provided to pioneering work by over a dozen groups on four continents.


Signal Transduction during Metabolic and Inflammatory Reprogramming in Pulmonary Vascular Remodeling.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by (mal)adaptive remodeling of the pulmonary vasculature, which is associated with inflammation, fibrosis, thrombosis, and neovascularization. Vascular remodeling in PAH is associated with cellular metabolic and inflammatory reprogramming that induce profound endothelial and smooth muscle cell phenotypic changes. Multiple signaling pathways and regulatory loops act on metabolic and inflammatory mediators which influence cellular behavior and trigger pulmonary vascular remodeling in vivo. This review discusses the role of bioenergetic and inflammatory impairments in PAH development.


G-Quadruplexes Formation at the Upstream Region of Replication Origin (OriL) of the Pseudorabies Virus: Implications for Antiviral Targets.
Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease, which still causes large economic losses for the swine industry. Therefore, it is urgent to find a new strategy to prevent and control PRV infection. Previous studies have proven that guanine (G)-rich DNA or RNA sequences in some other viruses' genomes have the potential to form G-quadruplex (G4), which serve as promising antivirus targets. In this study, we identified two novel G4-forming sequences, OriL-A and OriL-S, which are located at the upstream origin of replication (OriL) in the PRV genome and conserved across 32 PRV strains. Circular dichroism (CD) spectroscopy and a gel electrophoresis assay showed that the two G-rich sequences can fold into parallel G4 structures in vitro. Moreover, fluorescence resonance energy transfer (FRET) melting and a Taq polymerase stop assay indicated that the G4 ligand PhenDC3 has the capacity to bind and stabilize the G4. Notably, the treatment of PRV-infected cells with G4-stabilizer PhenDC3 significantly inhibited PRV DNA replication in host cells but did not affect PRV's attachment and entry. These results not only expand our knowledge about the G4 characteristics in the PRV genome but also suggest that G4 may serve as an innovative therapeutic target against PRV.


Knockdown of transient receptor potential melastatin 2 reduces renal fibrosis and inflammation by blocking transforming growth factor-β1-activated JNK1 activation in diabetic mice.
Diabetic nephropathy is a major complication of diabetes. We explore the protective effect of TRPM2 knockdown on the progression of diabetic nephropathy. A type 2 diabetes animal model was established in C57BL/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100 mg/kg streptozotocin (STZ). Genetic knockdown of TRPM2 in mouse kidneys was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 2 carrying TRPM2 shRNA. Mice with HFD/STZ-induced diabetes exhibited kidney dysfunction, as demonstrated by increased blood creatinine and urea nitrogen levels, accompanied by glomerulus derangement, tubule damage and extracellular matrix deposition in the interstitium. The protein expression of TRPM2, transforming growth factor-β1 (TGF-β1), connective tissue growth factor, α-smooth muscles actin, fibronectin, collagen I and collagen III, and the mRNA expression and contents of inflammatory factors, including interleukin-1β, interleukin-6, interferon-α, tumour necrosis factor -α and monocyte chemotactic protein -1, were significantly elevated in the renal tissues of the HFD/STZ-induced diabetes group compared to those of the two control groups. Furthermore, fluorescent staining of TRPM2 was markedly increased in the renal tubular epithelial cells from diabetic mice. Knockdown of TRPM2 significantly attenuated HFD/STZ-induced renal inflammatory responses and fibrosis, which was accompanied by activation of TGF-β1-activated c-Jun N-terminal protein kinase-1 (JNK1) signalling. JNK1 inactivation reversed hyperglycaemia-induced fibrosis and inflammation in HK-2 cells. TRPM2 silencing significantly attenuated fibrosis and inflammation in the kidneys of mice with HFD/STZ-induced diabetes, which was largely achieved via the inhibition of TGF-β1-activated JNK1 activation.


Long time dynamics of complex systems.
Molecular dynamics trajectories of large biological molecules are restricted to nanoseconds. We describe a computational method, based on optimization of a functional, to extend the time of molecular simulations by orders of magnitude. Variants of our technique have already produced microsecond and millisecond trajectories. The large steps enable feasible computations of atomically detailed approximate trajectories. Numerical examples are provided: (i) a conformational change in blocked glycine peptide and (ii) helix formation of an alanine-rich peptide.


Arthroscopic approach and anatomy of the stifle joint in the rabbit.
To describe a technique and normal findings for arthroscopy of the stifle in rabbits. Cadaver study. Twenty cadaveric stifles from New Zealand White rabbits were examined. The arthroscope was placed through a medial portal, and instrument portals were created on the lateral aspect of the joint. The same portals were used for examination of the entire joint and palpation of structures with a probe. Structures identified in the proximal aspect of the stifle included the suprapatellar pouch, suprapatella, patella, medial and lateral proximal recesses, medial and lateral trochlear ridges, trochlear groove. Structures identified in the distal aspect of the joint included the cranial and caudal cruciate ligaments, medial and lateral menisci, medial and lateral femoral condyles, the long digital extensor tendon, and the cranial meniscal ligaments were identified. All of the proximal structures could be seen in 16/20 limbs. Distally, the cranial cruciate ligament could be identified and manipulated most often (17/20 limbs), followed by the caudal cruciate ligament (11/20), the menisci (9/20), and condyles (9/20). The average examination time was 27 minutes. There was a variably present femorotibial membrane. We conclude that the arthoscopic evaluation of the stifle in rabbits is a viable surgical approach and could be used for rabbit models or to examine clinical cases with stifle pathology. Precise portal placement and adequate infrapatellar fat pad debridement were critical for success.


The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway.
beta-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell-cell contacts to the actin cytoskeleton and an additional role in signaling that involves transactivation in complex with transcription factors of the lymphoid enhancing factor (LEF-1) family. Elevated beta-catenin levels in colorectal cancer caused by mutations in beta-catenin or by the adenomatous polyposis coli molecule, which regulates beta-catenin degradation, result in the binding of beta-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes. Here, we show that the cyclin D1 gene is a direct target for transactivation by the beta-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. Inhibitors of beta-catenin activation, wild-type adenomatous polyposis coli, axin, and the cytoplasmic tail of cadherin suppressed cyclin D1 promoter activity in colon cancer cells. Cyclin D1 protein levels were induced by beta-catenin overexpression and reduced in cells overexpressing the cadherin cytoplasmic domain. Increased beta-catenin levels may thus promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle.


Preparation of a colored conductive paint electrode for electrochemical inactivation of bacteria.
In this study we describe the preparation of a colored conductive paint electrode containing In(2)O(3), SnO(2), or TiO(2) for the electrochemical inactivation of marine bacteria. When each colored conductive paint electrode was immersed in seawater containing 10(6) cells/mL for 90 min, marine microbe attachment to the TiO(2)/SnO(2)/Sb electrode surface was minimal. Preparation of electrodes coated with 40% particles is shown to be more cost-effective, and because of their more translucent coatings they can be painted over with bright colors. When a potential of 1.0 V was applied for 30 min to the colored conductive paint electrode (40 wt% TiO(2)/SnO(2)/Sb) in sterile seawater, the survival ratio decreased to 55%. When 1.5 V vs. saturated calomel electrode (SCE) was applied, all attached cells were inactivated. Chlorine was not detected below an applied potential of 1.5 V. A change in pH was not observed in the range of 0 to 1.5 V. This method might be effective for preventing bacterial cell accumulation and the formation of biofilms.


Low awareness of stroke guidelines and preference for Chinese herbs in community physicians: a national survey in China.
Physicians' adherence to stroke guidelines is becoming a critical part of public stroke care system. The objective of this national survey was to examine Chinese physicians' awareness of the guidelines in secondary stroke prevention. This is a non-commercial and no-incentive internet survey. Respondents were asked to perform a self-examination of 13 questions regarding their stroke practice. Their awareness of stroke guidelines, preference for Chinese traditional herbs (CTH), and patients' expense for stroke treatment were surveyed and compared between physicians from community and from tertiary hospitals using univariate analysis and logistic regression. A total of 8,581 physicians (70.1% from community hospitals) responded to the survey. Only 32.1% physicians considered risk factors control necessary for stroke. For the treatments of symptomatic carotid stenosis, only 10.4% physicians selected carotid endarterectomy and anti-platelet plus controlling stroke risk factors. Only 21.45% physicians selected warfarin anticoagulation for stroke patients with atrial fibrillation. In contrast, a high percentage (64.56%) of physicians had positive attitude towards CTH. Compared with those from tertiary hospitals, community physicians were more likely unaware of the guidelines and preferred CTH. Those who prescribed CTH reported more patients' cost (P<0.001, OR 1.78, 95% CI, 1.55-2.04) than who didn't. There is a very low awareness of stroke guidelines in Chinese community physicians. A well-organized continuing stroke-guidelines education should be an essential part of public stroke-care system in China. Also, more well-designed clinical trials are required to establish the safety and effectiveness of CTH.


Is the increase in renal papillary phospholipid biosynthesis a protective mechanism against injury?
Mercuric chloride (HgCl2) is a well-known renal toxic that causes acute renal failure. The effect of HgCl2 treatment and the protection by thyroxine were studied in rat renal papilla (P), outer medullary inner stripe (OMIS), outer medullary outer stripe (OMOS) and cortical phospholipids (PhLs). HgCl2 brought about an increase in the total phospholipid content in P and OMIS but a drop in OMOS and cortex. Only phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) accounted for such changes. Thyroxine, injected on HgCl2-treated rats, partially reversed the effect of the toxic metal in P and OMIS while completely reversed the PtdCho drop in OMOS and cortex. However, the hormone failed to recover the sphingomyelin increase in P, the PtdEtn shortage in OMIS, OMOS and partially reversed the drop in the cortex. When thyroxine was injected without toxic treatment, no effect was observed in the phospholipid content of any kidney zone. Results obtained by using 32P as a precursor to study the PhL de novo synthesis were consistent with those of the phospholipid content. Thus a radioactivity increase--associated with PtdCho and PtdEtn--was observed in the kidney zones where said endogenous PhLs had risen. But in OMOS and cortex, where PtdCho and PtdEtn had dropped, they were also accompanied by a decrease in radioactivity. The thyroxine-induced recovery phase also paralleled the phospholipid content results with those of the de novo synthesis. We suggest that the decrease in the renal phospholipid de novo synthesis may constitute one biochemical explanation of the selective renal toxic effect exerted by HgCl2 and that the increase observed in the renal phospholipid metabolism--induced by the toxic treatment in OMIS and P--may represent a protective mechanism of these zones against toxic injury. Moreover, recovery promoted by thyroxine treatment in OMOS and cortex was accompanied by the reversion of the corresponding PtdCho decrease induced by HgCl2.


Decreased cAMP Level and Decreased Downregulation of β1-Adrenoceptor Expression in Therapeutic Hypothermia-Resuscitated Myocardium Are Associated With Improved Post-Resuscitation Myocardial Function.
Epinephrine administered during cardiopulmonary resuscitation (CPR) is associated with severe post-resuscitation myocardial dysfunction. We previously demonstrated that therapeutic hypothermia reduced the severity of post-resuscitation myocardial dysfunction caused by epinephrine; however, the relationship between myocardial adrenoceptor expression and myocardial protective effects by hypothermia remains unclear. Rats weighing between 450 and 550 g were randomized into 5 groups: (1) normothermic placebo, (2) normothermic epinephrine, (3) hypothermic placebo, (4) hypothermic epinephrine, and (5) sham (not subject to cardiac arrest and resuscitation). Ventricular fibrillation was induced and untreated for 8 minutes for all other groups. Hypothermia was initiated coincident with the start of CPR and maintained at 33±0.2°C for 4 hours. Placebo or epinephrine was administered 5 minutes after the start of CPR and 3 minutes before defibrillation. Post-resuscitation ejection fraction was measured hourly for 4 hours then hearts were harvested. Epinephrine increased coronary perfusion pressure during CPR (27±6 mm Hg versus 21±2 mm Hg P<0.05). Post-resuscitation myocardial function was impaired in the normothermic epinephrine group compared with other groups. The concentration of myocardial cAMP doubled in the normothermic epinephrine group (655.06±447.63 μmol/L) compared with the hypothermic epinephrine group (302.51±97.98 μmol/L; P<0.05). Myocardial β1-adrenoceptor expression decreased with normothermia cardiac arrest but not with hypothermia regardless of epinephrine. Epinephrine, administered during normothermic CPR, increased the severity of post-resuscitation myocardial dysfunction. This adverse effect was inhibited by intra-arrest hypothermia resuscitation. Declined cAMP with more preserved β1-adrenoceptors in hypothermia-resuscitated myocardium is associated with improved post-resuscitated myocardial function in vivo.


Diagnosis of Lung Cancer by FTIR Spectroscopy Combined With Raman Spectroscopy Based on Data Fusion and Wavelet Transform.
Lung cancer is a fatal tumor threatening human health. It is of great significance to explore a diagnostic method with wide application range, high specificity, and high sensitivity for the detection of lung cancer. In this study, data fusion and wavelet transform were used in combination with Fourier transform infrared (FTIR) spectroscopy and Raman spectroscopy to study the serum samples of patients with lung cancer and healthy people. The Raman spectra of serum samples can provide more biological information than the FTIR spectra of serum samples. After selecting the optimal wavelet parameters for wavelet threshold denoising (WTD) of spectral data, the partial least squares-discriminant analysis (PLS-DA) model showed 93.41% accuracy, 96.08% specificity, and 90% sensitivity for the fusion data processed by WTD in the prediction set. The results showed that the combination of FTIR spectroscopy and Raman spectroscopy based on data fusion and wavelet transform can effectively diagnose patients with lung cancer, and it is expected to be applied to clinical screening and diagnosis in the future.


[Effects of recombinant Balillus Calmette-Guerin secreting IL-12 vaccination on development of T cell subsets in neonatal BALB/c mice].
To explore the effects of recombinant Balillus Calmette-Guerin secreting IL-12 on the development of spleen T cell subsets of neonatal BALB/c mice. Twenty-four neonatal BALB/c mice were divided 3 groups: Control, BCG, r-BCG groups, which inoculated with BCG and r-BCG intraperiotoneally within 2-3 days after birth. Four weeks later, spleen cells of mice were isolated and the percentage of CD3(+) CD8(+) INF-gamma(+)/CD3(+) CD8(-) IFN-gamma(+)/CD3(+) CD8(+) IL-4(+)/CD3(+) CD8(-) IL-4(+)/ CD4(+) Foxp3(+) T cells, which represent Tc1/Th1/Tc2/Th2/Treg cells respectively were detected by flow cytometry at single cells level, and Th1/Th2, Tc1/Tc2 ratio were calculated. The percentages of Th1, Tc1 cell of BCG-vaccinated mice, r-BCG -vaccinated mice were significant higher than control mice (P < 0.01), and there was no difference between the two vaccinated groups. The ratio of Th1/Th2, Tc1/Tc2 and total IFN-gamma/IL-4 of two vaccinated groups were higher than control group. The percentages of Treg cells were no difference among the three groups (P > 0.05). Neonatal BCG and r-BCG vaccination can significantly increase Tc1 and Th1 cells and Th1/Th2, Tc1/Tc2 ratio in spleen cells. Neonatal BCG and r-BCG vaccination may have an same effects on development of T cell subsets in neonatal BALB/c mice. The percentage of CD4(+) Foxp3(+) T cells among three groups were no significant difference.


Mixture models in haematology: a series of case studies.
Two specific applications of finite mixture distributions in haematology include (1) the analysis of the distribution of red blood cell volumes to characterize and quantify alterations in erythrocyte subpopulations in anaemia and (2) the analysis of the distribution of transferrin saturation to estimate subpopulation parameters based on individual genotype for haemochromatosis. For these applications, we describe the comprehensive approach that was taken to distribution modeling. The choice of distributions and the number of mixture components to be fit were based upon theoretical and physiological considerations and a variety of additional statistical problems were considered. These included fitting mixtures of doubly-truncated data and evaluating model fit in the presence of extremely large sample sizes. As a result of the comprehensive approach taken to statistical problem solving in haematology, methods developed for analysis of red blood cell volume distributions have now been adopted by the International Council for Standardization in Haematology. Additionally, analysis of population transferrin saturation distributions from the white population of the USA has led to an independent estimate of the prevalence of homozygotes for haemochromatosis, confirming that the gene for haemochromatosis is common.


Persistent effects of interleukin-1 on smooth muscle preparations from adrenalectomized rats: implications for increased phospholipase-A2 activity via stimulation of 5-lipoxygenase.
Human recombinant interleukin-1 beta (hrIL-1 beta) potentiated CaCl2-induced contractions of isolated stomach strip preparations from adrenalectomized rats (ADXSS). Associated with this effect were increased prostaglandin E2 and peptidyl leukotriene (LT) synthesis. Unlike preparations from normal rat stomach strips or sham-operated animals, tissue responses and eicosanoid production of ADXSS failed to return to pre-hrIL-1 beta control levels after washout of the interleukin, these effects being abrogated by the lipoxygenase inhibitor nordihydroguaiaretic acid. Additionally, the LTD4 antagonist FPL55712 also prevented the increase in contraction and prostaglandin E2 synthesis caused by hrIL-1 beta without decreasing peptidyl LT synthesis. In separate experiments, hrIL-1 beta failed to increase the recovery of arachidonic acid-induced contractions after aspirin pretreatment in both ADXSS and rat stomach strips. The data indicate that the effects caused by hrIL-1 beta on ADXSS are possibly the result of an exacerbated phospholipase A2 activity particularly inasmuch as increases in cellular cyclooxygenase synthesis are unlikely in this experimental system. It appears likely that a peptidyl LT is involved in this process. Elevation of phospholipase A2 activity by interleukin-1 like drugs may be an important factor limiting the use of these agents as adjuvants particularly in patients with low blood glucocorticoid levels.


Critical role of IL-25 in nematode infection-induced alterations in intestinal function.
IL-25 (IL-17E) is a member of the IL-17 cytokine family. IL-25-deficient mice exhibit impaired Th2 immunity against nematode infection, implicating IL-25 as a key component in mucosal immunity. The sources of IL-25 and mechanisms responsible for the induction of Th2 immunity by IL-25 in the gastrointestinal tract remain poorly understood. There is also little information on the regulation of IL-25 during inflammation or its role in gut function. In the current study, we investigated the regulation of IL-25 during Nippostrongylus brasiliensis infection and the contribution of IL-25 to the infection-induced alterations in intestinal function. We found that epithelial cells, but not immune cells, are the major source of IL-25 in the small intestine. N. brasiliensis infection-induced upregulation of IL-25 depends upon IL-13 activation of STAT6. IL-25(-/-) mice had diminished intestinal smooth muscle and epithelial responses to N. brasiliensis infection that were associated with an impaired Th2 protective immunity. Exogenous IL-25 induced characteristic changes similar to those after nematode infection but was unable to restore the impaired host immunity against N. brasiliensis infection in IL-13(-/-) mice. These data show that IL-25 plays a critical role in nematode infection-induced alterations in intestinal function that are important for host protective immunity, and IL-13 is the major downstream Th2 cytokine responsible for the IL-25 effects.


[Femoropopliteal bypass for patients with arteriosclerosis obliterans].
In this paper the current technical trend for femoro-popliteal bypasses (FP) was discussed. There is a broad consensus that vascular prostheses such as Dacron or ePTFE are reliable alternatives to autogenous vein grafts (AVG) for FP above the knee (FPAK). However, AVG is employed for FP below the knee (FPBK), while there is no significant difference in long term patency between reversed vein and in situ vein grafts. Use of heparinized autogenous blood for preparation of AVG is superior to heparinized saline solution in the reendothelialization. The value for %-area of endothelial cell coverage in the AVGs is 20% at 2 hours after implantation, whereas 80% of the area is covered after one week. FPs for diabetic patients with intermittent claudication should be limited because there is a possibility of occurrence of isolated popliteal segment due to disease progression. 5-year primary cumulative patency rates of prostheses for FPAK and AVGs for FPBK are about 70%, justifying the strategy of using vascular prostheses for FPAKs.


A case of ischemic duodenitis associated with superior mesenteric artery syndrome caused by an abdominal aortic aneurysm.
A 74-year-old woman was admitted to our hospital with upper abdominal pain and bloody vomiting. An abdominal aneurysm compressed the third portion of the duodenum and the second portion of duodenum was distended with thickened walls as in superior mesenteric artery syndrome. Endoscopic examination showed an edematous mucosa with hemorrhagic erosions, shallow longitudinal ulcers, and star-shaped ulcers in the duodenum. We diagnosed this case as ischemic duodenitis associated with superior mesenteric artery syndrome caused by compression by an abdominal aortic aneurysm. The symptoms improved on treatment with bowel rest, total parenteral nutrition and administration of a proton pump inhibitor. We present here a rare case of ischemic duodenitis and summarize the previous medical literature on the disease.


Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors.
Lineage tracing approaches have provided new insights into the cellular mechanisms that support tissue homeostasis in mice. However, the relevance of these discoveries to human epithelial homeostasis and its alterations in disease is unknown. By developing a novel quantitative approach for the analysis of somatic mitochondrial mutations that are accumulated over time, we demonstrate that the human upper airway epithelium is maintained by an equipotent basal progenitor cell population, in which the chance loss of cells due to lineage commitment is perfectly compensated by the duplication of neighbours, leading to "neutral drift" of the clone population. Further, we show that this process is accelerated in the airways of smokers, leading to intensified clonal consolidation and providing a background for tumorigenesis. This study provides a benchmark to show how somatic mutations provide quantitative information on homeostatic growth in human tissues, and a platform to explore factors leading to dysregulation and disease. DOI:http://dx.doi.org/10.7554/eLife.00966.001.


Metabolic and microbial perspectives on the "evolution of evolution".
Identifying and theorizing major turning points in the history of life generates insights into not only world-changing evolutionary events but also the processes that bring these events about. In his treatment of these issues, Bonner identifies the evolution of sex, multicellularity, and nervous systems as enabling the "evolution of evolution," which involves fundamental transformations in how evolution occurs. By contextualizing his framework within two decades of theorizing about major transitions in evolution, we identify some basic problems that Bonner's theory shares with much of the prevailing literature. These problems include implicit progressivism, theoretical disunity, and a limited ability to explain major evolutionary transformations. We go on to identify events and processes that are neglected by existing views. In contrast with the "vertical" focus on replication, hierarchy, and morphology that preoccupies most of the literature on major transitions, we propose a "horizontal" dimension in which metabolism and microbial innovations play a central explanatory role in understanding the broad-scale organization of life.


The effectiveness of web-based Mathematics instruction (WBMI) on K-16 students' mathematics learning: a meta-analytic research.
Given the increasing prevalence of web technology, web-based mathematics environments have been increasingly widely used in mathematics education for the past two decades. The COVID-19 pandemic has led to an urgent transition from traditional mathematics instruction (TMI) to web-based mathematics instruction (WBMI) at all levels of mathematics education. At this point, it is crucial to scrutinize the effects of WBMI on K-16 students' mathematics learning comprehensively. This meta-analysis research contained a total of 63 studies with 115 effect sizes, which aimed to investigate the effectiveness of WBMI on K-16 students' mathematics learning by incorporating potential moderators, namely mathematics topics, mathematical content standards, feedback status, type of instructional features, age (i.e., grade level), and assessment methods. Based on findings, WBMI has a significantly strong effect on K-16 students' mathematics learning (g = 1.10, p = 0.01, 95% CI [0.95, 1.27]). Moderator analyses reveal that the effect sizes of WBMI on K-16 students' mathematics learning varied significantly depending on all these potential moderators. Additionally, higher-level mathematical concepts, statistics and probability, WBMI with providing feedback, tutorial systems, undergraduate students, and traditional paper-pencil assessment are the strongest moderators in their context. The most notable results of this research are that WBMI is significantly more effective on students' mathematics learning than TMI, while even in the context of WBMI, traditional paper-pencil assessment is significantly more effective than online assessment. This meta-analytic research provides a comprehensive and up-to-date perspective on the effectiveness of WBMI on K-16 students' mathematics learning.


Methotrexate is a new selectable marker for tobacco immature pollen transformation.
We report here a new selectable marker for tobacco immature pollen transformation based on the expression of dihydrofolate reductase (dhfr) gene which confers resistance to methotrexate (Mtx). Two immature pollen transformation approaches, i.e., male germ line transformation and particle bombardment of embryogenic mid-bicellular pollen have been used for the production of stable transgenic tobacco plants. In the first method, two methotrexate-resistant plants were selected from a total of 7161 seeds recovered after transformation experiments. In the second method, four methotrexate-resistant plants were obtained from 29 bombardments using 3.7 x 10(5) pollen grains per bombardment. Southern analysis confirmed the transgenic nature of T0 and T1 candidate transgenic plants, and a genetic analysis showed that the transgenes are transmitted to subsequent generations.