Cleavage of human cytomegalovirus protease pUL80a at internal and cryptic sites is not essential but enhances infectivity.
The cytomegalovirus (CMV) maturational protease, assemblin, contains an "internal" (I) cleavage site absent from its homologs in other herpesviruses. Blocking this site for cleavage did not prevent replication of the resulting I(-) mutant virus. However, cells infected with the I(-) virus showed increased amounts of a fragment produced by cleavage at the nearby "cryptic" (C) site, suggesting that its replication may bypass the I-site block by using the C site as an alternate cleavage pathway. To test this and further examine the biological importance of these cleavages, we constructed two additional virus mutants-one blocked for C-site cleavage and another blocked for both I- and C-site cleavage. Infectivity comparisons with the parental wild-type virus showed that the I(-) mutant was the least affected for virus production, whereas infectivity of the C(-) mutant was reduced by approximately 40% and when both sites were blocked virus infectivity was reduced by nearly 90%, providing the first evidence that these cleavages have biological significance. We also present and discuss evidence suggesting that I-site cleavage destabilizes assemblin and its fragments, whereas C-site cleavage does not.


Convergence of retinal inputs onto visual cortical cells: II. A study of the cells disynaptically excited from the lateral geniculate body.
Spike discharges were recorded extracellularly from cells located in the superficial layer of cat's visual cortex. These cells were disynaptically excited and trisynaptically inhibited from the lateral geniculate cells. The vast majority of them responded to stationary and moving light stimuli. Their ON and OFF responses to a flash of light slit consisted of three components: (1) initial excitation, (2) depression and (3) later rebound. The three components were evoked from a broad area of the retinal receptive field. In one group of these cells, exploration of the receptive field with light slits of different lengths revealed a strong depressant zone at one or both ends of the excitatory receptive area, the characteristics property of 'hypercomplex' cell of Hubel and Wiesel. Another population of cells, however, did not show such length-specificity, and apparently correspond to 'complex' cell. In both groups of cells electrical stimulation at the excitatory receptive area produced a sequence of excitation, depression and later rebound, but only depression was evoked from the depressant zones. The latency of the excitation (6 msec) and the depression (7 msec) are in accordance with the view that the excitation is transmitted through disynaptic pathway and the depression through trisynaptic pathway after being mediated by the lateral geniculate cells.


Bacteriological findings after premature rupture of the membranes.
Of 243 children born after premature rupture of the membranes (PROM) 61 (26%) had the same bacteria in placental arterial blood, in ear swabs (taken deep from the external auditory canal) and in meconium. The predominant organisms were E. coli, Bacteroides fragilis, Streptococcus faecalis (enterococci) and Streptococcus agalactiae (group B streptococci). The infection rate was only 10% if the membranes had ruptured within 24 h of the onset of labour and 30% if the interval was longer than 24 h. Of 131 children born without premature rupture of the membranes but with risk factors for sepsis 9 (7%) had a positive blood culture with the same organism in the ear swabs and in meconium. The organisms were Streptococcus agalactiae (6 cases) and E. coli, Streptococcus faecalis and Klebsiella pneumoniae (one case each). Contamination of placental blood cultures was rare.


Schistosomiasis is more prevalent than previously thought: what does it mean for public health goals, policies, strategies, guidelines and intervention programs?
Mapping and diagnosis of infections by the three major schistosome species (Schistosoma haematobium, S. mansoni and S. japonicum) has been done with assays that are known to be specific but increasingly insensitive as prevalence declines or in areas with already low prevalence of infection. This becomes a true challenge to achieving the goal of elimination of schistosomiasis because the multiplicative portion of the life-cycle of schistosomes, in the snail vector, favors continued transmission as long as even a few people maintain low numbers of worms that pass eggs in their excreta. New mapping tools based on detection of worm antigens (circulating cathodic antigen - CCA; circulating anodic antigen - CAA) in urine of those infected are highly sensitive and the CAA assay is reported to be highly specific. Using these tools in areas of low prevalence of all three of these species of schistosomes has demonstrated that more people harbor adult worms than are regularly excreting eggs at a level detectable by the usual stool assay (Kato-Katz) or by urine filtration. In very low prevalence areas this is sometimes 6- to10-fold more. Faced with what appears to be a sizable population of "egg-negative/worm-positive schistosomiasis" especially in areas of very low prevalence, national NTD programs are confounded about what guidelines and strategies they should enact if they are to proceed toward a goal of elimination. There is a critical need for continued evaluation of the assays involved and to understand the contribution of this "egg-negative/worm-positive schistosomiasis" condition to both individual morbidity and community transmission. There is also a critical need for new guidelines based on the use of these more sensitive assays for those national NTD programs that wish to move forward to strategies designed for elimination.


Nano-TiO2 modifies heavy metal bioaccumulation in Daphnia magna: A model study.
Due to special properties, nano-TiO2 will interact with heavy metals and other pollutants in water, thus affecting the environmental behavior and ecotoxicity of these pollutants. However, the exact manner in which nano-TiO2 affects the bioaccumulation mechanisms of heavy metals is still unclear now. In the present study, quantitative structure bioaccumulation relationship (QSBAR) models were established to explore the relationships between physicochemical parameters of heavy metals and their accumulation in Daphnia magna in the absence and presence of nano-TiO2 at low metal exposure concentrations. The results showed that different physicochemical parameters affected the bioaccumulation of metals in Daphnia magna. The metal accumulation could be described by means of a Comprehensive Parameter composed of seven parameters, i.e., atomic number (AN), relative atomic weight (AW), atomic radius (AR), atomic ionization potential (AN/ΔIP), covalent index (X2r), second ionization energy (I2) and electrochemical potential (E0), in the absence of nano-TiO2, whereas the metal accumulation increased with the increase in Van Der Waals radius (rw) of metals in the presence of nano-TiO2. It was demonstrated that the bioaccumulation mechanism of the metals to Daphnia magna changed in the presence of nano-TiO2. Moreover, the bioaccumulation of more than 85% of the metals increased in the presence of nano-TiO2, but it increased differently for different metals. The present study provides an alternative approach to understand the mechanism of heavy metal bioaccumulation at low metal exposure concentrations and the effect of nano-TiO2 on metal bioaccumulation.


Therapeutic plasma exchange in multiple sclerosis patients with an aggressive relapse: an observational analysis in a high-volume center.
An evidence-based treatment for a Multiple Sclerosis (MS) relapse is an intravenous administration of 3-5 g of Methylprednisolone. In case of insufficient effect or corticosteroids intolerance, the therapeutic plasma exchange (TPE) is indicated. To assess the clinical effect of TPE in treatment of relapse in patients with relapsing-remitting MS (RRMS), we enrolled 155 patients meeting the following criteria (study period: January 2011 to February 2021): (1) age > 18, (2) RRMS according to the McDonald´s 2017 criteria, (3) MS relapse and insufficient effect of corticosteroids/corticosteroids intolerance, (4) baseline EDSS < 8. Exclusion criteria: (1) progressive form of disease, (2) history of previous TPE. Following parameters were monitored: EDSS changes (before and after corticosteroid treatment, before and after TPE; EDSS after TPE was assessed at the next clinical follow-up at the MS Center), and improvement of EDSS according to the number of procedures and baseline severity of relapse. 115 females (74%) and 40 males (26%) were included. The median age was 41 years (IQR 33-47)-131 patients underwent the pulse corticosteroids treatment and TPE, while 24 patients underwent only TPE without any previous corticosteroid treatment. Median baseline EDSS was 4.5 (IQR 3.5-5.5), median EDSS after finishing steroids was 4.5 (IQR 4.0-5.5). EDSS prior to the TPE was 4.5 (IQR 4-6), EDSS after TPE was 4.5 (IQR 3.5-5.5). We observed a significant improvement in the EDSS after TPE (p < 0.001). Sex differences were seen in TPE effectiveness, with median improvement of EDSS in females being -0.5 (IQR 1-0) and in males being 0 (IQR -0.5 to 0), p = 0.048. There was no difference in EDSS improvement by age category: 18-30 years, 31-40 years, 41-50 years, > 50 (p = 0.94), nor by total TPE count (p = 0.91). In this retrospective study of patients with an aggressive relapse and insufficient effect of intravenous corticosteroid treatment, a significant effect of TPE on EDSS improvement was observed. There was no significant difference in TPE effectivity according to the number of procedures, age, nor severity of a relapse. In this cohort, TPE was more effective in females.


Supramolecular structure of banana peel pectin and its transformations during extraction by acidic methods.
In this study, the approaches to describe the mesh structure in the homogalacturonate domains of pectin and the effect of the native structure violations on the stabilization effectiveness of the oil-in-water emulsion were demonstrated. Pectin with a native structure was isolated from banana peel by enzymolysis of insoluble dietary fibres. This pectin was compared with pectins, which were isolated using hydrochloric and citric acids. The properties of pectins were analyzed taking into account the ratio of galacturonate units in nonsubstituted, methoxylated and calcium-pectate forms. The content of calcium-pectate units determines the density of inter-molecular crosslinking formation. The simulation results reflect the structure of rigid "egg-box" crosslinking blocks and flexible segments formed in native pectin mainly by methoxylated links. Hydrochloric acid extraction is accompanied by the destruction of the crosslinking blocks and depolymerization of pectin. Citric acid partially demineralizes the crosslinking blocks contributing to the release of macromolecular chains that do not have calcium-pectate units. The granulometric data indicates that the individual macromolecules take the thermodynamically stable form of a statistical tangle. Such conformation is an ideal basis for the formation of "host-guest" microcontainers having a hydrophilic shell and a hydrophobic core with an oil-soluble functional substance.


A potential competition bias in the detection of safety signals from spontaneous reporting databases.
To study whether reports related to known drug-event associations could hinder the detection of new signals by increasing the detection thresholds when using disporportionality analyses in spontaneous reporting (SR) databases. The French SR database (2005-2006 data) was used to test this hypothesis for the following events: bleeding, headache, hepatitis, myalgia, myocardial infarction, stroke, and toxic epidermal necrolysis (TEN). For each of these, using the Proportional Reporting Ratio (PRR) and the Reporting Odds Ratio (ROR), the number of cases needed to trigger a signal out of 50, 100, and 200 reports for a hypothetical newly introduced drug were computed before and after removing from the database reports involving drugs known to be associated with the event. For bleeding and stroke, removing potentially competitive data resulted in a decrease of the number of cases needed to trigger a signal for a newly introduced drug for both PRR and ROR (e.g., from 9 to 4, and 5 to 3 cases out of 50 reports for bleeding and stroke, respectively using the PRR). They were not or only slightly modified for the other studied events. Removing reports related to known drug-event associations could increase the sensitivity of signal detection in SR databases. This should be considered when using SR databases for signal detection as it could result in earlier identification of new drug-event associations.


Effectiveness and safety of adalimumab in Japanese patients with rheumatoid arthritis: retrospective analyses of data collected during the first year of adalimumab treatment in routine clinical practice (HARMONY study).
We retrospectively investigated the ability of adalimumab (ADA) to reduce disease activity, improve physical function, and retard the progression of structural damage in 167 patients with rheumatoid arthritis. Clinical and functional outcomes were compared between patients with or without prior biologic treatment and those with or without concomitant methotrexate (MTX) treatment. At week 52, 38.3% achieved clinical remission: 42.4 and 28.6% of patients achieved remission in those without and with previous biologics, respectively, while 42.7 and 12.5% of patients achieved remission in those with and without concomitant MTX, respectively. ADA treatment significantly reduced the rate of radiographic progression from 27.1 ± 46.0 (median 13.6; 25th-75th percentiles 8.3 to 28.9) at baseline to 0.8 ± 5.0 (median 0.0; 25th-75th percentiles -0.9 to 2.0) at week 52 (P < 0.0001). Radiographic progression was absent in 59.8% of patients. Sixty adverse events (34.21/100 patient-years) were reported, 16 of which were serious (9.12/100 patient-years). ADA therapy is highly effective for reducing disease activity, improving physical function, and limiting radiographic progression. It is generally safe and well tolerated by Japanese RA patients in routine clinical practice.


Integrated morphological awareness intervention as a tool for improving literacy.
This study evaluated the effects of an intervention program aimed to improve reading and spelling ability through instruction in morphological awareness together with other forms of linguistic awareness, including knowledge of phonology, orthography, syntax, and semantics. Sixteen children aged between 8;07 (years;months) and 11;01 who demonstrated specific spelling difficulties were randomly assigned to either an experimental or a control group. Participants received an average of 19.4 sessions of intervention that focused on increasing awareness of the morphological structure of words, with particular attention to the orthographic rules that apply when suffixes are added to the base word. Participants in the experimental group made significantly greater gains in reading and spelling accuracy than those in the control group on both experimental and standardized measures of reading and spelling. The results also show that participants were able to generalize to new words what they had learned in the intervention sessions. Practitioners should consider the likely benefits of literacy intervention that focuses on developing morphological awareness in conjunction with other types of linguistic awareness.


Advances in clinical outcomes: What we have learned during the COVID-19 pandemic.
Our understanding of risk factors and interventions influencing outcomes from coronavirus disease 2019 (COVID-19) has continued to evolve, revealing advances emerging from hypotheses formed at the start of the pandemic. Epidemiologic studies have shown that asthma control, rather than a diagnosis of asthma, is a determinant of COVID-19 severity. Clinical outcomes in patients with primary immunodeficiencies, even in those with impaired cellular immunity, are variable. IL-6 has emerged as a reliable biomarker of COVID-19 severity, and large clinical trials have shown the potential for improving outcomes through inhibition of IL-6 signaling in some patients. Studies of genetic risk factors for severe COVID-19 have also revealed the importance of interferon homeostasis in the defense against severe acute respiratory syndrome coronavirus 2. Because COVID-19 vaccines constitute the primary tool for ending this pandemic, strategies have been developed to address potential allergic and immune-mediated reactions. Here, we discuss advances in our understanding of COVID-19 risk factors and outcomes within the context of allergic and immunologic mechanisms.


Associations between vascular endothelial growth factor gene polymorphisms and pre-eclampsia susceptibility: a meta-analysis.
The aim of this study was to assess whether vascular endothelial growth factor (VEGF) polymorphisms are associated with susceptibility to pre-eclampsia. A meta-analysis was conducted on the associations between the -634 C/G, +936 C/T, -1154 A/G, and -2578 A/C polymorphisms of VEGF and pre-eclampsia. Ten studies involving 2068 subjects (pre-eclampsia, 950; controls, 1118) were included in the meta-analysis. The meta-analysis revealed an association between pre-eclampsia and the VEGF -634 C allele in overall group (OR = 1.351, 95% CI = 1.105-1.651, p = 0.003) and in European group (OR = 1.427, 95% CI = 1.139-1.787, p = 0.002). The meta-analysis revealed an association between pre-eclampsia and the VEGF -936 T allele in Asians, but not in Europeans (OR = 1.555, 95% CI = 1.232-1.961, p = 1.9 × 10(-5); OR = 1.587, 95% CI = 0.933-2.699, p = 0.088). However, the meta-analysis revealed no association between pre-eclampsia and the VEGF -1154 A/G and 2578 A/C polymorphisms This meta-analysis suggested that the VEGF -634 C/G polymorphism is associated with susceptibility to pre-eclampsia in Europeans and that the VEGF -634 C/G polymorphism is associated with pre-eclampsia in Asians.


Eco-friendly sonoluminescent determination of free glycerol in biodiesel samples.
This paper proposes a flow-batch methodology for the determination of free glycerol in biodiesel that is notably eco-friendly, since non-chemical reagents are used. Deionized water (the solvent) was used alone for glycerol (sample) extractions from the biodiesel. The same water was used to generate water-cavitation sonoluminescence signals, which were modulated by the quenching effect associated with the amount of extracted glycerol. The necessarily reproducible signal generation was achieved by using a simple and inexpensive piezoelectric device. A linear response was observed for glycerol within the 0.001-100 mg/L range, equivalent to 0.004-400 mg/kg free glycerol in biodiesel. The lowest measurable concentration of free glycerol was estimated at 1.0 µg/L. The selectivity of the proposed method was confirmed by comparing the shape and retention of both real and calibration samples to standard solution chromatograms, presenting no peaks other than glycerol. All samples (after extraction) are greatly diluted; this minimizes (toward non-detectability) potential interference effects. The methodology was successfully applied to biodiesel analysis at a high sampling rate, with neither reagent nor solvent (other than water), and with minimum waste generation. The results agreed with the reference method (ASTM D6584-07), at a 95% confidence level.


In-microbe formation of nucleotide sugars in engineered Escherichia coli.
Numerous different nucleotide sugars are used as sugar donors for the biosynthesis of glycans by bacteria, humans, fungi, and plants. However, many of these nucleotide sugars are not available either in their native form or with the sugar portion labeled with a stable or radioactive isotope. Here we demonstrate the use of Escherichia coli metabolically engineered to contain genes that encode proteins that convert monosaccharides into their respective monosaccharide-1-phosphates and subsequently into the corresponding nucleotide sugars. In this system, which we designated "in-microbe", reactions occur within 2 to 4 h and can be used to generate nucleotide sugars in amounts ranging from 5 to 12.5 μg/ml cell culture. We show that the E. coli can be engineered to produce the seldom observed nucleotide sugars UDP-2-acetamido-2-deoxy-glucuronic acid (UDP-GlcNAcA) and UDP-2-acetamido-2-deoxy-xylose (UDP-XylNAc). Using similar strategies, we also engineered E. coli to synthesize UDP-galacturonic acid (UDP-GalA) and UDP-galactose (UDP-Gal). ¹³C- and ¹⁵N-labeled NDP-sugars are formed using [¹³C] glucose as the carbon source and with [¹⁵N]NH₄Cl as the nitrogen source.


Isoenzyme characterisation of 15 stocks of Trypanosoma evansi isolated from camels in the Sudan.
Fifteen stocks of T. evansi isolated in Sudan were compared using isoenzyme banding patterns. Differences between the stocks were found but overall they formed a homogeneous group. The results were similar to those obtained for other stocks of T. evansiisolated from Kenya, W. Africa, S. America and Kuwait and indicate that little genetic variation occurs in T. evansi over its geographical range. This low variation may have important implications in the development of new methods of controlling trypanosomiasis caused by T. evansi.


Social Entrepreneurship for Obesity Prevention: What Are the Opportunities?
In recent years, social entrepreneurship has emerged as a new field to address social and public health challenges. Social entrepreneurship, which harnesses traditional business practices and market forces to address social challenges, may produce solutions that are more cost-effective and sustainable than those produced by governmental and nonprofit sectors. In this paper, we discuss whether and how social entrepreneurship can be harnessed for obesity prevention by defining and briefly reviewing the rise of social entrepreneurship in the USA, outlining the threat that obesity poses to US society and offering some examples of how social ventures are addressing the problem of obesity. Additional untapped opportunities are also discussed and recommendations given for how social entrepreneurship might impact obesity prevention in the future.


Functional changes in the caudate and accumbens nuclei during amygdaloid and hippocampal seizure development in kindled cats.
Electroencephalographic changes were examined in the caudate nucleus and accumbens nucleus during limbic seizure development in eight kindled cat preparations. The emergence of self-sustained after-discharge and interictal discharge was demonstrated in the accumbens nucleus during limbic seizure development. This finding suggests secondary epileptogenic functional alterations in the mesolimbic dopamine neuron systems. Moreover, the epileptiform responses triggered from the accumbens and caudate nuclei increased markedly with progressive limbic seizure development. These results suggest that a limbic seizure could produce a secondary functional reorganization of the brain dopaminergic neuron systems, especially of the mesolimbic dopamine neuron systems that has been reported to play an important role in the manifestation of psychotic symptom.


N-acetyltransferase and inflammation: Bridging an unexplored niche.
Protein N-terminal (Nt) acetylation is an essential post-translational process catalysed by N-acetyltransferases or N-terminal acetyltransferases (NATs). Over the past several decades, several types of NATs (NatA- NatH) have been identified along with their substrates, explaining their significance in eukaryotes. It affects protein stability, protein degradation, protein translocation, and protein-protein interaction. NATs have recently drawn attention as they are associated with the pathogenesis of human diseases. In particular, NAT-induced epigenetic modifications play an important role in the control of mitochondrial function, which may lead to inflammatory diseases. NatC knockdown causes a marked reduction in mitochondrial membrane proteins, impairing their functions, and NatA affects mitophagy via reduced phosphorylation and transcription of the autophagy receptor. However, the NAT-mediated mitochondrial epigenetic mechanisms involved in the inflammatory process remain unexplored. The current review will impart an overview of the biological functions and aberrations of various NAT, which may provide a novel therapeutic strategy for inflammatory disorders.


Clinical relevance of St. John's wort drug interactions revisited.
The first clinically relevant reports of preparations of St. John's wort (SJW), a herbal medicine with anti-depressant effects, interacting with other drugs, altering their bioavailability and efficacy, were published about 20 years ago. In 2000, a pharmacokinetic interaction between SJW and cyclosporine caused acute rejection in two heart transplant patients. Since then, subsequent research has shown that SJW altered the pharmacokinetics of drugs such as digoxin, tacrolimus, indinavir, warfarin, alprazolam, simvastatin, or oral contraceptives. These interactions were caused by pregnane-X-receptor (PXR) activation. Preparations of SJW are potent activators of PXR and hence inducers of cytochrome P450 enzymes (most importantly CYP3A4) and P-glycoprotein. The degree of CYP3A4 induction correlates significantly with the hyperforin content in the preparation. Twenty years after the first occurrence of clinically relevant pharmacokinetic drug interactions with SJW, this review revisits the current knowledge of the mechanisms of action and on how pharmacokinetic drug interactions with SJW could be avoided. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.


Similarity between the estrogen receptor and the DNA-binding domain of the tetracycline repressor.
The amino-terminus region of tetracycline (tet) repressors contains a helix-turn-helix structure that binds to DNA. A computer-based comparison of a residues 18-61 of the tet repressor, which contains this DNA-binding domain, with a residues 304-347 of the human estrogen receptor (ER) yields a score that is 6.7 standard deviations higher than that obtained with 2,500 comparisons of randomized sequences of these segments. The probability of getting this score by chance is less than 10(-11). This part of the ER could be important in nuclear actions of ER in target tissues.


Conformational studies of two bradykinin antagonists by using two-dimensional NMR techniques and molecular dynamics simulations.
The solution conformations of two potent antagonists of bradykinin (Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9), [Aca(-1),DArg0,Hyp3,Thi5,DPhe7,(N-Bzl)Gly8]BK (1) and [Aaa(-1),DArg0,Hyp3,Thi5,(2-DNal)7,Thi8]BK (2), were studied by using 2D NMR spectroscopy in DMSO-d6 and molecular dynamics simulations. The NMR spectra of peptide 1 reveals the existence of at least two isomers arising from isomerization across the DPhe7-(N-Bzl)Gly8 peptide bond. The more populated isomer possesses the cis peptide bond at this position. The ratio of cis/trans isomers amounted to 7:3. With both antagonists, the NMR data indicate a beta-turn structure for the Hyp3-Gly4 residues. In addition, for peptide 2, position 2,3 is likely to be occupied by turn-like structures. The cis peptide bond between DPhe7 and (N-Bzl)Gly8 in analogue 1 suggests type VI beta-turn at position 7,8. The molecular dynamics runs were performed on both peptides in DMSO solution. The results indicate that the structure of peptide 1 is characterized by type VIb beta-turn comprising residues Ser6-Arg9 and the betaI or betaII-turn involving the Pro2-Thi5 fragment, whereas peptide 2 shows the tendency towards the formation of type I beta-turn at position 2,3. The structures of both antagonists are stabilized by a salt bridge between the guanidine moiety of Arg1 and the carboxyl group of Arg9. Moreover, the side chain of DArg0 is apart of the rest of molecule and is not involved in structural elements except for a few calculated structures.


Surgical management of otitis externa.
The surgical management of otitis externa is discussed in conjunction with failed medical management, primary causes, and proper case selection. The techniques of lateral ear canal resection and vertical ear canal ablation are described in detail.


A comparison of plasma levobupivacaine concentrations following transversus abdominis plane block and rectus sheath block.
Levobupivacaine is commonly used as the local anaesthetic of choice in peripheral nerve blocks, but its pharmacokinetics have not been fully investigated. We compared the changes in plasma concentrations of levobupivacaine following transversus abdominis plane block and rectus sheath block. Fifty woman undergoing laparoscopy were randomly allocated to receive either a transversus abdominis plane block or an rectus sheath block. In both groups, 2.5 mg.kg(-1) levobupivacaine was administered, and blood samples were obtained 15 min, 30 min, 60 min and 120 min after injection. The mean maximum plasma concentration (Cmax) and mean time to reach Cmax (Tmax) as determined by non-linear regression analysis were 1.05 μg.ml(-1) and 32.4 min in the transversus abdominis plane group and 0.95 μg.ml(-1) and 60.9 min in the rectus sheath group, respectively. The plasma concentration of levobupivacaine peaked earlier in the transversus abdominis plane group than in the rectus sheath group and the maximum plasma concentration depended on the dose administered but not the procedure.


A proteolytic 140-kDa fragment of neurite outgrowth factor and its cell-binding activity.
A neurite outgrowth factor (NOF) from chicken gizzard was treated with elastase, and a protease-resistant fragment of 140 kDa (F-140) with heparin-binding activity, was isolated from the digested mixture. Although F-140 showed no neurite outgrowth activity, it could bind dissociated cells from the dorsal root ganglia of chick embryos. The antiserum to F-140 inhibited the cell binding activity of native NOF in a dose-dependent manner, but not the neurite outgrowth activity. When membrane proteins from whole chick embryos were incubated with NOF or F-140, a protein band of 41 kDa was detected as a major NOF-binding component.


Self-association, conformation and binding equilibria of concanavalin A.
The discovery of distinct intact and fragmented forms of Con A, together with the observation that Con A self-associates near neutrality raises questions that may be important when interpreting experiments concerned with the biological actions of the protein. Do intact and fragmented units have the same affinity for carbohydrate? Do intact and fragmented units differ in conformation? Are all dimeric units of a homologous type or do hybrid dimers consisting of one intact and one fragmented unit also exist? Can all dimeric types self-associate to the tetramer form? Do dimer and tetramer species differ in their affinity for carbohydrate? These questions have been made amenable to investigation by the development of a method which separates intact and fragmented species under conditions which do not cause time-dependent or irreversible changes in protein conformation. It is found that intact dimeric units preferentially associate to the tetramer form. Under appropriate conditions of pH and ionic strength, dimer and tetramer species, and therefore fragmented and intact forms, can be separated by chromatography on Bio Gel P-100. Hybrid dimers are not present in appreciable amounts. Both types of homologous dimers (intact and fragmented) have similar affinity for carbohydrate, but dimer and tetramer species show significant differences. The results of near UV circular dichroism studies indicate that fragmented units possess slightly different conformation than intact units. An ionization-linked conformational transition in Con A does not appear to be linked directly with the self-association of the protein between pH 5 and 7. Ligand-induced changes in the conformation of Con A are now being examined in detail. Pflumm et al. (1971) have shown that occupation of the sugar binding site of Con A results in a perturbation of conformation as revealed by near UV circular dichroism measurements. The perturbation is relatively small and does not result in more than 1-2% increase in the rotational relaxation time (Shinitzky et al., 1973). On the other hand, removal of metal ions causes a hydrodynamic change sufficient to increase the frictional coefficient and to decrease the sedimentation coefficient (S20, w) from 3.98 S to 3.78 S. Differences between the native and the apoprotein conformation are now being examined using fluorescence polarization and the hydrophobic fluorescent probe 1-anilinonaphthalene-8-sulfonate.


Intraoperative dreams reported after general anaesthesia are not early interpretations of delayed awareness.
Dreams are more frequently reported than awareness after surgery. We define awareness as explicit recall of real intraoperative events during anaesthesia. The importance of intraoperative dreaming is poorly understood. This study was performed to evaluate whether intraoperative dreams can be associated with, or precede, awareness. We also studied whether dreams can be related to case-specific parameters. A cohort of 6991 prospectively included patients given inhalational anaesthesia were interviewed for dreams and awareness at three occasions; before they left the post-anaesthesia care unit, days 1-3 and days 7-14 after the operation. Uni- and multivariate statistical relations between dreams, awareness and case-specific parameters were assessed. Two hundred and thirty-two of 6991 patients (3.3%) reported a dream. Four of those also reported awareness and remembered real events that were distinguishable from their dream. Awareness was 19 times more common among patients who after surgery reported a dream [1.7% vs. 0.09%; odds ratio (OR) 18.7; P=0.000007], but memories of dreams did not precede memories of awareness in any of the 232 patients reporting a dream. Unpleasant dreams were significantly more common when thiopentone was used compared with propofol (OR 2.22; P=0.005). Neutral or pleasant dreams were related to lower body mass index, female gender and shorter duration of anaesthesia. We found a statistically significant association between dreams reported after general anaesthesia and awareness, although intraoperative dreams were not an early interpretation of delayed awareness in any case. A typical dreamer in this study is a lean female having a short procedure.


Extracellular and transmembrane region of a podocalyxin-like protein 1 fragment identified from colon cancer cell lines.
Regulated intramembrane proteolysis of membrane proteins has been shown to play an important role in cell differentiation and in the pathogenesis of diseases. The aim of the present study was to identify novel peptides generated by intramembrane proteolysis. The peptides were identified in serum-free cultured (SFC) media from various cell lines by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). A 2315-Da peptide found only in medium from SFC colon cancer cell lines was identified and shown to consist of a portion of both the extracellular and transmembrane regions of human podocalyxin-like 1. This protein fragment was not found in lung or pancreatic cancer cell lines by immunoprecipitation-SELDI tests using an antibody specific to this fragment, suggesting that this human podocalyxin-like protein 1 fragment may be unique to colon cancer cell lines.


Long-term supervised domiciliary EEG monitoring in epileptic patients employing radio telemetry and telephone telemetry. II. Radio telemetry system.
A miniaturized 8-channel EEG amplifier- submodulator unit is used in combination with a standard radio transmitter/receiver system for long-term ambulatory EEG recording at the patient's residence. The EEG frequency response (0.16-30 Hz) and amplitude range (1:1000) of the system are in accordance with the object in view, the recording of seizures. The submodulator characteristics conform to regulations for radio telemetry.


Uropathogenic bacteria and deductive genomics towards antimicrobial resistance, virulence, and potential drug targets.
Urinary tract infections (UTIs) are among the most prevalent bacterial infections affecting people in inpatient and outpatient settings. The current study aimed to sequence the genome of uropathogenic Escherichia coli strain CUI-B1 resourced from a woman having uncomplicated cystitis and pyelonephritis. Followed by deductive genomics towards potential drug targets using E. coli strain CUI-B1, strain O25b: H4-ST131, Proteus mirabilis strain HI4320, Klebsiella pneumoniae strain 1721, and Staphylococcus saprophyticus strain ATCC 15305 uropathogenic strains. Comparative genome analysis revealed that genes related to the survival of E. coli, P. mirabilis, K. pneumoniae, and S. saprophyticus, such as genes of metal-requiring proteins, defense-associated genes, and genes associated with general physiology, were found to be highly conserved in the genomes including strain CUI-B1. However, the genes responsible for virulence and drug resistance, mainly those that are involved in bacterial secretion, fimbriae, adherence, and colonization, were found in various genomic regions and varied from one species to another or within the same species. Based on the genome sequence, virulence, and antimicrobial-resistant gene dataset, the subtractive proteomics approach revealed 22 proteins mapped to the pathogen's unique pathways and among them, entB, clbH, chuV, and ybtS were supposed to be potential drug targets and the single drug could be utilized for all above-mentioned strains. These results may provide the foundation for the optimal target for future discovery of drugs for E. coli-, P. mirabilis-, K. pneumoniae-, and S. saprophyticus-based infections and could be investigated further to employ in personalized drug development.


Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain.
Prevailing notions of cerebral vascularization imply that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations. Endothelial cells, building blocks of blood vessels, are thought to be homogeneous in the brain with respect to their origins, gene expression patterns and developmental mechanisms. These current notions that cerebral angiogenesis is regulated by local environmental signals contrast with current models of cell-autonomous regulation of neuronal development. Here we demonstrate that telencephalic angiogenesis in mice progresses in an orderly, ventral-to-dorsal gradient regulated by compartment-specific homeobox transcription factors. Our data offer new perspectives on intrinsic regulation of angiogenesis in the embryonic telencephalon, call for a revision of the current models of telencephalic angiogenesis and support novel roles for endothelial cells in brain development.


Application of a transparent window vibrational probe (azido probe) to the structural dynamics of model dipeptides and amyloid β-peptide.
The azido asymmetric stretching motion is widely used for the elucidation of the intrinsic conformational preference and folding mechanism of protein since it has strong vibrational absorbance in the spectral transparent windows. However, the possible secondary structural disturbance induced by the insertion of azido group in the side chain of polypeptides should be carefully evaluated. Here, DFT calculation and enhanced sampling method were employed for model dipeptides with or without azido substitution, and the outcome results show that the lower potential energy basins of isolated model dipeptides are consistent with the preferred structural distributions of model dipeptides in aqueous solution. The azido asymmetric stretching frequency shows its sensitivity to the backbone configurations just like amide-I vibration does, and the azido vibration exhibits great potential as a structural reporter in the transparent window. For the evaluation of the application of azido group in biologically related system, the structural dynamics of Aβ37-42 and N3-Aβ37-42 fragments and the self-assemble process of their protofiliments in aqueous solution were demonstrated. The outcome results show that the structural fluctuations of Aβ37-42 and its protofilament in aqueous solution are quite similar with or without azido substitution, and the dewetting transitions of Aβ37-42 and N3-Aβ37-42 β-sheet layers are both complete within 30 ns and assemble into stable protofilaments. Therefore, the azido asymmetric vibrational motion is a minimally invasive structural probe and would not introduce much disturbance to the structural dynamics of polypeptides.


Triplex gene dosage effect of TPI and G3PD in a human lymphoblastoid cell line with partial trisomy 12p13 and 18p.
The EBV-induced lymphoblastoid line established from a patient carrying a duplication of the distal part of chromosome 12 short arm (12p13) retained the original partial trisomy and displayed the same triplex gene dosage effect for TPI and G3PD as found in the patient's RBC and WBC.


Doppler echocardiographic assessment of valvular regurgitation severity by measurement of the vena contracta: an in vitro validation study.
Noninvasive quantitation of valvular regurgitation remains a difficult problem. Measurements of the vena contracta (VC) by color Doppler echocardiography have been proposed but limited data are available on the actual accuracy of this method. To evaluate how closely the color Doppler VC reflects the true fluid dynamic VC and the anatomic regurgitant orifice and whether this measurement is affected by flow changes, various models of valvular regurgitation were studied in an in vitro flow circuit. The VC diameter was measured with color Doppler using two different ultrasound systems (Agilent Sonos 5500; Agilent Technologies Inc, Palo Alto, Calif and Vingmed CFM 800; GE Healthcare, Chalfront St Giles, UK). Optical planimetry of the anatomic regurgitant orifice was performed, the true VC diameter was determined by laser particle flow visualization. Because of flow contraction, the true VC diameter was consistently smaller than the anatomic regurgitant orifice diameter. Anatomic orifice and true VC only marginally changed with flow rate. The diameter of the color Doppler VC, however, not only overestimated the anatomic orifice diameter by 45% to 60% and the true VC diameter by 130% to 160%, but was also highly affected by the flow rate and the ultrasound system. Despite these limitations a color Doppler VC diameter of 0.77 cm or more (Agilent) and 0.89 cm or more (Vingmed) detected severe regurgitation with a sensitivity of 93% and 84% and a specificity of 96% and 79%, respectively. Color Doppler estimates of the VC markedly overestimate regurgitant orifice and true VC. In contrast to the true VC, Doppler measurements are significantly affected by flow rate and by the ultrasound system used. Nevertheless, they allow semiquantitative assessment of valvular regurgitation separating severe from nonsevere regurgitation with acceptable accuracy.


Combating herpesvirus encephalitis by potentiating a TLR3-mTORC2 axis.
TLR3 is a sensor of double-stranded RNA that is indispensable for defense against infection with herpes simplex virus type 1 (HSV-1) in the brain. We found here that TLR3 was required for innate immune responses to HSV-1 in neurons and astrocytes. During infection with HSV-1, TLR3 recruited the metabolic checkpoint kinase complex mTORC2, which led to the induction of chemokines and trafficking of TLR3 to the cell periphery. Such trafficking enabled the activation of molecules (including mTORC1) required for the induction of type I interferons. Intracranial infection of mice with HSV-1 was exacerbated by impairment of TLR3 responses with an inhibitor of mTOR and was significantly 'rescued' by potentiation of TLR3 responses with an agonistic antibody to TLR3. These results suggest that the TLR3-mTORC2 axis might be a therapeutic target through which to combat herpes simplex encephalitis.


Digitization of the Australian Parliamentary Debates, 1998-2022.
Public knowledge of what is said in parliament is a tenet of democracy, and a critical resource for political science research. In Australia, following the British tradition, the written record of what is said in parliament is known as Hansard. While the Australian Hansard has always been publicly available, it has been difficult to use for the purpose of large-scale macro- and micro-level text analysis because it has only been available as PDFs or XMLs. Following the lead of the Linked Parliamentary Data project which achieved this for Canada, we provide a new, comprehensive, high-quality, rectangular database that captures proceedings of the Australian parliamentary debates from 1998 to 2022. The database is publicly available and can be linked to other datasets such as election results. The creation and accessibility of this database enables the exploration of new questions and serves as a valuable resource for both researchers and policymakers.


Immuno-electron-microscopic localization of enkephalin in the secretory granules of C cells in the chicken ultimobranchial glands.
In the chicken, enkephalin-immunoreactive cells and nerve fibers are distributed in the ultimobranchial glands, which consist of C-cell groups and cyst structures. Ultrastructural features of the enkephalin cells and nerve fibers were examined by immuno-electron microscopy using both the streptavidin-biotin-peroxidase method and the protein A-colloidal gold method. Immunoreactivity for enkephalin was located on the secretory granules of C cells. In 1-day-old chickens, three types of C cells were distinguished on the basis of their granule size. Type-I cells were filled with large secretory granules (200-600 nm in diameter). These elements represented a majority of the C-cell population. Type-II cells contained medium-sized granules (100-280 nm in diameter). Type-III cells displayed small secretory granules (60-200 nm in diameter). The latter cells were elongate or irregular in shape and frequently extended cytoplasmic processes into the connective tissue stroma or contacted other C cells. Enkephalin-immunoactivity was revealed by dense deposits of immunogold particles on the secretory granules of type-II and type-III cells. There were only a few type-I cells showing immunoreactivity for enkephalin. A double immunogold labeling procedure demonstrated that calcitonin and enkephalin were colocalized in the same secretory granules of type-I and type-II cells. Type-III cells were devoid of immunoreactivity for calcitonin. Enkephalin-immunoreactive nerve fibers were characterized by the presence of granular vesicles, 60-160 nm in diameter, and frequently established direct contact with the surface of C cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Polymorphisms in the promoter region of estrogen receptor β gene in endometrial cancer.
The development of endometrial cancer is known to be affected by estrogens. Thus, genetic variations like single nucleotide polymorphisms (SNPs) in genes involved in estrogen biosynthesis, metabolism, and signal transduction might affect risk for endometrial cancer. In this study, we tested the hypothesis that polymorphisms in the promoter of ESR2 gene may be associated with susceptibility to this disease. We compared the frequency of three SNPs in the promoter region of ESR2 gene (rs2987983, rs3020450, and rs3020449) in 135 women with endometrial cancer and 135 healthy women serving as controls by means of allele-specific tetra-primer PCR. Regarding allele frequency, allele positivity or genotype frequencies of these SNPs we did not observe any significant difference between healthy women and women with endometrial cancer. Our data clearly suggest that the tested SNPs in the promotor region of human ESR2 gene are not associated with the development of endometrial cancer.


Inappropriate statistical method in a parallel-group randomized controlled trial results in unsubstantiated conclusions.
The conclusions of Cassani et al. in the January 2015 issue of Nutrition Journal (doi: 10.1186/1475-2891-14-5 ) cannot be substantiated by the analysis reported nor by the data themselves. The authors ascribed the observed decrease in inflammatory markers to the components of flaxseed and based their conclusions on within-group comparisons made between the final and the baseline measurements separately in each arm of the randomized controlled trial. However, this is an improper approach and the conclusions of the paper are invalid. A correct analysis of the data shows no such effects.


Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues.
The focal adhesion kinase (FAK) family kinases, including FAK and proline-rich kinase 2 (Pyk)2, are the predominant mediators of integrin alphavbeta3 signaling events that play an important role in cell adhesion, osteoclast pathology, and angiogenesis, all processes important in rheumatoid arthritis (RA). Using immunohistochemical and western blot analysis, we studied the distribution of phospho (p)FAK, pPyk2, pSrc, pPaxillin and pPLCgamma in the synovial tissue (ST) from patients with RA, osteoarthritis (OA) and normal donors (NDs) as well as in RA ST fibroblasts and peripheral blood differentiated macrophages (PB MPhis) treated with tumor necrosis factor-alpha (TNFalpha) or interleukin-1beta (IL1beta). RA and OA STs showed a greater percentage of pFAK on lining cells and MPhis compared with ND ST. RA ST fibroblasts expressed pFAK at baseline, which increased with TNFalpha or IL1beta stimulation. Pyk2 and Src were phosphorylated more on RA versus OA and ND lining cells and MPhis. pPyk2 was expressed on RA ST fibrobasts but not in MPhis at baseline, however it was upregulated upon TNFalpha or IL1beta activation in both cell types. pSrc was expressed in RA ST fibroblasts and MPhis at baseline and was further increased by TNFalpha or IL1beta stimulation. pPaxillin and pPLCgamma were upregulated in RA versus OA and ND lining cells and sublining MPhis. Activation of the FAK family signaling cascade on RA and OA lining cells may be responsible for cell adhesion and migration into the diseased STs. Therapies targeting this novel signaling pathway may be beneficial in RA.


Developmental expression of neural cell adhesion molecules of oligodendrocytes in vivo and in culture.
Previously, we have shown that oligodendrocyte adhesion molecules are related to the 120,000-Mr neural cell adhesion molecule (NCAM-120). In this report, we present further evidence that the oligodendrocyte adhesion molecule is NCAM-120. Studies on the expression of NCAM-120 and other molecular forms of NCAM in vivo in rat brain, in vitro in primary mixed cultures, and in cultures enriched for oligodendrocytes are described. Western blot analysis of rat brain using anti-NCAM showed that NCAM-120 first appears at postnatal day 7 and increases in quantity thereafter, coincident with the development of oligodendrocytes in vivo and comparable to the expression of myelin basic protein. Purified oligodendrocytes from 4-week-old rat brains expressed only NCAM-120. Quantitation of various forms of NCAMs in rat brain showed marked age-related differences in the expression of three molecular forms of NCAM. Immunofluorescence analysis showed that oligodendrocytes, at all ages tested, expressed NCAM, but in older oligodendrocytes, the intensity of staining was less. Western blot analysis of oligodendrocyte-enriched cultures showed that from day 1 after isolation (12 days of age) through day 7 after isolation (18 days of age) only NCAM-120 is seen. A possible role for NCAM in myelination and remyelination is discussed.


Reversed micelle formation in a model liquid-liquid extraction system.
The formation of reversed micelles and the roles of extractant and extracted complexes were investigated in the Cyanex923/n-heptane/H(2)SO(4) system. Interfacial tension (gamma), electrical conductivity (kappa), and water content measurements showed that Cyanex923 had a tendency to self-assemble, forming reversed micelles. The changes in electrical conductivity with concentration of H(2)SO(4) in the organic phase (C(H2)SO(4), o) exhibited an S-type curve: a correlation was found between the change in electrical conductivity and the water content as a function of C(H2)SO(4), o. The changes of electrical conductivity were mainly induced by the components and microstructure in the organic phase, while the conversion of extracted complex also resulted in the changes of components and microstructure in the organic phase. Fourier transform infrared (FTIR) spectroscopy and dynamic light scattering (DLS) were used to characterize the organic phases and sizes of the reversed micelles, respectively. The extractant and extracted complexes, such as Cyanex923H(2)SO(4), were involved in the formation of reversed micelles.


Mutation and methylation analysis of the transforming growth factor beta receptor II gene in polycythaemia vera.
Polycythaemia vera (PV) is a myeloproliferative disorder (MPD) thought to result from transformation of a haemopoietic stem cell. Transforming growth factor beta1 (TGF-beta1) is a negative regulator of haemopoietic stem cells, an effect mediated by direct binding to TGF-beta receptor II (TGF-beta RII). Reduced levels of TGF-beta RII mRNA or protein have been reported in several MPDs including PV, suggesting a role for TGF-beta RII in PV. No mutational analysis of the TGF-beta RII gene has yet been performed in PV. To investigate whether genetic or epigenetic alteration of the TGF-beta RII gene contributes to the pathogenesis of PV, we performed mutation and methylation analysis in 15 PV patients. The promoter, all seven exons and all intron/exon junctions were studied using single-strand conformation polymorphism (SSCP) and heteroduplex analysis (HA). In total, three single nucleotide polymorphisms (SNPs) were identified. These were located in the promoter, intron 2 and exon 5. No acquired mutations were detected in any patient sample. We also present a novel method, termed methylation-specific strand extension (MSSE), for the detection of methylated CpG dinucleotides. The combination of bisulphite modification and MSSE permits rapid analysis of the methylation status of CpG dinucleotides in multiple samples. We analysed the methylation status of the promoter and of a CpG island within exon 1 in 15 PV patients. No aberrant methylation was detected in either of these regions. These data demonstrate that neither mutation nor abnormal methylation of the TGF-beta RII gene is associated with the pathogenesis of PV. Furthermore, MSSE is a rapid and robust approach for assessing the methylation status of a given genomic region.


The role of metals in site-specific DNA damage with reference to carcinogenesis.
We reviewed the mechanism of oxidative DNA damage with reference to metal carcinogenesis and metal-mediated chemical carcinogenesis. On the basis of the finding that chromium (VI) induced oxidative DNA damage in the presence of hydrogen peroxide (H2O2), we proposed the hypothesis that endogenous reactive oxygen species play a role in metal carcinogenesis. Since then, we have reported that various metal compounds, such as cobalt, nickel, and ferric nitrilotriacetate, directly cause site-specific DNA damage in the presence of H2O2. We also found that carcinogenic metals could cause DNA damage through indirect mechanisms. Certain nickel compounds induced oxidative DNA damage in rat lungs through inflammation. Endogenous metals, copper and iron, catalyzed ROS generation from various organic carcinogens, resulting in oxidative DNA damage. Polynuclear compounds, such as 4-aminobiphenyl and heterocyclic amines, appear to induce cancer mainly through DNA adduct formation, although their N-hydroxy and nitroso metabolites can also cause oxidative DNA damage. On the other hand, mononuclear compounds, such as benzene metabolites, caffeic acid, and o-toluidine, should express their carcionogenicity through oxidative DNA damage. Metabolites of certain carcinogens efficiently caused oxidative DNA damage by forming NADH-dependent redox cycles. These findings suggest that metal-mediated oxidative DNA damage plays important roles in chemical carcinogenesis.


Platelet activation in patients with systemic scleroderma--pattern and significance.
The vasooclusive features of scleroderma are attributed to the vessel wall anomalies, while platelet's intervention is less studied. platelet activation markers (PAM) pattern and significance in systemic sclerosis. 20 scleroderma patients with severe Raynaud phenomenon, under aspirin treatment, were evaluated by quantitative flow-cytometry for PAM (P-selectin, GPIIbIIIa, CD40L) in correlation with scleroderma activity and severity, systemic endothelial dysfunction (flow-mediated vasodilatation), systemic inflammation (serum CRP and IL-6) and cold-provocation test. Associated autoantibodies (ANCA, antiTPO, anticardiolipin, antiplatelet, antimitochondrial antibodies) were evaluated in relation to IL-6. PAM were expressed in 11 (55%) cases: P-selectin in 5 (45.45%), GPIIbIIIa in 1 (9.1%), combined P-selectin and GPIIbIIIa in 5 (45.45%), CD40L in 0 cases. Scleroderma patients expressing PAM had increased incidence of disease activity and severity. There was no correlation between PAM and systemic endothelial dysfunction. CRP increased in 14(70%) cases was correlated with P-selectin and GPIIbIIIa expression (r = 0.28). Normal IL6 present in 19 (90.9%) cases was correlated with lack of CD40L expression (r = 0.69) and with low autoantibodies incidence (r = 0.69 for ANCA, 0.55 for anti TPO and antiplatelet, 0.39 for anti cardiolipin, 0.45 for antimitochondrial). After cold provocation test PAM were significantly lost and were not expressed de novo. In systemic scleroderma platelet activation markers are correlated with disease activity and severity and increased CRP and are not correlated with systemic endothelial dysfunction or exposure to cold. Normal IL-6 was correlated with lack of CD40L expression and with low incidence of associated autoantibodies.


Planar Brownian motion in the presence of an attractive force.
The two-dimensional Brownian motion of circular disks is considered where these join to form groups whenever they touch. The total number of groups Nt is considered as a function of time. An upper bound for Nt-1 is derived and compared to the experimental movement of erythrocytes. Cells at pH = 7.4 and pH = 6.3 are shown to have a group count that respectively exceeds and falls below the plotted bound. This provides evidence that live cells have a tendency to coalesce that is not explained by Brownian motion only.


Molecular aggregation characterized by high order autocorrelation in fluorescence correlation spectroscopy.
The use of high order autocorrelation in fluorescence correlation spectroscopy for investigating aggregation in a sample that contains fluorescent molecules is described. Theoretical expressions for the fluorescence fluctuation autocorrelation functions defined by gm,n(tau) = [(delta fm(t + tau)delta fm(t] - (delta Fm(t] (delta Fn(t]]/(F)m+n, where delta F(t) is the fluorescence fluctuation at time t, (F) is the average fluorescence, and m and n are integers less than or equal to 3, are derived. Methods for determining the number densities and relative fluorescence yields of aggregates of different sizes from a series of Gm,n(0) values are outlined. The method is applied to 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate suspended in solutions of water and ethyl alcohol. The technique presented may prove useful in detecting and characterizing aggregates of fluorescent-labeled biological molecules such as cell surface receptors.


Prospective randomized controlled clinical study comparing two types of two-piece dental implants supporting fixed reconstructions - results at 1 year of loading.
To analyze clinical, esthetic, radiographic, and prosthetic outcomes of implants and implant-supported reconstructions using two types of dental implants with non-matching implant abutment junctions. A total of 64 patients in need of dental implant therapy with fixed reconstructions were consecutively enrolled. They were randomly assigned to either one of two implant systems (S1: Astra Tech Osseospeed and S2: Straumann Bone Level). Baseline (day of loading) and 1-year measurements included demographics, radiographic, clinical, biologic, prosthetic, and esthetic outcomes. All data were analyzed at the patient level and at the implant level. The nonparametric Mann-Whitney U-test was used to detect differences in continuous variables between two independent groups. Ninety-seven implants (S1 = 54, S2 = 43) were placed and loaded with fixed reconstructions in 64 patients. No implant was lost during the 1-year observation period resulting in a 100% survival rate for both implant systems. At the patient level, the mean marginal bone level at implant insertion was -1.30 mm (SD ± 1.00 mm) for S1 and -1.26 mm (±1.22 mm) for S2 (negative values indicating bone levels coronal to the implant shoulder). At the time of loading, these distances measured 0.29 mm (±0.44 mm) for S1 and 0.22 mm (±0.43 mm) for S2. At the 1-year follow-up, these distances were 0.37 mm (±0.39 mm) for S1 and 0.39 mm (±1.02 mm) for S2. Technical complications of the reconstructions only occurred in Group S1, with a rate of 12% (patient level) (P > 0.05). Biologic complications were observed at a rate of 6% (S1) and 3.2% (S2) at the patient level (P > 0.05). Both implant systems revealed 100% survival rates and minimal changes of the marginal bone levels during 1 year of loading. Few technical and biologic complications occurred. Therefore, both implant systems can be recommended for fixed reconstructions.


Type-I Core-Shell ZnSe/ZnS Quantum Dot-Based Resistive Switching for Implementing Algorithm.
Core-shell semiconductor quantum dots (QDs) are one of the biggest nanotechnology successes so far. In particular, type-I QDs with straddling band offset possess the ability to enhance the charge carriers capturing which is useful for memory application. Here, the type-I core-shell QD-based bipolar resistive switching (RS) memory with anomalous multiple SET and RESET processes was demonstrated. The synergy and competition between space charge limited current conduction (arising from charge trapping in potential well of type-I QDs) and electrochemical metallization (ECM, originating from redox reaction of Ag electrode) process were employed for modulating the RS behavior. Through utilizing stochastic RS mechanisms in QD-based devices, four situations of RS behaviors can be classified into three states in Markov chain for implementing the application of a true random number generator. Furthermore, a 6 × 6 cross-bar array was demonstrated to realize the generation of random letters with case distinction.


Changes in Blood Pressure Outcomes Among Hypertensive Individuals During the COVID-19 Pandemic: A Time Series Analysis in Three US Healthcare Organizations.
The COVID-19 pandemic may have negatively affected medical care for and self-management of chronic hypertension. We sought to examine the impact of the pandemic on blood pressure (BP) among individuals with hypertension. Using an interrupted time series analysis, we compared the level and trend (slope) of BP outcomes before the public health emergency declaration (prepandemic period: August 2018 through January 2020) versus after the stay-at-home orders (pandemic period: April 2020 through November 2020) among adults with hypertension followed at 3 large health systems (n=137 593). Outcomes include systolic and diastolic BP recorded in electronic health records and the proportion of individuals with BP <140/90 mm Hg. The number of BP measurements substantially dropped early in the pandemic and then gradually increased. During the pandemic period, systolic and diastolic BP increased by 1.79 mm Hg (95% CI, 1.57-2.01; P<0.001) and 1.30 mm Hg (95% CI, 1.18-1.42; P<0.001), respectively, compared with the prepandemic period. Similarly, the proportion of patients with controlled BP decreased by 3.43 percentage points (95% CI, -3.97 to -2.90; P<0.001). A trend showing increasing control in the prepandemic period (+3.19 percentage points per year [95% CI, +2.96 to +3.42]; P<0.001) flattened during the pandemic period (+0.27 percentage points per year [95% CI, -0.81 to -1.37]; P=0.62). The first 8 months of the pandemic were associated with worsening BP outcomes among individuals with hypertension. Opportunities to ensure ongoing access to health care with telemedicine and home BP monitoring may mitigate adverse impacts on BP control for future disasters/emergencies.


Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β: identification of miR-153 target genes with functions related to IA-2β in pancreas and brain.
We analysed the genomic organisation of miR-153, a microRNA embedded in genes that encode two of the major type 1 diabetes autoantigens, islet-associated protein (IA)-2 and IA-2β. We also identified miR-153 target genes that correlated with IA-2β localisation and function. A bioinformatics approach was used to identify miR-153's genomic organisation. To analyse the co-regulation of miR-153 and IA-2β, quantitative PCR analysis of miR-153 and Ia-2β (also known as Ptprn2) was performed after a glucose stimulation assay in MIN6B cells and isolated murine pancreatic islets, and also in wild-type Ia-2 (also known as Ptprn), Ia-2β single knockout and Ia-2/Ia-2β double knockout mouse brain and pancreatic islets. Bioinformatics identification of miR-153 target genes and validation via luciferase reporter assays, western blotting and quantitative PCR were also carried out. Two copies of miR-153, miR-153-1 and miR-153-2, are localised in intron 19 of Ia-2 and Ia-2β, respectively. In rodents, only miR-153-2 is conserved. We demonstrated that expression of miR-153-2 and Ia-2β in rodents is partially co-regulated as demonstrated by a strong reduction of miR-153 expression levels in Ia-2β knockout and Ia-2/Ia-2β double knockout mice. miR-153 levels were unaffected in Ia-2 knockout mice. In addition, glucose stimulation, which increases Ia-2 and Ia-2β expression, also significantly increased expression of miR-153. Several predicted targets of miR-153 were reduced after glucose stimulation in vitro, correlating with the increase in miR-153 levels. This study suggests the involvement of miR-153, IA-2β and miR-153 target genes in a regulatory network, which is potentially relevant to insulin and neurotransmitter release.


Acute hemodynamic effects of converting enzyme inhibition in children with intracardiac shunts.
The short-term hemodynamic effects of intravenous enalaprilat were assessed in 26 infants and children, aged 6 months to 15 years, with intracardiac shunts undergoing cardiac catheterization. Pulmonary and systemic pressure, flow, and resistance indices were measured by the direct Fick method before and 30 min after enalaprilat at 0.06 mg/kg. Aortic and pulmonary artery pressure decreased 15 and 20%, respectively, by 10 min, with little further change at 30 min. The heart rate did not change significantly and there was no reduction in systemic flow. In those with a large ventricular septal defect and normal or near-normal pulmonary resistance (less than 3.5 u.m2, n = 8), the mean pulmonary-systemic flow ratio decreased from 2.9 +/- 0.3 to 2.4 +/- 0.3 (p less than 0.05) and the mean left-to-right shunt from 7.4 +/- 0.8 to 5.9 +/- 0.7 L/min/m2 (p less than 0.02). Those with an elevated pulmonary vascular resistance (greater than 5 u.m2, n = 8) showed a varied response. Two children, both with Down's syndrome, an atrioventricular canal defect, and reversible pulmonary hypertension (as assessed by an infusion of isoproterenol), had no decrease in pulmonary vascular resistance with enalaprilat. There were no adverse effects. Converting enzyme inhibitors may benefit "heart failure" associated with large ventricular septal defects and normal or mildly elevated pulmonary resistance.


Moderate expression of Wnt signaling genes is essential for porcine parthenogenetic embryo development.
Parthenogenetic embryos are invariably lost in mid-gestation, possibly due to the lack of the paternal genome and the consequent induction of aberrant gene expression. Wnt signaling is essential for embryonic development; however, the studies of this pathway in porcine parthenogenetic embryos have been limited. Here, the role of Wnt signaling in porcine parthenogenetic embryos was studied. In vivo embryos were used as controls. Single cell quantitative real-time PCR showed that Wnt signaling was down-regulated in porcine parthenogenetic embryos. Furthermore, immunofluorescence staining and real-time PCR demonstrated that porcine parthenogenetic embryo development was largely unaffected by the inhibition of Wnt signaling with IWP-2, but blastocyst hatching and trophectoderm development was blocked. In addition, parthenogenetic blastocyst hatching was improved by the activation of Wnt signaling by BIO. However, the developmental competency of porcine embryos, including blastocyst hatching, was impaired and apoptosis was induced upon the excessive activation of Wnt signaling. These findings constitute novel evidence that Wnt signaling is important for porcine pre-implantation development and that its down-regulation may lead to the low hatching rate of porcine parthenogenetic blastocysts.


Breast and pectoralis musculo-aponeurotic fibromatosis: two independent lesions occurring in the same patient. A case report.
We report the first case of primitive breast fibromatosis associated with a synchronous independent musculo-aponeurotic fibromatosis of the omolateral pectoralis major muscle in an otherwise healthy 29-year-old woman without clinical evidence of any genetic syndrome. The primary occurrence of the two lesions was supported by the absence of any macroscopic and microscopic connection. The present case suggests that a pre- or intraoperative frozen section diagnosis of breast fibromatosis should lead the surgeon and pathologist to exclude an independent fibromatosis of the underlying musculo-aponeurotic fascia.


Bioenergetic consequences of compromised mitochondrial DNA repair in the mouse heart.
The progeroid phenotype of mitochondrial DNA (mtDNA) mutator mice has been nebulously attributed to general mitochondrial 'dysfunction', though few studies have rigorously defined the bioenergetic consequences of accumulating mtDNA mutations. Comprehensive mitochondrial diagnostics was employed to interrogate the bioenergetic properties of isolated cardiac mitochondria from mtDNA mutator mice and wild type littermates. Assessment of respiratory flux in conjunction with parallel measurements of mitochondrial free energy all point to the cause of respiratory flux limitations observed in mtDNA mutator mouse mitochondria being due to impairments within the energy transduction step catalyzed by the electron transport system in which NADH/NAD+ free energy is transduced to the proton motive force (ΔP). The primary bioenergetic consequence of this limitation appears to be hyper-reduction of NAD(P)H/NAD(P)+ redox poise across multiple substrate conditions, particularly evident at moderate to high respiration rates. This hyper-reduced phenotype appears to result from specific reductions in both complex I and complex IV expression, presumably due to compromised mtDNA integrity. Translation of these findings to the working heart would suggest that the primary biological consequence of accumulated mtDNA damage is accelerated electron leak driven by an increase in electron redox pressure for a given rate of oxygen consumption.


Correction: HIV-related stigma and uptake of antiretroviral treatment among incarcerated individuals living with HIV/AIDS in South African correctional settings: A mixed methods analysis.
[This corrects the article DOI: 10.1371/journal.pone.0254975.].


Chronic dryness and wetness and especially pulsed drought threaten a generalist arthropod herbivore.
Under climate change, both wetter and drier conditions, as well as an increase in extreme events like floods or droughts are projected for many areas. So far, studies only investigate the impact of drier or wetter conditions at a single stress severity level but do not consider how different intensities and types of changes affect insect herbivores feeding on stressed plants. Further, how effects of acute stress pulses differ from milder, chronic soil moisture stress is unclear. We investigated how changing soil moisture conditions affect a generalist insect herbivore feeding on grassland plants. We transplanted multi-species sections of grassland into pots and subjected them to different intensities and durations of flooding and drying stress. We compared effects of short, extreme drought and flooding pulses against the effects of milder, but chronic stress. Constantly drier conditions decreased plant and herbivore performance at all levels of stress severity. Severe permanent wetness did not affect plant growth, but decreased pupal weight (- 23%) and survival of larvae (- 34%). Extreme pulsed drought exacerbated negative effects of chronic drying, as most larvae died before they could benefit from rewetting plants after the drought (94% mortality). Pulsed flooding did not affect plants or larval development more than chronic severe wetness. Our findings imply that plant stress negatively affects generalist chewing herbivores, even with mixed diets. Both drier and severely wet, but not mildly wetter conditions, will reduce survival of some species. Especially, extreme droughts appear to have strong negative effects on generalist grassland herbivores.


Identification of sheep lncRNAs related to the immune response to vaccines and aluminium adjuvants.
Long non-coding RNAs (lncRNAs) are involved in several immune processes, including the immune response to vaccination, but most of them remain uncharacterised in livestock species. The mechanism of action of aluminium adjuvants as vaccine components is neither not fully understood. We built a transcriptome from sheep PBMCs RNA-seq data in order to identify unannotated lncRNAs and analysed their expression patterns along protein coding genes. We found 2284 novel lncRNAs and assessed their conservation in terms of sequence and synteny. Differential expression analysis performed between animals inoculated with commercial vaccines or aluminium adjuvant alone and the co-expression analysis revealed lncRNAs related to the immune response to vaccines and adjuvants. A group of co-expressed genes enriched in cytokine signalling and production highlighted the differences between different treatments. A number of differentially expressed lncRNAs were correlated with a divergently located protein-coding gene, such as the OSM cytokine. Other lncRNAs were predicted to act as sponges of miRNAs involved in immune response regulation. This work enlarges the lncRNA catalogue in sheep and puts an accent on their involvement in the immune response to repetitive vaccination, providing a basis for further characterisation of the non-coding sheep transcriptome within different immune cells.


Adsorption and sensing of an anticancer drug on the boron nitride nanocones; a computational inspection.
The electrical response of boron nitride nanocones (BNNCs) to 5-Fluorouracil (5FU) drug was investigated by first-principle density functional theory (DFT). The adsorption of 5FU causes a significant decrease in the BNNCs HOMO-LUMO gap (from 4.60 to 3.39 eV), thereby, the electrical conductivity has also increased. It indicates that the BNNCs could be an appropriate candidate for 5FU detection and may be used in the electronic sensors. Furthermore, the work function of BNNCs is influenced by the 5FU adsorption and the work function of BNNCs is reduce about 18.99%, it could also be a work function based sensor for the detection of 5FU. The BNNCs have also the advantage of short recovery time about 4.25 ms for desorption of 5FU.


Simulating toxicokinetic variability to identify susceptible and highly exposed populations.
Toxicokinetic (TK) data needed for chemical risk assessment are not available for most chemicals. To support a greater number of chemicals, the U.S. Environmental Protection Agency (EPA) created the open-source R package "httk" (High Throughput ToxicoKinetics). The "httk" package provides functions and data tables for simulation and statistical analysis of chemical TK, including a population variability simulator that uses biometrics data from the National Health and Nutrition Examination Survey (NHANES). Here we modernize the "HTTK-Pop" population variability simulator based on the currently available data and literature. We provide explanations of the algorithms used by "httk" for variability simulation and uncertainty propagation. We updated and revised the population variability simulator in the "httk" package with the most recent NHANES biometrics (up to the 2017-18 NHANES cohort). Model equations describing glomerular filtration rate (GFR) were revised to more accurately represent physiology and population variability. The model output from the updated "httk" package was compared with the current version. The revised population variability simulator in the "httk" package now provides refined, more relevant, and better justified estimations. Fulfilling the U.S. EPA's mission to provide open-source data and models for evaluations and applications by the broader scientific community, and continuously improving the accuracy of the "httk" package based on the currently available data and literature.


Sexual behaviour and self-reported sexually transmitted diseases (STDs): comparison between White and Chinese American young people.
This study examined the sexual behaviour and self-reported incidence of STDs of White and Chinese American young people in a nationally representative US sample. 10,419 White and 340 self-identified Chinese American young people in grade 7 through 12 were selected from the National Longitudinal Study of Adolescent Health. Prevalence of sex initiation, ever having casual sex partners, number of lifetime sex partners, age of first sexual intercourse, and history of self-reported STD diagnoses were compared between these two groups. Chinese American young people reported significantly lower rates of sexual intercourse than Whites. Among sexually active young people, Chinese Americans were also less likely to report non-regular sexual partners and to report having a lower number of such sexual partners in the past year. There was no difference in self-reported STDs between the two groups. Ever having been romantically involved, older age, not living in a two-parent household, having more relaxed attitudes about sex, and reported substance use were associated with a higher likelihood of sexual intercourse in both groups. Being native-born was not associated with patterns of sexual behaviour among Chinese Americans.


Estimation of creatinine clearance using plasma creatinine or cystatin C: a secondary analysis of two pharmacokinetic studies in surgical ICU patients.
In ICU patients, glomerular filtration is often impaired, but also supraphysiological values are observed ("augmented renal clearance", >130 mL/min/1.73 m(2)). Renally eliminated drugs (e.g. many antibiotics) must be adjusted accordingly, which requires a quantitative measure of renal function throughout all the range of clinically encountered values. Estimation from plasma creatinine is standard, but cystatin C may be a valuable alternative. This was a secondary analysis of renal function parameters in 100 ICU patients from two pharmacokinetic studies on vancomycin and betalactam antibiotics. Estimated clearance values obtained by the Cockcroft-Gault formula (eCLCG), the CKD-EPI formula (eCLCKD-EPI) or the cystatin C based Hoek formula (eCLHoek) were compared with the measured endogenous creatinine clearance (CLCR). Agreement of values was assessed by modified Bland-Altman plots and by calculating bias (median error) and precision (median absolute error). Sensitivity and specificity of estimates to identify patients with reduced (<60 mL/min/1.73 m(2)) or augmented (>130 mL/min/1.73 m(2)) CLCR were calculated. The CLCR was well distributed from highly compromised to supraphysiological values (median 73.2, range 16.8-234 mL/min/1.73 m(2)), even when plasma creatinine was not elevated (≤0.8 mg/dL for women, ≤1.1 mg/dL for men). Bias and precision were +13.5 mL/min/1.73 m(2) and ±18.5 mL/min/1.73 m(2) for eCLCG, +7.59 and ±16.8 mL/min/1.73 m(2) for eCLCKD-EPI, and -4.15 and ±12.9 mL/min/1.73 m(2) for eCLHoek, respectively, with eCLHoek being more precise than the other two (p < 0.05). The central 95% of observed errors fell between -59.8 and +250 mL/min/1.73 m(2) for eCLCG, -83.9 and +79.8 mL/min/1.73 m(2) for eCLCKD-EPI, and -103 and +27.9 mL/min/1.73 m(2) for eCLHoek. Augmented renal clearance was underestimated by eCLCKD-EPI and eCLHoek. Patients with reduced CLCR were identified with good specificity by eCLCG, eCLCKD-EPI and eCLHoek (0.95, 0.97 and 0.91, respectively), but with less sensitivity (0.55, 0.55 and 0.83). For augmented renal clearance, specificity was 0.81, 0.96 and 0.96, but sensitivity only 0.69, 0.25 and 0.38. Normal plasma creatinine concentrations can be highly misleading in ICU patients. Agreement of the cystatin C based eCLHoek with CLCR is better than that of the creatinine based eCLCG or eCLCKD-EPI. Detection and quantification of augmented renal clearance by estimates is problematic, and should rather rely on CLCR.


Low-grade serous ovarian cancer: a unique disease.
Low-grade serous carcinomas represent approximately 10% of all serous ovarian carcinomas. A growing body of research has demonstrated several important differences between the clinical and molecular characteristics of these tumors and those of high-grade serous ovarian carcinomas. Patients with low-grade serous ovarian tumors are diagnosed at a younger age, have a longer overall survival, and have lower response rates to conventional chemotherapy. In addition, low-grade serous ovarian carcinomas have pathologic and molecular characteristics distinct from high-grade serous carcinomas, yet similar to serous tumors of low malignant potential. This suggests a common pathogenesis and a continuum of disease from serous tumors of low malignant potential to low-grade serous carcinomas. Further study, focusing specifically on low-grade serous carcinomas, is needed to determine the role of other chemotherapeutic agents, hormonal therapy, or targeted biologic agents in the treatment of this disease.


Scale up aspects of sparged insect-cell bioreactors.
In this chapter we have attempted to evaluate the most important parameters which can be useful for the pur-pose of design and scale up. Insect cells and animal cells in general can be grown well in large vessels. However, none of the theories and parameters discussed in this chapter have been validated on a larger scale than laboratory and small pilot reactors. Selection of the most suitable design and scale-up method there-fore needs in particular studies in larger vessels. The Kolmogorov theory and the killing-volume model are in this respect the most promising approaches for the optimal design of large-scale animal-cell bioreactors.


Chemotherapy individualization.
The current practice of dosing patients with anticancer drugs based on body size, leads to a large degree of interpatient variation in clinical outcome following standard doses of chemotherapy. Some patients may fail to respond to treatment, whilst others experience unacceptable side effects. Recent studies have identified more rational approaches to drug dosing, based on patient characteristics such as renal function, pharmacogenetic factors, and drug metabolizing activity. These can be used together with therapeutic drug monitoring and adaptive dosing to achieve a targeted systemic drug exposure in each patient, which may lead to more consistent clinical outcomes in patients receiving comparable chemotherapy dosing regimens. The purpose of this review is to present some approaches to chemotherapy individualization, examples of how this might be applied, and speculation as to how recent advances in pharmacogenetics may lead to further dose-optimization. Whilst it is hoped that the design of new agents, targeted to specific genes involved in oncogenesis, will lead to increased success in the treatment of cancer patients, it is essential that the drugs currently available are used to their maximum potential.


An interwoven carbon nanotubes/cerium dioxide electrocatalyst accelerating the conversion kinetics of lithium sulfide toward high-performance lithium-sulfur batteries.
Rechargeable lithium-sulfur (Li-S) batteries with environmental friendliness, low price, high specific capacity and energy density could be promising alternatives to a larger scope of energy storage in the near future. However, the practical application is impeded by the intrinsic insulation of sulfur and the fatal shuttle effect during the (dis)charging process. Herein, we report a strategy to address the drawbacks of Li-S batteries by inserting an interwoven carbon nanotubes/cerium dioxide electrocatalyst interlayer material (CNTs@CeO2) between the sulfur cathode and the separator. In the CNTs@CeO2 composite, the conductive network interwoven by CNTs facilitates electron transportation, and the abundant active sites in CeO2 cavities ensuring the adsorption-catalytic conversion of lithium polysulfides as well as the hollow structure of CeO2 is conducive to rapid electrolyte penetration and lithium ion migration. Benefiting from such multifunction, the battery with a CNTs@CeO2 interlayer exhibits superior rate performance, delivering a high discharge specific capacity of 1040.6 mAh g-1 at 0.2C and 652.5 mAh g-1 at 4C, respectively. Moreover, the battery shows excellent cycling stability with a capacity decay rate of 0.064% per cycle at 1C over 1000 cycles. These promising results demonstrate the potential application of CeO2-based electrocatalysts for high energy density Li-S batteries.


Degradation of rRNA in interferon-treated vaccinia virus-infected cells.
In interferon-treated mouse L cells, following infection with a DNA-containing virus, vaccinia, synthesis of unique 2'-5'-linked oligonucleotides of the general formula ppp5'A2'(p5'A)n, abbreviated as 2-5A, was detected by competition radiobinding assay. In addition, degradation of rRNA into discrete and characteristic products, similar to those produced by 2-5A-activated endonuclease, was observed. The degradation of rRNA may represent a significant component of antiviral action of interferon in vaccinia virus-infected cells.


Depuration of geosmin- and 2-methylisoborneol-induced off-flavors in recirculating aquaculture system (RAS) farmed European whitefish Coregonus lavaretus.
European whitefish Coregonus lavaretus has increasingly become an important species for aquatic food production, especially in the Nordic countries. Whitefish is produced in traditional cage and pond operations, and in recirculating aquaculture system (RAS) in which, unfortunately, off-flavors and odors, mostly caused by geosmin (GSM) and 2-methylisoborneol (MIB), can accumulate in fish flesh from the circulating water. GSM and MIB have very low human sensory detection limits and, therefore, often disliked by consumers even at low concentrations. In this study, concentrations of GSM and MIB in RAS farmed European whitefish were studied by an analytical method based on headspace solid phase microextraction and gas chromatography-mass spectrometry. Concentrations were determined in different parts of fish: fillet, neck, belly, and tail during a depuration period and in depuration water. The highest initial concentrations were on average 32 ng g-1 (GSM) and 24 ng g-1 (MIB) in European whitefish fillet and 128 ng L-1 (GSM) and 94 ng L-1 (MIB) in water, respectively. After a depuration period of 16 days, concentrations decreased to below the detection limits, indicating the importance of the depuration period.


Adult presentation of MCAD deficiency revealed by coma and severe arrythmias.
We report the case of a 33-year-old man who presented with headaches and vomiting. Soon after admission he became drowsy and agitated, developed ventricular tachycardia and his neurological state worsened (Glasgow coma score 6). Blood analysis showed respiratory alkalosis, hyperlactacidemia (8 mmol/l), hyperammonemia (390 micro mol/l) and hypoglycaemia (2.4 mmol/l). Subsequently, he developed supraventricular tachycardia, ventricular tachycardia and ultimately ventricular fibrillation resulting in cardiac arrest, which was successfully treated. A CT scan of the head revealed cerebral oedema. Whilst in the intensive care unit, he developed renal failure and rhabdomyolysis. The metabolic abnormalities seen at the time of admission normalised within 48 h with IV glucose infusion. Biological investigations, including urinary organic acids and plasma acylcarnitines, showed results compatible with MCAD deficiency. Mutation analysis revealed the patient was homozygous for the classical mutation A985G. This is one of only a few reports of severe cardiac arrhythmia in an adult due to MCAD deficiency. This condition is probably under-diagnosed in adult patients with acute neurological and/or cardiac presentations.


A modified TnphoA useful for single-stranded DNA sequencing.
The TnphoA transposon constructed by Manoil and Beckwith [Proc. Natl. Acad. Sci. USA 82 (1985) 8129-8133] has been modified to permit easy isolation of single-stranded (ss) DNA of target plasmids. The intergenic region (IG) of filamentous phage f1, which consists of the phage origin of replication and packaging signal, was inserted into a nonessential region of TnphoA. This modified transposon should be useful for the analysis of genes cloned in plasmids that lack a filamentous phage IG. Transposition of TnphoA-IG into a plasmid carries the IG with it; subsequently, after infection with a filamentous helper phage, ss plasmid DNA suitable for sequence analysis and useful for oligodeoxyribonucleotide-mediated mutagenesis of TnphoA-generated fusions can be isolated. The utility of TnphoA-IG was confirmed by analysis of 'blue hops' into the bla (encoding beta-lactamase) and pspE (encoding phage shock protein) genes whose products are secreted into the Escherichia coli periplasm.


Identification and management of clomiphene citrate responses.
Clomiphene citrate (CC) is widely used for induction of ovulation; however, adequate time is rarely used to monitor patients on this form of therapy. Two hundred thirty-one infertility patients qualified for this study in 1155 cycles, during which basal body temperature charts were kept and the quality of cervical mucus was evaluated. Nine types of responses were classified: three ovulatory (O1, O2, O3), three anovulatory (A1, A2, A3), and three miscellaneous (M1, M2, M3). The overall, uncorrected pregnancy rate was 54.9%, and 79.2% showed ovulatory responses. The most common response was O1 (normal responses, 38.5%) with the highest pregnancy rates (92.1%). Poor estrogenic response with poor cervical mucus (CM) (O2) was fairly common (13.4%) and had poor pregnancy rates, even with the addition of estrogens (12.9%). It is suggested that this new classification of CC responses will help to identify and more efficiently manage patients undergoing this form of therapy.


[Normal latencies of cortical somatosensory evoked potentials--an additional criterion for the diagnosis of Rett syndrome].
In four girls aged from 2 1/2 to 17 years with Rett's syndrome confirmed on the basis of clinical criteria, somatosensorically evoked cortical potentials were led off contralaterally on both sides following stimulation of the median nerve (Med SEP). Like three other children with Rett's syndrome reported by Verma et al. (1987) the present author's patients had normal latency times. Determination of normal latency times for somatosensorically evoked potentials may thus be regarded as an important additional diagnostic criterion for the diagnosis of Rett's syndrome.


Xanthine oxidase/NADPH oxidase inhibition by hydralazine attenuates acute kidney injury and prevents the transition of acute kidney injury to chronic kidney disease.
The enhancement of inflammation and reactive oxygen species leads to the damage of renal tubular cells in acute kidney injury (AKI), and the upregulation of inflammation increases the risk of AKI being converted into chronic kidney disease (CKD). Hydralazine has shown renoprotective effects in multiple kidney diseases and was shown to be a potent xanthine oxidase (XO) inhibitor. This study aimed to investigate the mechanisms of hydralazine in ischemia-reperfusion (I/R)-stimulated renal proximal tubular epithelial cells in vitro and in AKI animals in vivo. The effects of hydralazine in AKI-to-CKD transition were also evaluated. Human renal proximal tubular epithelial cells were stimulated by I/R conditions in vitro. To generate a mouse model of AKI, a right nephrectomy was performed, followed by left renal pedicle I/R using a small atraumatic clamp. In the in vitro part, hydralazine could protect renal proximal tubular epithelial cells against insults from the I/R injury through XO/NADPH oxidase inhibition. In the in vivo part, hydralazine preserved renal function in AKI mice and improved the AKI-to-CKD transition by decreasing renal glomerulosclerosis and fibrosis independently of blood pressure lowering. Furthermore, hydralazine exerted antioxidant, anti-inflammatory, and anti-fibrotic effects both in vitro and in vivo. Hydralazine, as a XO/NADPH oxidase inhibitor, could protect renal proximal tubular epithelial cells from the insults of I/R and prevent kidney damage in AKI and AKI-to-CKD. The above experimental studies strengthen the possibility of repurposing hydralazine as a potential renoprotective agent through its antioxidative mechanisms.


First record of Aedes koreicus (Diptera: Culicidae) in Germany.
Within the framework of a national mosquito monitoring programme, a mosquito specimen collected in mid-2015 in southern Germany was identified as Aedes koreicus, a non-endemic species originating from East Asia. After the Asian bush mosquito Aedes japonicus, which is already established in Germany and widely distributed, and the Asian tiger mosquito Aedes albopictus, which is increasingly often introduced from southern Europe, A. koreicus is the third demonstrated invasive mosquito species in Germany supposed to have significant vector potential for disease agents.


The Overlooked Glycan Components of the Cryptococcus Capsule.
Pathogenic species of Cryptococcus kill approximately 200,000 people each year. The most important virulence mechanism of C. neoformans and C. gattii, the causative agents of human and animal cryptococcosis, is the ability to form a polysaccharide capsule. Acapsular mutants of C. neoformans are avirulent in mice models of infection, and extracellularly released capsular polysaccharides are deleterious to the immune system. The principal capsular component in the Cryptococcus genus is a complex mannan substituted with xylosyl and glucuronyl units, namely glucuronoxylomannan (GXM). The second most abundant component of the cryptococcal capsule is a galactan with multiple glucuronyl, xylosyl, and mannosyl substitutions, namely glucuronoxylomannogalactan (GXMGal). The literature about the structure and functions of these two polysaccharides is rich, and a number of comprehensive reviews on this topic are available. Here, we focus our discussion on the less explored glycan components associated with the cryptococcal capsule, including mannoproteins and chitin-derived molecules. These glycans were selected for discussion on the basis that i) they have been consistently detected not only in the cell wall but also within the cryptococcal capsular network and ii) they have functions that impact immunological and/or pathogenic mechanisms in the Cryptococcus genus. The reported functions of these molecules strongly indicate that the biological roles of the cryptococcal capsule go far beyond the well-known properties of GXM and GXMGal.


Use of web-based patient education sessions on psychiatric wards.
To evaluate the use of web-based patient education sessions in the psychiatric inpatient care. The qualitative and quantitative data was collected from 93 patients' evaluation reports in two psychiatric hospitals in Finland completed by 83 nurses. The web-education included six patient education sessions which were used over a period lasting between 1 and 70 days and took 10-360 min per patient. Out of 508 sessions, 464 had no interruptions or disturbances, 37 sessions had disturbances and seven sessions were interrupted. Three fourths of the sessions were used successfully. Factors associated with use were patients' vocational education level, mental status, diagnoses, number of nurses involved and hospital. It is important to invest effort in web-based patient education during patients' hospitalization and to use it even with patients suffering from serious mental health disorders. This is meant to provide more alternatives in nursing.