Beta-adrenergic stimulation enhances left ventricular diastolic performance in normal subjects.
To determine the effects of beta-adrenergic stimulation on transmitral Doppler echocardiography flow characteristics of left ventricular diastolic filling, we studied 10 healthy volunteers aged 23-31 years (mean age, 26.6 years) during intravenous infusion of isoprenaline in consecutive steps of 0.1, 0.2, 0.4, 0.75, and 1.5 micrograms/min (each for 15 min). Saline control infusion was given in the same manner in a crossover and blinded protocol. Compared with the infusion of placebo, stepwise increasing doses of isoprenaline caused a dose-related increase in early and late diastolic filling velocities and velocity-time integrals, a lengthening of the acceleration time, and a shortening of the deceleration and filling time. The chosen method proved highly sensitive, as statistically significant changes were detectable at the lowest dose of 0.1 microgram/min for all variables except velocity-time integral of late filling and deceleration time (> or = 0.2 microgram/min). The effects related to dose in a log-linear fashion except for the lengthening of the acceleration time (early ceiling), the increase of peak early filling velocity (increased steepness at higher doses), and the shortening of the filling time. Inclusion of the associated increases in heart rate and systolic blood pressure and the decrease in diastolic blood pressure blunted all treatment contrasts except for the increase of peak early filling velocity. In addition, the hemodynamics with respect to heart rate and loading conditions were not altered at low dosages of drug (< 0.4 microgram/min). Effects of at least the peak early filling velocity must be interpreted as an active adrenergically mediated myocardial relaxation process. These findings have potentially important clinical implications for this noninvasive, readily available, and convenient technique in clinical pharmacology, stress testing, and possibly therapeutic interventions in diastolic dysfunction in humans.


Photoluminescence of Visible and NIR-Emitting Lanthanide-Doped Bismuth-Organic Materials.
A bismuth-organic compound containing 2,2':6'2"-terpyridine (terpy) and 2-thiophenecarboxylate (TC), of the general formula (terpy)Bi(κ2 -TC)3 ⋅0.47 H2 O (BiOM-1), has been synthesized under hydrothermal conditions. Addition of a lanthanide nitrate solution to the reaction mixture led to statistical replacement of the bismuth centers, and yielded isomorphous lanthanide containing compounds Bi1-x Lnx OM-1 (Ln=Nd, Sm, Eu, Tb, Dy, Er, and Yb) that showed bismuth and/or ligand sensitized lanthanide-centered emission, and the first example of NIR emission from a lanthanide doped BiOM. The structure was determined by single-crystal X-ray diffraction, and the level and uniformity of lanthanide ion incorporation into the bismuth host was determined by ICP-OES and electron microprobe analysis. For the visible emitters, lifetime data and quantum yields are presented. A high efficiency of sensitization was calculated for the europium analog (50.1 %), showing significant improvement over previously reported europium thiophenecarboxylates. These novel materials may provide strategies to address concerns over the long-term sustainability of the rare earth elements, especially relating to optical devices.


Law, Ethics, and Conversations between Physicians and Patients about Firearms in the Home.
Firearms in the home pose a risk to household members, including homicide, suicide, and unintentional deaths. Medical societies urge clinicians to counsel patients about those risks as part of sound medical practice. Depending on the circumstances, clinicians might recommend safe firearm storage, temporary removal of the firearm from the home, or other measures. Certain state firearm laws, however, might present legal and ethical challenges for physicians who counsel patients about guns in the home. Specifically, we discuss state background check laws for gun transfers, safe gun storage laws, and laws forbidding physicians from engaging in certain firearm-related conversations with their patients. Medical professionals should be aware of these and other state gun laws but should offer anticipatory guidance when clinically appropriate.


Effect of antioxidants after post-space irrigation on the adhesive interface of glass fiber post cementation.
This study evaluated the effects of antioxidants, 10% sodium ascorbate (SA) or 20% alpha-tocopherol (AT), after post-space irrigation with 2.5% sodium hypochlorite +17% EDTA (SH) or 1% peracetic acid (PA) on the adhesive interface after glass fiber post cementation. Sixty bovine roots were endodontically treated. After preparation, the post-space was irrigated with SH or PA followed or not by the use of antioxidants (SA or AT) (n = 10). Push-out bond strength test, failure mode, and dentin penetrability analysis using confocal laser microscope were performed in the cervical, middle, and apical thirds. Data from bond strength and dentinal penetrability were evaluated by one-way ANOVA and Tukey post hoc test (p < 0.05). SH showed the lowest bond strength regardless of the third (p < 0.05). In apical third, mixed failure was the most incident in all groups. Only in the cervical third of the post-space, SH-AT provided the greatest tag extension of the cementation system into dentin (p < 0.05). However, in the middle and apical thirds, SH-AT, SH-SA, and PA-SA provided the largest tag extensions (p < 0.05), but similar to each other (p > 0.05). The use of antioxidants only favored bond strength when SH was used and dentin penetrability of the adhesive and conventional resin cementation, regardless of the solution used to irrigate the post-space. The use of antioxidants (10% sodium ascorbate and 20% alpha-tocopherol) after post-space irrigation with sodium hypochlorite appears to increase the bond strength favoring the glass fiber post-cementation.


Genome homology and divergence in the SP beta-related bacteriophages of Bacillus subtilis.
Chromosomal organization in related temperate Bacillus subtilis bacteriophages SP beta, phi 3T, rho 11, Z, and E was compared. DNA-DNA hybridization studies done in conjunction with available restriction fragment maps of SP beta, phi 3T, and rho 11 demonstrated that DNA homology between these three phages extended over most of their respective genomes, although each contained unique chromosomal segments, phi 3T, rho 11, Z, and E, but not SP beta, possessed apparently homologous structural genes (thyP) for thymidylate synthetase. DNA from all thyP-containing phages transformed thymine auxotrophs of B. subtilis SP beta lysogens to prototrophy. This transformation commonly involved incorporation of the thyP gene into SP beta prophage within a region corresponding to the middle of the viral chromosome. Chimeric plasmids containing the thyP gene from phi 3T or cloned fragments of SP beta DNA were used in DNA-DNA hybridization studies to locate the thymidylate synthetase gene near the center of the phi 3T chromosome, and to demonstrate that the organization of this region resembled the analogous portion of the SP beta genome. Profiles of virion structural proteins from the five phages were also very similar, further suggesting functional homology between these viruses. However, despite these evidences of relatedness, populations of fragments generated by digesting SP beta, phi 3T, rho 11, Z, and E DNA with restriction enzymes were quite dissimilar.


Identification and Characterization of Genes Involved in Ecdysteroid Esterification Pathway Contributing to the High 20-Hydroxyecdysone Resistance of Helicoverpa armigera.
20-Hydroxyecdysone (20E), the most important regulator for insect development, is also a major component in phytoecdysteroids in plants. Therefore, this plant-derived hormone is considered as a potential natural product for use in pest management. However, some insects show high resistance to it, and the molecular mechanism of their resistance is still unclear. In this study, we find that the cotton bollworm Helicoverpa armigera larvae show high tolerance to artificial foods containing up to 50 μg 20E without any detrimental effects on growth and development. High performance liquid chromatography analysis indicates that high efficiency to transform the ingested 20E through an ecdysteroid esterification pathway may contribute to the resistance. Furthermore, comparative transcriptome analysis of the larvae's midgut after 20E treatment identifies two genes (long-chain-fatty-acid-CoA ligase, Long-FACL; sterol O-acyltransferase, SATF) involved in the pathway. Transcriptome and real-time PCR show the Long-FACL gene can be significantly induced by 20E, and this induction is only detected in the midgut. However, 20E has no effect on the transcript of the SATF gene. Moreover, the heterologously expressed protein of the SATF gene shows the ecdysteroid-22-O-acyltransferase activity that requires fatty acyl-CoA, which is produced by Long-FACL. Taken together, our results identify and demonstrate the genes involved in the ecdysteroid esterification pathway conferring high resistance to 20E in the cotton bollworm, H. armigera.


Volumetric capnography for the evaluation of chronic airways diseases.
Obstructive lung diseases of different etiologies present with progressive peripheral airway involvement. The peripheral airways, known as the silent lung zone, are not adequately evaluated with conventional function tests. The principle of gas washout has been used to detect pulmonary ventilation inhomogeneity and to estimate the location of the underlying disease process. Volumetric capnography (VC) analyzes the pattern of CO2 elimination as a function of expired volume. To measure normalized phase 3 slopes with VC in patients with non-cystic fibrosis bronchiectasis (NCB) and in bronchitic patients with chronic obstructive pulmonary disease (COPD) in order to compare the slopes obtained for the groups. NCB and severe COPD were enrolled sequentially from an outpatient clinic (Hospital of the State University of Campinas). A control group was established for the NCB group, paired by sex and age. All subjects performed spirometry, VC, and the 6-Minute Walk Test (6MWT). Two comparisons were made: NCB group versus its control group, and NCB group versus COPD group. The project was approved by the ethical committee of the institution. Statistical tests used were Wilcoxon or Student's t-test; P<0.05 was considered to be a statistically significant difference. Concerning the NCB group (N=20) versus the control group (N=20), significant differences were found in body mass index and in several functional variables (spirometric, VC, 6MWT) with worse results observed in the NCB group. In the comparison between the COPD group (N=20) versus the NCB group, although patients with COPD had worse spirometric and 6MWT values, the capnographic variables mean phase 2 slope (Slp2), mean phase 3 slope normalized by the mean expiratory volume, or mean phase 3 slope normalized by the end-tidal CO2 concentration were similar. These findings may indicate that the gas elimination curves are not sensitive enough to monitor the severity of structural abnormalities. The role of normalized phase 3 slope may be worth exploring as a more sensitive index of small airway disease, even though it may not be equally sensitive in discriminating the severity of the alterations.


Antiestrogens upregulate estrogen receptor beta expression and inhibit adrenocortical H295R cell proliferation.
The molecular mechanisms involved in adrenocortical tumorigenesis are still not completely understood. In this study, using the H295R cell line as a model system, we investigated the role of estrogens and estrogen receptor (ER) alpha and ER beta in the growth regulation of adrenocortical tumors. We demonstrated that H295R cells are able to convert androgens to estrogens by a constitutive expression of active cytochrome P450 aromatase protein and express ER beta to a greater extent than ER alpha. Moreover, physiological concentrations of 17beta-estradiol (E2) determined an increase of thymidine incorporation, suggesting the presence of an autocrine mechanism in maintaining H295R cell proliferation. Evaluating the response to ER antagonists like 4-hydroxytamoxifen (OHT) and ICI 182 780 (ICI), we observed an up-regulation of ER beta and a dose-dependent inhibition of H295R cell proliferation. Whereas ICI determined the growth arrest of H295R cells, OHT induced morphological changes that were characteristic of apoptosis. According to the above-mentioned observations, OHT but not ICI clearly induced a marked expression of FasL and the cleavage of both caspase-8 and caspase-3. Interestingly, the apoptotic effects of OHT in H295R cells may be consequent to the enhanced levels of ER beta which stimulate the expression of FasL interacting with activating protein (AP)-1 sites located within its promoter sequence. In conclusion, we have demonstrated that H295R cells are able to transform androgens to estrogens that activate an autocrine mechanism, mediated by their own receptors, and contribute to regulate the proliferation of these cells. Moreover, this study points towards a role for ER beta as an important mediator of the repressive effects exerted by antiestrogens on H295R cells; however, further studies are needed to clarify its role in the control of adrenocortical cell proliferation and on the potential benefits of antiestrogens for treatment of adrenocortical cancer.


Assessment of B Cell Repertoire in Humans.
The B cell receptor (BCR) repertoire is highly diverse. Repertoire diversity is achieved centrally by somatic recombination of immunoglobulin (Ig) genes and peripherally by somatic hypermutation and Ig heavy chain class-switching. Throughout these processes, there is selection for functional gene rearrangements, selection against gene combinations resulting in self-reactive BCRs, and selection for BCRs with high affinity for exogenous antigens after challenge. Hence, investigation of BCR repertoires from different groups of B cells can provide information on stages of B cell development and shed light on the etiology of B cell pathologies. In most instances, the third complementarity determining region of the Ig heavy chain (CDR-H3) contributes the majority of amino acids to the antibody/antigen binding interface. Although CDR-H3 spectratype analysis provides information on the overall diversity of BCR repertoires, this fairly simple technique analyzes the relative quantities of CDR-H3 regions of each size, within a range of approximately 10-80 bp, without sequence detail and thus is limited in scope. High-throughput sequencing (HTS) techniques on the Roche 454 GS FLX Titanium system, however, can generate a wide coverage of Ig sequences to provide more qualitative data such as V, D, and J usage as well as detailed CDR3 sequence information. Here we present protocols in detail for CDR-H3 spectratype analysis and HTS of human BCR repertoires.


Mental Illness And Brain Disease.
It has become common to say psychiatric illnesses are brain diseases. This reflects a conception of the mental as being biologically based, though it is also thought that thinking of psychiatric illness this way will reduce the stigma attached to psychiatric illness. If psychiatric illnesses are brain diseases, however, it is not clear why psychiatry should not collapse into neurology, and some argue for this course. Others try to maintain a distinction by saying that neurology deals with abnormalities of neural structure while psychiatry deals with specific abnormalities of neural functioning. It is not clear that neurologists would accept this division, nor that they should. I argue that if we take seriously the notion that psychiatric illnesses are mental illnesses we can draw a more defensible boundary between psychiatry and neurology. As mental illnesses, psychiatric illnesses must have symptoms that affect our mental capacities and that the sufferer is capable of being aware of, even if they are not always self-consciously aware of them. Neurological illnesses, such as stroke or multiple sclerosis, may be diagnosed even if they are silent, just as the person may not be aware of having high blood pressure or may suffer a silent myocardial infarction. It does not make sense to speak of panic disorder if the person has never had a panic attack, however, or of bipolar disorder in the absence of mood swings. This does not mean psychiatric illnesses are not biologically based. Mental illnesses are illnesses of persons, whereas other illnesses are illnesses of biological individuals.


fMRI in patients implanted with a vagal nerve stimulator.
To demonstrate the feasibility and safety of using functional magnetic resonance imaging (fMRI) to determine the blood oxygen level dependent changes (BOLD) in patients undergoing vagal nerve stimulation (VNS) for the treatment of epilepsy. Four patients with an implanted vagus nerve stimulator had fMRI images acquired during several cycles of intermittent VNS. Blood oxygen level dependent changes were detected. These regions were then superimposed upon the patients' structural MR images. Patients undergoing VNS tolerated fMRI without difficulty. No complications with the implanted stimulators were encountered. Areas of activation were noted in several cortical regions, including frontal, temporal, parietal, and occipital cortices. Our study in four patients shows fMRI can be performed safely in patients with an implanted vagal nerve stimulator. The successful use of fMRI during VNS offers potential advantages over PET imaging by allowing rapid image acquisition and the ability to repeatedly study patients over time. Our preliminary results differ from previous PET or SPECT studies in failing to detect changes in subcortical areas. This finding could be due to the smaller n in this study compared with the other studies.


Diverse interactions and ecosystem engineering can stabilize community assembly.
The complexity of an ecological community can be distilled into a network, where diverse interactions connect species in a web of dependencies. Species interact directly with each other and indirectly through environmental effects, however to our knowledge the role of these ecosystem engineers has not been considered in ecological network models. Here we explore the dynamics of ecosystem assembly, where species colonization and extinction depends on the constraints imposed by trophic, service, and engineering dependencies. We show that our assembly model reproduces many key features of ecological systems, such as the role of generalists during assembly, realistic maximum trophic levels, and increased nestedness with mutualistic interactions. We find that ecosystem engineering has large and nonlinear effects on extinction rates. While small numbers of engineers reduce stability by increasing primary extinctions, larger numbers of engineers increase stability by reducing primary extinctions and extinction cascade magnitude. Our results suggest that ecological engineers may enhance community diversity while increasing persistence by facilitating colonization and limiting competitive exclusion.


Zirconium(IV) compounds as efficient catalysts for synthesis of alpha-aminophosphonates.
Zirconium(IV) compounds are reported as excellent catalysts for a three-component one-pot reaction of an amine, an aldehyde or a ketone, and a di/trialkyl/aryl phosphite to form alpha-aminophosphonates under solvent-free conditions at rt. Among the various zirconium compounds, ZrOCl2 x 8 H2O and ZrO(ClO4)2 x 6 H2O were most effective. The reactions were faster with dialkyl/diaryl phosphites than with trialkyl/triaryl phosphites. No O-Me cleavage occurs with aryl methyl ether and methyl ester groups. alpha,beta-Unsaturated carbonyl moiety does not undergo conjugate addition with the phorphorous moiety.


[Acute interstitial nephritis induced by loratadine].
Loratadine is a second generation histamine H1 receptor antagonist, that has high potency antiallergic properties and is associated with low adverse effects compared with other antihistamines. Acute interstitial nephritis is a cause of acute renal failure that is most often induced by drugs or, less frequently, infection or sarcoidosis. Although the number of drugs associated with acute intersticial nephritis is too large, the antihistaminic loratadine have never been reported before. We report a case of an interstitial nephritis with acute renal failure that suggesting hypersensitivity reaction in a 77 old man who had received loratadine (10 mg/day) during ten days before his assessment to our hospital by disseminated pruritic syndrome. The initial suspect was rapidly progressive glomerulonephitis and renal biopsy was practice and treatment with corticosteroids were initiated (prednisone bolus of 500 mg three days and 1 mg/kg/day/later). The loratadine therapy was cessation. He exhibiting a slow and progressive improvement on renal function and one month later, urea and creatinine levels was normal and hematuria and proteinuria had disappeared. The corticosteroids therapy were progressive decreased until withdrawal. We think that this is an interesting case, basing in its clinical presentation and that it had never been reported before.


Therapeutic renal arterial occlusion for elimination of proteinuria: 'medical nephrectomy'.
A patient with severe nephrotic syndrome who was too debilitated to undergo surgical nephrectomies, underwent therapeutic bilateral renal artery occlusion by the selective injection of isobutyl 2-cyanoacrylate into the renal arteries. The therapy resulted in dramatic cessation of urine flow and elimination of proteinuria.


Oligonucleotide therapeutics in neurodegenerative diseases.
Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2. We demonstrated that reduction of ATXN2 expression in SCA2 mice treated by intracerebroventicular injection (ICV) of ATXN2 ASO delayed motor phenotype onset, improved the expression of several genes demonstrated abnormally reduced by transcriptomic profiling of SCA2 mice, and restored abnormal Purkinje cell firing frequency in acute cerebellar sections. Here we discuss RNA abnormalities in disease and the prospects of targeting neurodegenerative diseases at the level of RNA control using ASOs and other RNA-targeted therapeutics.


Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal.
The ability of adult stem cells to maintain their undifferentiated state depends upon residence in their niche. While simple models of a single self-renewal signal are attractive, niche-stem cell interactions are likely to be more complex. Many niches have multiple cell types, and the Drosophila testis is one such complex niche with two stem cell types, germline stem cells (GSCs) and somatic cyst progenitor cells (CPCs). These stem cells require chemokine activation of Jak/STAT signaling for self-renewal. We identified the transcriptional repressor Zfh-1 as a presumptive somatic target of Jak/STAT signaling, demonstrating that it is necessary and sufficient to maintain CPCs. Surprisingly, sustained zfh-1 expression or intrinsic STAT activation in somatic cells caused neighboring germ cells to self-renew outside their niche. In contrast, germline-intrinsic STAT activation was insufficient for GSC renewal. These data reveal unexpected complexity in cell interactions in the niche, implicating CPCs in GSC self-renewal.


Downregulation of AQP2 in the anterior vaginal wall is associated with the pathogenesis of female stress urinary incontinence.
The pathogenesis of stress urinary incontinence (SUI) is unclear. Aquaporins (AQPs) are a family of transmembrane proteins that transport water and small solutes, including glycerol, across cell membranes. AQPs have been demonstrated to serve a role in skin hydration, cellular proliferation, migration, immunity, wound healing and vascular remodeling in multiple organs. Furthermore, studies have confirmed that abnormal synthesis and degradation of collagens in extracellular matrix (ECM) remodeling contributes to SUI, by altering normal tissue architecture and mechanical properties. The authors previously demonstrated that AQP2 expressed in the human endometrium varies during the menstrual cycle. However, it is unknown whether AQP2 serves a role in the pathogenesis of SUI in the urethral supporting tissue. In the present study, AQP2 location and expression was examined in the anterior vaginal wall, and investigated the association between AQP2 and collagen I/III in female SUI. Western blotting, immunohistochemistry and immunofluorescence were used to measure AQP2 expression levels, and to reveal the location of AQP2 in the anterior vaginal wall, as well as fibroblasts in SUI and non‑SUI. The association between AQP2 and collagen I/III was subsequently investigated by AQP2‑small interfering RNA knockdown and overexpression 2 in fibroblasts. AQP2 expression in the anterior vaginal wall was significantly increased in women without SUI compared with those with SUI (P<0.05). Downregulation of AQP2 significantly decreased the mRNA and protein expression of collagen I/III, while AQP2 overexpression significantly increased the mRNA and protein expression of collagen I/III in fibroblasts (P<0.05). AQP2 was demonstrated to be expressed in the anterior vaginal wall and fibroblasts, and to regulate the expression level of collagen I/III in the anterior vaginal wall and fibroblasts, suggesting that AQP2 is associated with the pathogenesis of female SUI through collagen metabolism during ECM remodeling.


Reduction in Medical Evacuations from Iraq and Syria Following Introduction of an Asynchronous Telehealth System.
While deployed, military medical personnel manage routine medical issues that fall under the category of Disease Non-Battle Injury (DNBI). The 86th Combat Support Hospital (CSH) partnered with Combined Joint Task Force-Operation Inherent Resolve (CJTF-OIR) Surgeon Cell, and Special Operations Joint Task Force-Operation Inherent Resolve (SOJTF-OIR) Surgeon Cell, to introduce the Health Experts onLine Portal (HELP) telemedicine system to medical personnel in Iraq and Syria. HELP is an asynchronous (store and forward) online system that provides secure provider-to-provider teleconsultation services for routine patient care and medical evacuation (MEDEVAC) coordination. The goal was to reduce the need for MEDEVAC by providing expert consultation to medical providers in farther-forward deployed units. In June 2017, the 86th CSH launched HELP telemedicine services for Kuwait. Following the successful implementation of the telemedicine system in Kuwait, the 86th CSH leadership partnered with CJTF-OIR and SOJTF-OIR medical leadership in launching the system within Iraq and Syria as well as making the system available to all deployed locations in Central Command (CENTCOM). This was a prospective cohort study designed to determine if having convenient and secure access to remote subspecialty consultation would be associated with a reduction in routine MEDEVACs from far forward in the battle space. In August 2017, new-user training was completed and the program launched in Iraq and Syria. This study analyzes the baseline MEDEVAC rate in 3 months before the implementation of HELP telemedicine compared to 3 months following the implementation. Iraq and Syria cases in the HELP telemedicine system accounted for 17.2% (76) of total CENTCOM telemedicine case volume over the 7-month study period. Comparing the 3-month period before and after implementation of HELP, use of asynchronous telemedicine in Iraq and Syria was associated with a reduction in total MEDEVACs from 157 to 68 (56.7% reduction, p < 0.001). DNBI represented the majority of the change, (65.0% reduction, p < 0.001). MEDEVAC for battle-related injuries decreased slightly from 13 to 6 per 3-month period (p = 0.03). This is the first prospective study to demonstrate an association between the initiation of asynchronous telemedicine capabilities in a combat zone and decreased MEDEVACs. Annualized numbers would predict a reduction of 328 MEDEVACs/year for each 10,000 personnel by utilizing asynchronous telemedicine. This represents a significant potential cost savings of $1.2 million/year through avoidance of routine medical movement of personnel and supports unit readiness by retaining service members in areas of combat operations.


SFPQ, a multifunctional nuclear protein, regulates the transcription of PDE3A.
Phosphodiesterase 3A (PDE3A), a member of the cGMP-inhibited cyclic nucleotide phosphodiesterase (PDE) family, plays important roles in oocyte maturation and vascular smooth muscle cell proliferation. However, the molecular mechanisms that regulate PDE3A gene expression remain largely unknown. In this study, we investigated the transcriptional regulation of PDE3A , and found that the splicing factor proline and glutamine rich (SFPQ) protein modulated PDE3A mRNA levels. Multiple transcription start sites (TSS1, 2, and 3) were identified within the first exon of PDE3A using 5'-rapid amplification of cDNA ends (RACE). Variable expression levels of three PDE3A variants were also observed in human tissues and HeLa cells. Several putative SFPQ-binding sites were identified upstream of the regulatory region of PDE3A -TSSs using chromatin immunoprecipitation sequencing (ChIP-seq). Serum-induced PDE3A expression was affected by increasing the amount of SFPQ binding to the upstream regulatory region of PDE3A In addition, transcription of PDE3A was lower in human cervical adenocarcinoma cells compared to normal cervical tissue. Furthermore, over-expression of PDE3A induced sensitivity to anti-cancer therapeutic agent, 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP), in HeLa cells. Taken together, these results suggest that SFPQ functions as a transcriptional activator of PDE3A, which is involved in the regulation of DNMDP sensitivity , offering a novel molecular target for the development of anticancer therapies.


Food and feed safety of DAS-444Ø6-6 herbicide-tolerant soybean.
DAS-444Ø6-6 soybean was genetically engineered (GE) to withstand applications of three different herbicides. Tolerance to glufosinate and glyphosate is achieved through expression of the phosphinothricin acetyltransferase (PAT) and double-mutated maize 5-enolpyruvyl shikimate-3-phosphate synthase (2mEPSPS) enzymes, respectively. These proteins are expressed in currently commercialized crops and represent no novel risk. Tolerance to 2,4-dichlorophenoxyacetic acid (2,4-D) is achieved through expression of the aryloxyalkanoate dioxygenase 12 (AAD-12) enzyme, which is novel in crops. The safety of the AAD-12 protein and DAS-444Ø6-6 event was assessed for food and feed safety based on the weight of evidence and found to be as safe as non-GE soybean.


The Biogenetic Synthesis of Metallic Nanoparticles and the Role They Play in Anti-inflammatory Drug Treatment.
Nanoscience and nanotechnology have resulted in the continuous development of new nanomaterials with remarkable properties that make them appealing for pharmaceutical applications. The biocompatibility of metallic nanoparticles is of increasing interest for research scientists currently working towards developing novel nano-based medicines, industrial chemicals, and antigens. There is also a particular interest in using them to counter mutations that up-regulate inflammation enhancers to produce a range of inflammation-related pathologies. The following review discusses the anti-inflammatory mechanisms of metallic bioconjugated (silver, gold, zinc oxide, titanium dioxide, and selenium) nanoparticles. The current study focuses on nanoparticle manufacturing technologies and the inflammatory response. A thorough search was conducted in several databases, including Scopus, Embase, Cochrane, and PubMed. The search terms used included: Alzheimer's disease, mechanism of action, neuroinflammation, the reaction of Mast cells to stress and neuroinflammation. The study included all publications published in English. Green-synthesised nanoparticles can suppress the NF-B and cyclooxygenase-2 pathways, preventing the production of proinflammatory cytokines and ROS scavenging mechanisms. Metallic nanoparticles with anti-inflammatory properties, such as stability and specific targeting, have been briefly discussed. The current research focuses on metallic nanoparticles employed as anti-inflammatory medication molecules, although nanoparticles have applications in various areas (medicine, chemical engineering, and agriculture). Nanoparticles have a large surface-to-volume ratio, which can help them to penetrate cell membranes, and because of their solid ligand-binding capabilities, nanoparticles have been used in the medical treatment of inflammatory pathologies.


Rapidly growing mycobacteria: clinical and microbiologic studies of 115 cases.
We analyzed clinical and microbiologic features of 115 cases involving rapidly growing mycobacteria (RGM) isolated at the University of Texas M.D. Anderson Cancer Center, Houston (2000-2005) and identified by 16S ribosomal RNA gene sequencing analysis. At least 15 RGM species were included: Mycobacterium abscessus (43 strains [37.4%]), Mycobacterium fortuitum complex (33 strains [28.7%]), and Mycobacterium mucogenicum (28 strains [24.3%]) most common, accounting for 90.4%. Most M abscessus (32/43) were isolated from respiratory sources, whereas most M mucogenicum (24/28) were from blood cultures. Antimicrobial susceptibility tests showed that M abscessus was the most resistant species; M mucogenicum was most susceptible. From blood and catheter sources, 46 strains (40.0%) were isolated; 44 represented bacteremia or catheter-related infections. These infections typically manifested high fever (mean temperature, 38.9 degrees C), with a high number of RGM colonies cultured. All infections resolved with catheter removal and antibiotic therapy. Six strains (M abscessus and M fortuitum only) were from skin, soft tissue, and wound infections. There were 59 strains from respiratory sources, and 28 of these represented definitive to probable infections. Prior lung injuries and coisolation of other pathogenic organisms were common. Overall, 78 RGM strains (67.8%) caused true to probable infections without direct deaths.


Increase of Soluble Programmed Cell Death Ligand 1 in Patients with Chronic Hepatitis C.
Objectives: To determine whether the soluble programmed cell death ligand 1 (sPD-L1) levels in patients with chronic hepatitis C (CHC) are associated with the clinical features of the disease and the efficacy of treatment, including interferon (IFN)-α. Methods: We investigated the sPD-L1 levels in the sera of 80 genotype 1b Japanese patients with CHC who underwent 12 weeks of telaprevir (TVR)- or simeprevir (SMV)-based triple therapy followed by 12 weeks of dual therapy with pegylated IFN-α plus ribavirin. Serum was also obtained from 22 patients with chronic hepatitis B (CHB) and from 10 healthy donors (HC). The sPD-L1 levels were measured using an ELISA kit. In addition, we examined the PD-L1 expression on the cell surface of immortalized hepatocytes (HPT1) after incubation with cytokines, including IFN-γ. Results: The pretreatment serum sPD-L1 levels were significantly increased in patients with CHC (median 109.3 pg/ml, range 23.1-402.3) compared with patients with CHB (69.2 pg/ml, 15.5-144.8; P <0.001) and HC (100.3 pg/ml, 40.1-166.6; P = 0.039). No significant differences in the sustained virological response (SVR) rates were found between the TVR- (85.0%, n=40) and SMV-treated (80.0%, n=40) groups, and the pretreatment levels of serum sPD-L1 were not significantly different between patients who achieved SVR (105.0 pg/ml, 23.1-402.3) and non-SVR patients (133.5 pg/ml, 39.9-187.2; P = 0.391). The pretreatment level of sPD-L1 was positively correlated with the alanine aminotransferase and alpha-fetoprotein levels (R2 = 0.082, P = 0.016, and R2 = 0.149, P = 0.002, respectively). Although immortalized hepatocytes do not express PD-L1, we confirmed that PD-L1 expression was induced after stimulation with IFN-γ. Conclusions: In this study, we first found that sPD-L1 was increased in patients with CHC. Our results indicate that the level of serum sPD-L1 might be associated with the progression of CHC and the generation of hepatocellular carcinoma.


Blood kinins, their concentration in normal subjects and in patients with congenital deficiency in plasma prekallikrein and kininogen.
Kinins are potent vasodilator peptides that may participate in the regulation of local blood flow and blood pressure. Here we report a new method to measure kinins in blood. For this, 6 ml of blood are collected in less than 10 sec directly into 25 ml of ethanol. Kinins are further purified by extracting lipids with ether and by removing kininogen and other interfering substances by chromatography on QAE Sephadex and BioRex 70; then they are measured by a sensitive RIA. In 22 normal subjects, after correction for recovery (50%), the kinin concentration in peripheral venous blood was 25.2 +/- 2.6 pg/ml (mean +/- S.E.M.). To determine whether the circulating kinins are formed by plasma kallikrein or other kininogenases, the concentration of blood kinins was measured in the venous blood of three patients with congenital deficiency in plasma prekallikrein (Fletcher trait) and in one patient with congenital deficiency in the substrate of plasma kallikrein, high-molecular-weight kininogen (Fitzgerald trait). In the three subjects with Fletcher trait, blood kinins were 16, 21, and 31 pg/ml, whereas in the subject with Fitzgerald trait they were 26 pg/ml. Normal subjects had concentrations in the same range (9 to 55 pg/ml), indicating that the concentration of blood kinins in normal subjects is much lower than previously reported (70 to 5000 pg/ml). These results also suggest that kininogenases other than plasma kallikrein may generate circulating kinins.


Intraperitoneal cancer spread after laparoscopic cystectomy for mature teratoma with malignant transformation.
Laparoscopic surgery for ovarian dermoid cysts has been accepted. However, its potential limitations should be considered, including technique difficulty, intraoperative tumor spillage and malignant transformation. We report a case of ovarian dermoid cysts with malignant transformation that was initially treated using laparoscopic cystectomy, but was complicated by intraperitoneal tumor dissemination.


Alkyl chain length dependent hydrogelation of L-tryptophan-based amphiphile.
The search for low molecular weight hydrogelators (LMWHs) with varying structural motif is getting intense because of its potential application in biomedicines as well as the diversified area of nanobiotechnology. Hydrophobic interaction is one of the most crucial parameters in the design and development of such LMWHs. To this notion, a methodical investigation was carried out to find the influence of varying alkyl chain length of amphiphile on water gelation efficacy, which has been only marginally addressed in the literature to date. We have synthesized a series of low molecular weight L-tryptophan-based gelators, some of which are excellent gelator for plain water, an essential criterion for biological use. The alkyl chain induced hydrophobicity at the molecular level has remarkable influence in modulating water immobilization. Water gelation efficiency was improved more than 100 times on moving from 10 to 18 carbon atoms. The self-aggregation behavior of these thermoreversible hydrogelators investigated through different spectroscopic and microscopic techniques showed that an optimum balance between hydrophilicity and hydrophobicity is indeed essential, which can be largely regulated by varying the alkyl chain length. Thus, the study offers better understanding toward tailoring the properties of gel in plain water and thereby paving the way for potential applications.


Research-based practice: myth or reality? A review of the barriers affecting research utilisation in practice.
A research-practice gap still exists despite the promotion and strategies for research-based practice by governments and nursing organisations. Hunt (1981 Journal of Advanced Nursing 12:101-110) and Walsh and Ford (1989 Nursing rituals: research and rati onal action. Butterworth-Heinemann) report a wealth of anecdotal evidence to support the failure of nurses to use research in practice. A body of evidence confirms that the number of identified barriers to research utilisation is great. Drawing on the wo rk of Rogers (1983 Diffusion of innovations. The Free Press, New York) or the Barriers Scale (Funk et al. 1991a Applied Nursing Research 4(1):39-45), many authors (Dunn et al. 1997 Emergency Nurse 5(2):24-27; Walsh 1997a 1997b Nursing Standard 11(19):34- 37; 1997c Nursing Standard 11(29):34-39; Kajermo et al. 1998 Journal of Advanced Nursing 27(4):798-807; 2000 Journal of Advanced Nursing 31(1):99-109; Parahoo 2000 Journal of Advanced Nursing 31(1):89-98) have structured the barriers into sub-groups: the characteristics of the organisation, of the adopter, of the communication and of the research. Several studies reveal that the actual 'setting' poses the greatest barrier to the utilisation of research. Walsh (1997b) describes this as a paradox, in othe r words: practice is perceived as the biggest obstacle to change in practice. A systematic approach to research utilisation is outlined aimed at targeting these specific identified barriers, and third level institutes and practice settings are urged to c onsider strategic and focused approaches to the development of research plans.


[Multiparametric analysis of the effect of ethanol in various doses on EEG in rats].
Multiparametric EEG analysis (840 parameters) was performed for 24 points over the entire dorsal cerebral cortex in outbred rats intraperitoneally injected with ethanol in low (0.75 g/kg), medium (2.0 g/kg), and high subnarcotic (4.5 g/kg) doses. Acute intoxication with low ethanol doses led to an increase in the spectral power and coherence in the frequency band of the dominating theta-rhythm peak (5.75-7.25 Hz), which was indicative of activation of the septo-hippocampal system (with improvement of the related functions such as attention, memory, and exploratory activity). The coherence was also increased in several high-frequency bands of the EEG alpha- and beta-rhythm. Ethanol administered in medium and high doses produced a shift of the dominating theta-rhythm peak to lower frequencies (4.50-5.75 Hz), which was evidence of reduced activity of the septo-hippocampal system and the related CNS functions. These doses of ethanol significantly decreased the spectral power and coherence in most of the high-frequency bands of the EEG alpha- and beta-rhythm, which can be explained by reduced energy and synaptic activity of the cortex leading to impaired high brain functions and the development of somnolent and narcotic effects. Using special sets of reliably modified parameters and a special algorithm, it is possible to solve the inverse problem of identifying experiments (EEG fragments) corresponding to low, medium, and high doses of ethanol.


Cross-cultural adaptation and validation to Brazil of the scale of attitudes toward physician-pharmacists collaboration.
Despite the increasing complexity of medication therapies and the expansion of pharmaceutical clinical services to optimize patient care working in collaboration with physicians. In this sense, interdisciplinary education has been encouraged. However, no instrument is available to measure attitudes toward collaborative relationships. To translate, cross-cultural adaptation and validation an instrument to measure collaboration attitudes toward students of medicine/pharmacy and physicians/pharmacists. The process of cross-cultural adaptation was carried out using international recommendations and was performed from January 2014 to April 2015. The instrument under consideration was translated and re-translated. A panel of experts compared the generated documents and the translation was evaluated for 20 undergraduate students of Pharmacy, 20 undergraduate students of Medicine and professionals (20 pharmacists and 20 physicians). The process of cross-cultural translation and validation result in the Portuguese version. Modifications to the grammatical structures were made in order to establish a cross-cultural similarity between the English and Portuguese versions. Regarding the evaluation of the expert panel, six questions required modifications. Psychometric evaluation demonstrated and confirmed the validity of the Brazilian-Portuguese version to assess collaborative attitudes among pharmacists and physicians. Moreover, the scale can be used to evaluate undergraduates and postgraduates and foster the development of teaching methods that promote comprehensive attitudes in patient care.


Extreme ultraviolet spectroscopy of low-Z ion plasmas for fusion applications.
The study of impurities is a key component of magnetic fusion research as it is directly related to plasma properties and steady-state operation. Two of the most important low-Z impurities are carbon and oxygen. The appropriate method of diagnosing these ions in plasmas is extreme ultraviolet (EUV) spectroscopy. In this work the results of two different sets of experiments are considered, and the spectra in a spectral region from 40 to 300 A are analyzed. The first set of experiments was carried out at the Sustained Spheromak Physics Experiment at LLNL, where EUV spectra of oxygen ions were recorded. The second set of experiments was performed at the compact laser-plasma x-ray/EUV facility "Sparky" at UNR. In particular, Mylar and Teflon slabs were used as targets to produce carbon, oxygen, and fluorine ions of different ionization stages. Nonlocal thermodynamic equilibrium kinetic models of O, F, and C were applied to identify the most diagnostically important spectral features of low-Z ions between 40 to 300 A and to provide plasma parameters for both sets of experiments.


[Free thyroxine estimation for screening of hyper- and hypothyroidism in an adult population].
Serum free thyroxine (FT4) was determined in 1,114 adults (male 239, female 875) in a periodic health evaluation in 1980 to detect unsuspected thyroid dysfunction, especially hyper- and hypothyroidism. The participants were dwelling in two towns of Miyagi prefecture. Beside FT4, serum T4 and T3 were also determined by radioimmunoassay. If thyroid dysfunction was suspected, further detailed examinations such as TRH-test (500 micrograms i.v.), radioimmunologic determinations of serum TSH and TBG, resin-sponge T3-uptake, 24-hr thyroid radioiodine 131I-uptake, radioiodine thyroid scan and anti-thyroid antibodies were performed. There were 3 patients with hyperthyroidism (0.27%), 4 with hypothyroidism (0.36%), 3 taking thyroid medication (2; Hashimoto's disease, 1; goiter), 3 on estrogen administration, 4 with Hashimoto's disease and 1 with goiter. Excluding these 18 patients, FT4, T4 and T3 values in 1,096 euthyroid subjects, 236 males and 860 females, were 1.1 +/- 0.3 (mean +/- S.D.), 1.1 +/- 0.3 and 1.0 +/- 0.3 ng/100 ml, 8.9 +/- 1.5, 8.8 +/- 1.6 and 9.0 +/- 1.5 micrograms/100 ml, and 122 +/- 33, 125 +/- 26 and 122 +/- 35 ng/100 ml, respectively. Serum FT4, T4 and T3 showed the distribution of logarithmic normal probability. The 95% normal range for free T4 was 0.60 to 1.80 ng/100 ml, total T4 6.0 to 11.8 micrograms/100 ml, and T3 84 to 176 ng/100 ml, respectively. Out of 1,114 subjects examined, the cases to be reexamined for the higher serum concentration than normal were 26 in FT4, 35 in T4 and 27 in T3, respectively. And the cases for lower values were 28 in FT4, 31 in T4 and 24 in T3, respectively. Serum FT4 values in the subjects during the administration of estrogens were within the normal range. FT4 and T4 were low in four patients with hypothyroidism, but two of them showed normal T3 values. Determinations of serum FT4, total T4 and total T3 were all useful for the screening of hyperthyroidism. But serum FT4 was the most reliable of the three. Determination of either serum FT4 or total T4 was suitable for the screening of hypothyroidism, but serum total T3 measurement did not cover all patients with hypothyroidism.


Medical Students Are Not Essential Workers: Examining Institutional Responsibility During the COVID-19 Pandemic.
In light of the evolving COVID-19 pandemic, the Association of American Medical Colleges (AAMC) and Liaison Committee on Medical Education (LCME) released a joint statement in March 2020 recommending an immediate suspension of medical student participation in direct patient contact. As graduating medical students who will soon begin residency, the authors fully support this recommendation. Though paid health care workers, like residents, nurses, and environmental services staff, are essential to the management of COVID-19 patients, medical students are not. Students' continued involvement in direct patient care will contribute to SARS-CoV-2 exposures and transmissions and will waste already limited personal protective equipment. By decreasing nonessential personnel in health care settings, including medical students, medical schools will contribute to national and global efforts to "flatten the curve."The authors also assert that medical schools are responsible for ensuring medical student safety. Without the protections provided to paid health care workers, students are uniquely disadvantaged within the medical hierarchy; these inequalities must be addressed before medical students are safely reintegrated into clinical roles. Although graduating medical students and institutional leadership may worry that suspending clinical rotations might prevent students from completing graduation requirements, the authors argue the ethical obligation to "flatten the curve" supersedes usual teaching responsibilities. Therefore, the authors request further guidance from the LCME and AAMC regarding curricular exemptions/alternatives and adjusted graduation timelines. The pool of graduating medical students affected by this pause in direct patient contact represents a powerful reserve, which may soon need to be used as the COVID-19 pandemic continues to challenge the U.S. health care infrastructure.


Frozen Section Timeout: Pilot Study to Reconcile Margins Using 3D Resected Specimen and Defect Scans.
Opportunities exist to improve intraoperative communication and documentation of resection margin details. We instituted a "frozen section timeout" that centers around visualization of the paired resection specimen and surgical defect-facilitating effective, bidirectional exchange of information. We designed an interactive form for use during the "frozen section timeout" including annotated 3D virtual models of the resected specimen and surgical defect, plus a "line-item" table for primary and supplemental margin results. The "timeout" was conducted over a Zoom call between the operating room and frozen section laboratory. The form was simultaneously projected and discussed while all members of the surgical care team stopped activities. Nurses, co-surgeons, and all other members of the surgical team were encouraged to take part in this process. Twenty-six frozen section timeouts were conducted during head and neck surgeries in the Department of Otolaryngology at Mount Sinai West Hospital. These timeouts were facilitated by the lead surgeon, and all other activities were halted to ensure that critical information was shared, documented, and agreed upon. During the timeout, the annotated specimen and defect scans were displayed, clearly demonstrating the at-risk margins and the corresponding location and breadth of supplemental margins harvested. Incorporating a frozen section timeout can improve intraoperative communication, increase transparency, and potentially eliminate uncertainty regarding margin status and tumor clearance. Visualization of at-risk margins and the corresponding location and breadth of supplemental margins promises an unprecedented level of documentation and understanding. This novel technique can establish a new and improved standard of care. N/A Laryngoscope, 2023.


Legal aspects of child abuse: guidelines for the nurse.
Legislation provides certain mandates for the identification and treatment of child abuse and neglect. State intervention on behalf of the child occurs at the onset of suspected abuse or neglect. Court involvement may be necessary to ensure the protection of children through court-ordered provision of services to families. The implementation of legal mandates requires a multidisciplinary effort, so that nurses who work with children and families need to know the child abuse legislation of the state in which they practice. Because of their professional skills, nurses are in a vital position to identify and assist vulnerable children and families. Through effective reporting, record-keeping, and an understanding of the uses and benefits of court intervention, nurses can effect a positive impact upon the legal system in behalf of abused children and their families.


Short stature caused by a natural growth hormone antagonist.
Severe short stature in a male child due to a single mutation in the GH-1 gene was first reported in 1996 by Takahashi et al. [N Engl J Med 1996;334:432-436]. This missense mutation was predicted to convert codon 77 from arginine (R) to cysteine (C). The child's chronological age was 4 years and 11 months, and his bone age 2 years and 6 months, i.e., equal to only 51% of his chronological age. Body proportions were normal except for the prominent forehead and saddle nose. Pituitary size was normal on magnetic resonance imaging examinations. Serum IGF-1, IGFBP-3 and GHBP were all decreased or at the lower limit of the normal range. Nocturnal urinary growth hormone (GH) excretion was high. Isoelectric focusing analysis revealed the presence of an abnormal GH peak in addition to the normal one. The R77C mutant GH possessed a 6 times greater affinity to GHBP than the wild-type GH, and inhibited tyrosine phosphorylation in IM-9 cells 10 times more potently than the wild-type GH, showing an antagonistic or a dominant negative action. In agreement with the antagonistic property of the mutant GH exhibited, the child did not show any increase in serum IGF-1 levels after exogenous hGH administration. It should be noted that the child in this study is not a typical case of Kowarski syndrome in which endogenous GH is found to be simply bioinactive, as in the patient we recently described elsewhere. Therefore, this patient's condition should be categorized as a new syndrome of short stature caused by a natural GH antagonist.


Aberrant activation of CDK5 is involved in the pathogenesis of OPIDN.
Exposure to triorthocresyl phosphate (TOCP) may result in a late neurological complication, i.e. organophosphate-induced delayed neuropathy (OPIDN). The aim of this study was to examine changes in levels of cyclin-dependent kinase 5 (CDK5) and of its activator, p35/p25, in the spinal cord of hens treated by TOCP. After exposure to a single dose of TOCP, groups of adult hens were examined in 3, 5, 7, 9, 14, and 18 days after exposure. CDK5, p35/p25 expression and distribution in the lumbar spinal cord were evaluated by immunohistochemistry and Western blotting. The hens showed signs of OPIDN around day 9 after exposure. The number of p (phosphorylated) -CDK5 and p35 positive cells increased significantly. Co-localization and mislocalization of p-CDK5 and p35/p25 was identified and became evident in neurons around the 9th day. Meanwhile, CDK5, p-CDK5, p35, p25 protein levels and p25/p35 ratio were increased, and peaked around the 9th day, then decreased. Some hens' unilateral common peroneal was treated by roscovitine 3 days after TOCP exposure. Axonal transport of these nerves was faster than of their opposite side and of those simply treated by TOCP. These findings indicate aberrant activation of CDK5 may be involved in the pathogenesis of OPIDN.


How Hemodialysis Patients Perceive the SARS-CoV-2 Health Crisis: Lessons from Austria.
The ongoing SARS-CoV-2 pandemic forced many countries to implement strict and unprecedented precautions to stop the spread of the virus. On top of these measures, hemodialysis units have adopted their own rules to protect wards and patients from infection with SARS-CoV-2. Despite the rapidly growing knowledge on epidemiology, virology, and clinical disease, little is known about how these measures are perceived by patients themselves on hemodialysis. The study was performed in the three hemodialysis units in Vorarlberg, Austria's westernmost state. A questionnaire was developed consisting of 22 questions on patients' perceptions of the COVID-19 crisis and their feelings about the general precautions and specific steps implemented on dialysis wards. All adult patients were asked to fill out the questionnaire anonymously. Of 202 patients on hemodialysis, 148 completed the questionnaire (66.9% men, mean age 68.3±13.3 years). The vast majority (83.1%) were worried by the COVID-19 crisis, but only 28.4% reported a negative effect on emotional well-being. Daily life was most affected by the general ban on visitors (58.6%) and home confinement (35.9%). Of the patients, 64.2% feared contracting COVID-19, 30.7% were afraid of financial consequences, and 14.6% were afraid of loneliness and isolation. The safety measures on dialysis wards were classified as adequate by 97.3% of the respondents. Of the patients, 78.2% felt safe during dialysis treatment. All dialysis-specific precautions (individual patient transport, health check, hand disinfection, wearing a face mask, and physical distancing) were rated important or very important by almost all patients. To date, none of the patients have acquired SARS-CoV-2 infection. Although the SARS-CoV-2 crisis brought worry to and affected the lives of most patients on hemodialysis, its effect on their emotional well-being was moderate. Patients felt safe on dialysis wards, and acceptance of specific precautions was high.


A meta-analysis of the experimental evidence on the near- and far-transfer effects among children's executive function skills.
In the present meta-analysis we examined the near- and far-transfer effects of training components of children's executive functions skills: working memory, inhibitory control, and cognitive flexibility. We found a significant near-transfer effect (g+ = 0.44, k = 43, p < .001) showing that the interventions in the primary studies were successful in training the targeted components. However, we found no convincing evidence of far-transfer (g+ = 0.11, k = 17, p = .11). That is, training a component did not have a significant effect on the untrained components. By showing the absence of benefits that generalize beyond the trained components, we question the practical relevance of training specific executive function skills in isolation. Furthermore, the present results might explain the absence of far-transfer effects of working memory training on academic skills (Melby-Lervag & Hulme, 2013; Sala & Gobet, 2017). (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Improved Prediction of Drug-Target Interactions Using Self-Paced Learning with Collaborative Matrix Factorization.
Identifying drug-target interactions (DTIs) plays an important role in the field of drug discovery, drug side-effects, and drug repositioning. However, in vivo or biochemical experimental methods for identifying new DTIs are extremely expensive and time-consuming. Recently, in silico or various computational methods have been developed for DTI prediction, such as ligand-based approaches and docking approaches, but these traditional computational methods have several limitations. This work utilizes the chemogenomic-based approaches for efficiently identifying potential DTI candidates, namely, self-paced learning with collaborative matrix factorization based on weighted low-rank approximation (SPLCMF) for DTI prediction, which integrates multiple networks related to drugs and targets into regularized least-squares and focuses on learning a low-dimensional vector representation of features. The SPLCMF framework can select samples from easy to complex into training by using soft weighting, which is inclined to more faithfully reflect the latent importance of samples in training. Experimental results on synthetic data and five benchmark data sets show that our proposed SPLCMF outperforms other existing state-of-the-art approaches. These results indicate that our proposed SPLCMF can provide a useful tool to predict unknown DTIs, which may provide new insights into drug discovery, drug side-effect prediction, and repositioning existing drug.


Identification of StiR, the first regulator of secondary metabolite formation in the myxobacterium Cystobacter fuscus Cb f17.1.
Myxobacteria are well established as proficient producers of natural products with numerous biological activities. Although some knowledge has been gained regarding the biosynthesis of secondary metabolites in this class of bacteria, almost nothing is known about the underlying regulatory mechanisms. In order to identify regulatory elements, we submitted the argyrin and stigmatellin producer Cystobacter fuscus to a random transposon mutagenesis strategy and screened 1,000 mutants for the occurrence of strains showing remarkably increased or decreased production of these compounds. In addition to the identification of the stigmatellin biosynthetic gene cluster, a novel positive regulator (stiR) of stigmatellin production was identified after transposon recovery. In order to exclude secondary mutagenesis effects, a double cross-over mutagenesis strategy was applied to the strain resulting in the repeated generation of the transposon genotype. This strain was shown to be equally effected in natural product biosynthesis.


Perioperative Risk Assessment in Patients Aged 75 Years or Older: Comparison between Bilateral and Unilateral Total Knee Arthroplasty.
The purpose of this study is to evaluate the risk of sequential bilateral total knee arthroplasty (TKA) under 1 anesthesia in patients 75 years or older. Patients aged 75 years or older who underwent sequential bilateral TKA (bilateral group, n=159) and unilateral TKA (unilateral group, n=159) between 2002 and 2012 were selected. All patients were evaluated for underlying medical diseases, such as cardiac, pulmonary, and renal problems, and high-risk patients were recommended to postpone the surgery. We compared the underlying diseases, major postoperative complications, and the length of hospital stay between bilateral and unilateral groups. The prevalence of underlying diseases of the bilateral group was 74.8% and major complications occurred in 6 patients (3.8%). The prevalence of underlying diseases of the unilateral group was 52.4% and complications were observed in 4 patients (2.4%). Although the complication rate of the bilateral group was slightly higher than that of the unilateral group, the difference was not statistically meaningful (p=0.204). The length of hospital stay was 21.9 days for the bilateral group and 24.9 days for the unilateral group. There was no significant difference in postoperative complications between groups. The result shows that bilateral TKA can be relatively safe compared with unilateral TKA in patients 75 years or older. However, careful selection of low-risk patients is advised.


Arsenic removal from groundwater by household sand filters: comparative field study, model calculations, and health benefits.
Arsenic removal efficiencies of 43 household sand filters were studied in rural areas of the Red River Delta in Vietnam. Simultaneously, raw groundwater from the same households and additional 31 tubewells was sampled to investigate arsenic coprecipitation with hydrous ferric iron from solution, i.e., without contact to sand surfaces. From the groundwaters containing 10-382 microg/L As, < 0.1-48 mg/L Fe, < 0.01-3.7 mg/L P, and 0.05-3.3 mg/L Mn, similar average removal rates of 80% and 76% were found for the sand filter and coprecipitation experiments, respectively. The filtering process requires only a few minutes. Removal efficiencies of Fe, phosphate, and Mn were > 99%, 90%, and 71%, respectively. The concentration of dissolved iron in groundwater was the decisive factor for the removal of arsenic. Residual arsenic levels below 50 microg/L were achieved by 90% of the studied sand filters, and 40% were even below 10 microg/L. Fe/As ratios of > or = 50 or > or = 250 were required to ensure arsenic removal to levels below 50 or 10 microg/L, respectively. Phosphate concentrations > 2.5 mg P/L slightly hampered the sand filter and coprecipitation efficiencies. Interestingly, the overall arsenic elimination was higher than predicted from model calculations based on sorption constants determined from coprecipitation experiments with artificial groundwater. This observation is assumed to result from As(lll) oxidation involving Mn, microorganisms, and possibly dissolved organic matter present in the natural groundwaters. Clear evidence of lowered arsenic burden for people consuming sand-filtered water is demonstrated from hair analyses. The investigated sand filters proved to operate fast and robust for a broad range of groundwater composition and are thus also a viable option for mitigation in other arsenic affected regions. An estimation conducted for Bangladesh indicates that a median residual level of 25 microg/L arsenic could be reached in 84% of the polluted groundwater. The easily observable removal of iron from the pumped water makes the effect of a sand filter immediately recognizable even to people who are not aware of the arsenic problem.


Voltage dependent activation of tonic contraction in cardiac myocytes.
Contractions of isolated single myocytes of guinea pig heart stimulated by rectangular depolarizing pulses consist of a phasic component and a voltage dependent tonic component. In this study we analyzed the mechanism of activation of the graded, sustained contractions elicited by slow ramp depolarization and their relation to the components of contractions elicited by rectangular depolarizing pulses. Experiments were performed at 37 degrees C in ventricular myocytes of guinea pig heart. Voltage-clamped myocytes were stimulated by the pulses from the holding potential of -40 to +5 mV or by ramp depolarization shifting voltage within this range within 6 s. [Ca2+]i was monitored as fluorescence of Indo 1-AM and contractions were recorded with the TV edge-tracking system. Myocytes responded to the ramp depolarization between -25 and -6 mV by the slow, sustained increase in [Ca2+]i and shortening, the maximal amplitude of which was in each cell similar to that of the tonic component of Ca2+ transient and contraction. The contractile responses to ramp depolarization were blocked by 200 microM ryanodine and Ca2+-free solution, but were not blocked by 20 microM nifedipine or 100-200 microM Cd2+ and potentiated by 5 mM Ni2+. The responses to ramp depolarization were with this respect similar to the tonic but not to the phasic component of contraction: both components were blocked by 200 microM ryanodine, and were not blocked by Cd2+ or Ni2+ despite complete inhibition of the phasic Ca2+ current. However, the phasic component but not the tonic component of contraction in cells superfused with Ni2+ was inhibited by nifedipine. Both components of contraction were inhibited by Ca2+-free solution superfused 15 s prior to stimulation. In myocytes of guinea pig heart the contractile response to ramp depolarization is equivalent to the tonic component of contraction. It is activated by Ca2+ released from the sarcoplasmic reticulum by the ryanodine receptors. Their activation and inactivation is voltage dependent and it does not depend on the Ca2+ influx by the Ca2+ channels or reverse mode Na+/Ca2+ exchange, however, it may depend on Ca2+ influx by some other, not yet defined route.


Identification of Listeria monocytogenes determinants required for biofilm formation.
Listeria monocytogenes is a Gram-positive, food-borne pathogen of humans and animals. L. monocytogenes is considered to be a potential public health risk by the U.S. Food and Drug Administration (FDA), as this bacterium can easily contaminate ready-to-eat (RTE) foods and cause an invasive, life-threatening disease (listeriosis). Bacteria can adhere and grow on multiple surfaces and persist within biofilms in food processing plants, providing resistance to sanitizers and other antimicrobial agents. While whole genome sequencing has led to the identification of biofilm synthesis gene clusters in many bacterial species, bioinformatics has not identified the biofilm synthesis genes within the L. monocytogenes genome. To identify genes necessary for L. monocytogenes biofilm formation, we performed a transposon mutagenesis library screen using a recently constructed Himar1 mariner transposon. Approximately 10,000 transposon mutants within L. monocytogenes strain 10403S were screened for biofilm formation in 96-well polyvinyl chloride (PVC) microtiter plates with 70 Himar1 insertion mutants identified that produced significantly less biofilms. DNA sequencing of the transposon insertion sites within the isolated mutants revealed transposon insertions within 38 distinct genetic loci. The identification of mutants bearing insertions within several flagellar motility genes previously known to be required for the initial stages of biofilm formation validated the ability of the mutagenesis screen to identify L. monocytogenes biofilm-defective mutants. Two newly identified genetic loci, dltABCD and phoPR, were selected for deletion analysis and both ΔdltABCD and ΔphoPR bacterial strains displayed biofilm formation defects in the PVC microtiter plate assay, confirming these loci contribute to biofilm formation by L. monocytogenes.


A comparison of health-related quality of life and personal, social, and environmental factors of older adults according to a residential area: a propensity score matching analysis.
This study identified individual, social, and environmental factors affecting the health-related quality of life (HRQoL) of older individuals living in urban and non-urban areas of the Republic of Korea and investigated their effects on HRQoL. A secondary data analysis study was conducted using raw data from Korea's 2017 Community Health Survey. Propensity score matching (PSM) was performed to compare the individual, social, and environmental characteristics of older individuals living in urban and non-urban areas (16,695 and 29,106 individuals, respectively). Statistical analyses were performed using R program 4.0.5. The differences between variables were analyzed using chi-squared and t-tests, whereas factors influencing HRQoL were analyzed using multiple regression analysis. Among the individual factors, the living arrangement (p = 0.001, confidence interval [CI] = 0.00-0.02) was an influencing factor in urban areas, whereas it showed no statistical significance in non-urban areas. Moreover, Helping their neighbors (p = 0.001, CI = 0.00-0.01) among the social factors and satisfaction with the living environment (p = 0.011, CI = 0.00-0.02) and with healthcare services (p = 0.047, CI = 0.00-0.01) among the environmental factors were influencing factors in urban areas, whereas they showed no statistical significance in non-urban areas. Satisfaction with the living environment and with healthcare services was positively associated with HRQoL among older individuals living in urban areas. Therefore, factors associated with regional health inequality should be identified, and health equality sought through the development of local government policies that consider diversity in population composition and health indicators by region.


A prospective study of electrocardiographic features in adult black hypertensive patients at the Kenyatta National Hospital, Nairobi.
A prospective study of electrocardiograms (ECG's) was carried out on 102 adult hypertensive African patients at the Kenyatta National Hospital. Their mean age was 45.2 years. All the patients had normal sinus rhythm. Forty seven percent of the patients had sinus bradycardia, although this could be attributable to the drugs they were taking. The duration of the P wave increased with the severity of hypertension. Twenty five percent of the patients had evidence of first degree A-V block. This was an expected finding as most of the patients were on treatment with B-adrenoreceptor blocking agents. Two patients had LBBB and none had RBBB. There were 13 patients with evidence of left axis deviation (LAD) and the incidence increased with the severity of hypertension. S-T, T changes were noted in 12.8% and 29% of patients respectively. Q-Tc duration did not increase with severity of hypertension. Left ventricular hypertrophy was noted in 27.5% of the patients using the criteria devised by Romhilt et al.


Temperament factors and dimensional, latent bifactor models of child psychopathology: Transdiagnostic and specific associations in two youth samples.
Common emotional and behavioral symptoms co-occur and are associated with core temperament factors. This study investigated links between temperament and dimensional, latent psychopathology factors, including a general common psychopathology factor (p factor) and specific latent internalizing and externalizing liabilities, as captured by a bifactor model, in two independent samples of youth. Specifically, we tested the hypothesis that temperament factors of negative affectivity (NA), positive affectivity (PA), and effortful control (EC) could serve as both transdiagnostic and specific risks in relation to recent bifactor models of child psychopathology. Sample 1 included 571 youth (average age 13.6, SD =2.37, range 9.3-17.5) with both youth and parent report. Sample 2 included 554 preadolescent children (average age 7.7, SD =1.35, range =5-11 years) with parent report. Structural equation modeling showed that the latent bifactor models fit in both samples. Replicated in both samples, the p factor was associated with lower EC and higher NA (transdiagnostic risks). Several specific risks replicated in both samples after controlling for co-occurring symptoms via the p factor: internalizing was associated with higher NA and lower PA, lower EC related to externalizing problems.


Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis.
Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine interleukin-8 (IL-8) is overexpressed in HCC and is a potential target for therapy. Although the transcription factor NF-κB regulates IL-8 expression, and while thymoquinone (TQ; the most bioactive constituent of black seed oil) inhibits NF-κB activity, the precise mechanisms by which TQ regulates IL-8 and cancer cell growth remain to be clarified. Here, we report that TQ inhibited growth of HCC cells in a dose- and time-dependent manner, caused G2M cell cycle arrest, and stimulated apoptosis. Apoptosis was substantiated by activation of caspase-3 and -9, as well as cleavage of poly(ADP-ribose)polymerase. TQ treatments inhibited expression of NF-κB and suppressed IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS) and mRNAs of oxidative stress-related genes, NQO1 and HO-1. Pretreatment of HepG2 cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-induced cell death. TQ treatment stimulated mRNA expression of pro-apoptotic Bcl-xS and TRAIL death receptors, and inhibited expression of the anti-apoptotic gene Bcl-2. TQ enhanced TRAIL-induced death of HepG2 cells, in part by up-regulating TRAIL death receptors, inhibiting NF-κB and IL-8 and stimulating apoptosis. Altogether, these findings provide insights into the pleiotropic molecular mechanisms of TQ-dependent suppression of HCC cell growth and underscore potential of this compound as anti-HCC drug.


The after breakfast 50-g, 1-hour glucose challenge test in urban Mexican pregnant women: its sensitivity and specificity evaluated by three diagnostic criteria for gestational diabetes mellitus.
To study the sensitivity and specificity of the 50-g, 1-hour gestational glucose challenge test performed 1 to 2 hours after a non-standardized home breakfast in urban Mexican women by using three different gestational diabetes mellitus diagnostic criteria. Four hundred and forty-five consecutive women of 24-28 weeks gestation were studied. The glucose challenge test was performed in the fed state and a week later a fasting 100-g, 3-hours oral glucose tolerance test was carried out in all of them. Duplicate serum glucose concentrations were determined by a glucose-oxidase method. Sensitivity and specificity were calculated using three different diagnostic criteria for gestational diabetes mellitus. The glucose challenge test performed as indicated, with a cutoff of 7.8 mmol/L, had 88-89% sensitivity and 85-87% specificity when using as diagnostic criteria those proposed by the National Diabetes Data Group and by Carpenter & Coustan; by using Sacks et al. criteria, the values were 82% and 88%, respectively. Considering only pregnant women > or = 25 years of age, the sensitivity increased to 92% with the National Diabetes Data Group criteria. Pregnant women < 25 years of age had significantly lower blood glucose values than those with age > or = 25 years during the glucose tolerance test. For the general group the sensitivity of the glucose challenge test performed 1 to 2 hours after breakfast was similar, based on the National Diabetes Data Group and the Carpenter & Coustan's diagnostic criteria for gestational diabetes mellitus. However, when pregnant women > or = 25 years of age were considered, the use of the former criteria yielded a slightly better sensitivity.


Mouse mammary epithelial cells express the Na-K-Cl cotransporter, NKCC1: characterization, localization, and involvement in ductal development and morphogenesis.
Despite the fact that physiological evidence points to the existence of a functional Na-K-Cl cotransporter in the mammary gland, the molecular identity of this transport process remains unknown. We now show that the Na-K-Cl cotransporter isoform, NKCC1, is expressed in mammary tissue. Developmental profiling revealed that the level of NKCC1 protein was significantly influenced by the stage of mammary gland development, and immunolocalization studies demonstrated that NKCC1 was present on the basolateral membrane of mammary epithelial cells. To examine whether functional NKCC1 is required for mammary epithelial cell development, we used NKCC1 -/- mice. We demonstrate that NKCC1 -/- mammary epithelium exhibited a significant delay in ductal outgrowth and an increase in branching morphogenesis during virgin development. These effects were autonomous to the epithelium as assessed by mammary gland transplantation. Although the absence of NKCC1 had no apparent effect on gross mammary epithelial cell morphology during lactation, pups born to NKCC1 -/- mice failed to thrive. Finally, analysis of NKCC1 protein in mouse models that exhibit defects in mammary gland development demonstrate that high levels of NKCC1 protein are indicative of ductal epithelial cells, and the presence of NKCC1 protein is characteristic of mammary epithelial cell identity.


[Automatic analyzing systems for blood chemistry and urinalysis].
We constructed two new automatic analyzing systems for blood chemistry and urinalysis. The blood chemistry system consists of centrifuge station, on-line allotting station, belt line, Hitachi 736 -60, -40, off-line allotting station, storage allotting station and sample stocker, these are connected with belt line. If only specimens are set and switched on, analytical process from serum separation to measurement is advanced automatically, and then printed out the analytical results, it is the highest speed of 1.8 test/sec, in the world. Urinalysis system consists of qualitative analyzing station, quantitative analyzing station and urinary sediment analyzer, two station are logically coupled with belt line. It is a unique system of urinalysis that qualitative and quantitative analysis of urine is logically done by computerizing program.


[Organization and evolution of the subtelomeric regions of the rye chromosomes].
Subtelomeric regions of chromosomes are particularly dynamic and variable parts in the evolution of the eukaryotic genomes. A specific feature of the rye (Secale) chromosomes is large heterochromatin blocks at the arms of all seven pairs of chromosomes. Within the genus Secale, an interspecific variation in the genome size reaches nearly 15% between Secale cereale (cultivated rye) and the ancient species S. silvestre and an increase in the size of subtelomeric heterochromatin regions is the main contributor to these differences. Earlier works have demonstrated that the subtelomeric hetechromatin of rye is enriched for a few multicopy tandemly organized DNA families which form the long arrays of monomers. Here we aimed to clarify the fine large-scale organization and mutual arrangement within the tandem arrays of these families and the flanking genomic nonarray DNA. Restriction analysis of the BAC-clones containing genetic material of the short arm of the first rye chromosome (1RS) showed that within arrays the bulk of monomers is organized in the specific higher-order repeat units (up to hexamers) which are generated in the central part of tandem arrays, while only monomers and dimers are present near the boundaries. Sequencing of the genomic nonarray DNA flanking the tandem arrays has demonstrated that this DNA in the studied BAC-clones consists completely of retrotransposons of various classes which are also present in the wheat and barley genomes. Thus, only an explosive amplificcation ofpSc200 and pSc250 monomers, on the background of a saturated mixture of various retrotransposons, can be regarded as a specific molecular process in formation of subtelomeric hetechromatin during the divergence of rye genome from the common ancestor of cereals. Evidently, this process resulted in the enlargement of subtelomeric hetechromatin of S. cereale and an increasing of its genome size.


[Intracranial dermoid cyst (clinico-pathologic description of a case)].
The authors describe the case of a female patient aged 49 years who received neurological treatment for various complaints over a period of 19 years. The disorder defied exact diagnosis despite the application of all neurological and other diagnostic techniques. Suspicions ranged from somnolence accompanied by cephalalgia, through demyelination, expansive processes in the region of the cerebellum or the diencephalon, encephalitis or tuber- cubma of the brain stem to multiple sclerosis. The autopsy revealed a dermoidal cyst that exerted a slight pressure on the extension of the medulla. This explained all of the patient's complaints. The occurrence of such cysts is discussed on the basis of data taken from the literature.


Sickle cell disease pathophysiology.
The primary pathophysiological event in the erythrocytes of individuals with the various sickle syndromes is the intracellular aggregation or polymerization of sickle haemoglobin (HbS). The extent of polymerization is determined by the intracellular haemoglobin composition (% HbS and % HbS A, A2 and F), concentration (MCHC and % of dense cells) and oxygen saturation, as well as minor factors such as intracellular pH and DPG concentration. Intracellular HbS polymerization leads to a marked decrease in the flexibility or rheological properties of the sickle erythrocytes and obstruction in various microcirculatory beds, as well as chronic anaemia. Other abnormalities in the properties of the sickle erythrocytes, including membrane abnormalities, changes in ion fluxes and volume and endothelial adhesion, result from acute and chronic oxygen-linked polymerization events and may, in turn, modify polymerization. However, within a good approximation, many aspects of sickle cell disease pathophysiology--for example variations in anaemia among the different sickle syndromes--can be explained in terms of differences in polymerization tendency. Thus, the effects of alpha-thalassaemia can be explained with reference to changes in MCHC and syndromes with high HbF are understandable in terms of the sparing effect of HbF on polymerization. Recent therapeutic approaches to sickle cell disease focus on attempts to reduce intracellular HbS polymerization by altering the haemoglobin molecules, erythrocyte properties, or the distribution of intracellular haemoglobin species. The last, through pharmacological elevation of HbF, has become the central focus of much laboratory and clinical research in recent years. Agents such as hydroxyurea (with or without recombinant erythropoietin) and butyrate compounds elevate HbF (and reduce HbS) in a majority of sickle erythrocytes, thus decreasing intracellular polymerization. Current prospective protocols are designed to see if these changes cause clinical improvement at acceptable doses. Other treatment strategies, including bone marrow transplantation and possible gene replacement therapies, are also under active clinical or laboratory investigation.


SPHK1-S1PR1-RANKL Axis Regulates the Interactions Between Macrophages and BMSCs in Inflammatory Bone Loss.
Accumulating evidence indicates that the immune and skeletal systems interact with each other through various regulators during the osteoclastogenic process. Among these regulators, the bioactive lipid sphingosine-1-phosphate (S1P), which is synthesized by sphingosine kinase 1/2 (SPHK1/2), has recently been recognized to play a role in immunity and bone remodeling through its receptor sphingosine-1-phosphate receptor 1 (S1PR1). However, little is known regarding the potential role of S1PR1 signaling in inflammatory bone loss. We observed that SPHK1 and S1PR1 were upregulated in human apical periodontitis, accompanied by macrophage infiltration and enhanced expression of receptor activator of NF-κB ligand (RANKL, an indispensable factor in osteoclastogenesis and bone resorption) and increased numbers of S1PR1-RANKL double-positive cells in lesion tissues. Using an in vitro co-culture model of macrophages and bone marrow stromal cells (BMSCs), it was revealed that in the presence of lipopolysaccharide (LPS) stimulation, macrophages could significantly induce SPHK1 activity, which resulted in activated S1PR1 in BMSCs. The activated S1P-S1PR1 signaling was responsible for the increased RANKL production in BMSCs, as S1PR1-blockage abolished this effect. Applying a potent S1P-S1PR1 signaling modulator, Fingolimod (FTY720), in a Wistar rat apical periodontitis model effectively prevented bone lesions in vivo via downregulation of RANKL production, osteoclastogenesis, and bone resorption. Our data unveiled the regulatory role of SPHK1-S1PR1-RANKL axis in inflammatory bone lesions and proposed a potential therapeutic intervention by targeting this cell-signaling pathway to prevent bone loss. © 2018 American Society for Bone and Mineral Research.


The use of critical care echocardiography in peri-arrest and cardiac arrest scenarios: Pros, cons and what the future holds.
Echocardiography is being increasingly deployed as a diagnostic and monitoring tool in the critically ill. This rise in popularity has led to its recommendation as a core competence in intensive care, with several training routes available. In the peri-arrest and cardiac arrest population, point of care focused echocardiography has the potential to transform patient care and improve outcomes. Be it via diagnosis of shock aetiology and reversibility or assessing response to treatment and prognostication. This narrative review discusses current and future applications of echocardiography in this patient group and provides a structure with which one can approach such patients.


Essential benefits of nucleoside analogue regimens in failing therapy.
Since the introduction of highly active antiretroviral therapy, nucleoside and more recently nucleotide reverse transcriptase inhibitors (NRTIs) have provided a highly effective backbone to antiretroviral regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Nonetheless, treatment failure can result from poor adherence, unfavourable pharmacokinetics, advanced disease or infection with a drug-resistant virus. Recent data have also indicated a high risk of virological failure with triple NRTI regimens, reflecting overall lower potency compared to combinations of NRTIs with either NNRTIs or PIs. Resistance mutations emerging upon failure can cause extensive cross-resistance among available NRTIs, and potentially affect susceptibility to newly developed antiretroviral drugs. However, despite the emergence of resistance, NRTIs can retain significant antiviral activity in treatment-experienced patients. This may reflect residual direct viral load suppression, as well as indirect effects related to impaired viral fitness of NRTI-resistant mutants and antagonist interactions between resistance mutations.


Moulded by humans: The domestication of blue-veined cheese fungi.
It is hard to imagine a world without food-associated microbes. The production of bread, wine, beer, salami, coffee, chocolate, cheese and many other foods and beverages all rely on specific microbes. In cheese, myriad microbial species collaborate to yield the complex organoleptic properties that are appreciated by millions of people worldwide. In the early days of cheese making, these complex communities emerged spontaneously from the natural flora associated with the raw materials, the equipment, the production environment or craftsmen involved in the production process. However, in some cases, the microbes shifted their natural habitat to the new cheese-associated environment. The most obvious cause of this is backslopping, where part of a fermented product is used to inoculate the next batch. In addition, some microbes may simply adhere to the tools used in the production process. These microbial communities gradually adapted to the novel man-made niches, a process referred to as "domestication." Domestication is associated with specific genomic and phenotypic changes and ultimately leads to lineages that are genetically and phenotypically distinct from their wild ancestors. In this issue of Molecular Ecology, Dumas et al. have investigated a prime example of cheese-associated microbes, the fungus Penicillium roqueforti. The authors identified several hallmarks of domestication in the genome and phenome of this species, allowing them to hypothesize about the origin of blue-veined cheese fungi domestication, and the specific evolutionary processes involved in adaptation to the cheese matrix.


Low factor H-related 5 levels contribute to infection-triggered haemolytic uraemic syndrome and membranoproliferative glomerulonephritis.
Dysregulation of the alternative complement pathway is a major pathogenic mechanism in two rare renal diseases: atypical haemolytic uraemic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN). We report on a 66-year-old male with chronic hepatitis C virus (HCV) infection and a combined liver-kidney transplant that was diagnosed with MPGN at the age of 63 years and a 5-year-old boy who presented with aHUS at the age of 21 months following a Streptococcus pneumoniae infection. Both patients carried similar frameshift variants in the complement CFHR5 gene that segregate with reduced levels of factor H-related 5 (FHR-5). We conclude that low FHR-5 levels may predispose to viral and bacterial infections that then trigger different renal phenotypes.


Differential var gene transcription in Plasmodium falciparum isolates from patients with cerebral malaria compared to hyperparasitaemia.
The Plasmodium falciparum variant erythrocyte surface antigens known as PfEMP1, encoded by the var gene family, are thought to play a crucial role in malaria pathogenesis because they mediate adhesion to host cells and immuno-modulation. Var genes have been divided into three major groups (A, B and C) and two intermediate groups (B/A and B/C) on the basis of their genomic location and upstream sequence. We analysed expressed sequence tags of the var gene DBLalpha domain to investigate var gene transcription in relation to disease severity in Malian children. We found that P. falciparum isolates from children with cerebral malaria (unrousable coma) predominantly transcribe var genes with DBLalpha1-like domains that are characteristic of Group A or B/A var genes. In contrast, isolates from children with equally high parasite burdens but no symptoms or signs of severe malaria (hyperparasitaemia patients) predominantly transcribe var genes with DBLalpha0-like domains that are characteristic of the B and C-related var gene groups. These results suggest that var genes with DBLalpha1-like domains (Group A or B/A) may be implicated in the pathogenesis of cerebral malaria, while var genes with DBLalpha0-like domains promote less virulent malaria infections.


Segmentation of kidneys using a new active shape model generation technique based on non-rigid image registration.
Active shape models (ASMs) are widely used for applications in the field of image segmentation. Building an ASM requires to determine point correspondences for input training data, which usually results in a set of landmarks distributed according to the statistical variations. State-of-the-art methods solve this problem by minimizing the description length of all landmarks using a parametric mapping of the target shape (e.g. a sphere). In case of models composed of multiple sub-parts or highly non-convex shapes, these techniques feature substantial drawbacks. This article proposes a novel technique for solving the crucial correspondence problem using non-rigid image registration. Unlike existing approaches the new method yields more detailed ASMs and does not require explicit or parametric formulations of the problem. Compared to other methods, the already built ASM can be updated with additional prior knowledge in a very efficient manner. For this work, a training set of 3-D kidney pairs has been manually segmented from 41 CT images of different patients and forms the basis for a clinical evaluation. The novel registration based approach is compared to an already established algorithm that uses a minimum description length (MDL) formulation. The presented results indicate that the use of non-rigid image registration to solve the point correspondence problem leads to improved ASMs and more accurate segmentation results. The sensitivity could be increased by approximately 10%. Experiments to analyze the dependency on the user initialization also show a higher sensitivity of 5-15%. The mean squared error of the segmentation results and the ground truth manually classified data could also be reduced by 20-34% with respect to varying numbers of training samples.


Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension.
Pulmonary hypertension (PH) is the end result of interaction between pulmonary vascular tone and a complex series of cellular and molecular events termed 'vascular remodelling'. The remodelling process, which can involve the entirety of pulmonary arterial vasculature, almost universally involves medial thickening, driven by increased numbers and hypertrophy of its principal cellular constituent, smooth muscle cells (SMCs). It is noted, however that SMCs comprise heterogeneous populations of cells, which can exhibit markedly different proliferative, inflammatory, and extracellular matrix production changes during remodelling. We further consider that these functional changes in SMCs of different phenotype and their role in PH are dynamic and may undergo significant changes over time (which we will refer to as cellular plasticity); no single property can account for the complexity of the contribution of SMC to pulmonary vascular remodelling. Thus, the approaches used to pharmacologically manipulate PH by targeting the SMC phenotype(s) must take into account processes that underlie dominant phenotypes that drive the disease. We present evidence for time- and location-specific changes in SMC proliferation in various animal models of PH; we highlight the transient nature (rather than continuous) of SMC proliferation, emphasizing that the heterogenic SMC populations that reside in different locations along the pulmonary vascular tree exhibit distinct responses to the stresses associated with the development of PH. We also consider that cells that have often been termed 'SMCs' may arise from many origins, including endothelial cells, fibroblasts and resident or circulating progenitors, and thus may contribute via distinct signalling pathways to the remodelling process. Ultimately, PH is characterized by long-lived, apoptosis-resistant SMC. In line with this key pathogenic characteristic, we address the acquisition of a pro-inflammatory phenotype by SMC that is essential to the development of PH. We present evidence that metabolic alterations akin to those observed in cancer cells (cytoplasmic and mitochondrial) directly contribute to the phenotype of the SM and SM-like cells involved in PH. Finally, we raise the possibility that SMCs transition from a proliferative to a senescent, pro-inflammatory and metabolically active phenotype over time.