Filamentous actin destabilization by H2O2 favors DnmA aggregation, with crucial roles of cysteines 450 and 776 in mitochondrial and peroxisomal division in Aspergillus nidulans.
Mitochondria constitute major sources of H2O2 and other reactive oxygen species in eukaryotic cells. The division of these organelles is crucial for multiple processes in cell biology and relies on highly regulated mechano-GTPases that are oligomerization dependent and belong to the dynamin-related protein family, like A. nidulans DnmA. Our previous work demonstrated that H2O2 induces mitochondrial constriction, division, and remodeling of the outer membrane. Here, we show that H2O2 also induces a DnmA aggregation consistent with higher-order oligomerization and its recruitment to mitochondria. The study of this response uncovered that H2O2 induces the depolymerization and reorganization of actin as well as the critical role that cysteines 450 and 776 play in DnmA function. Our results provide new insights into the mechanisms of reactive oxygen species cell signaling and how they can regulate the dynamics of the actin cytoskeleton and the division of mitochondria and peroxisomes.


Selection of donors and organization of a donor system for liver transplantation in India.
Organ transplantation has been a major scientific advance of this century. There is an attempt to start liver transplantation (LTx) in India in the near future. Donor selection is an integral part of the transplantation programme. Donor organs are a scarce resource and optimising their use will not only contribute to the success of the programme but also will ensure a steady flow of donors in the long term. Various factors essential for consideration while selecting a donor for liver transplantation are discussed. I have suggested guidelines for organising a viable donor system in the Indian setting to make the transplant programme long lasting.


The role of omega-3 fatty acids in the secondary prevention of cardiovascular disease.
It has long been recognized from epidemiological studies that Greenland Eskimos have substantially reduced rates of acute myocardial infarction (MI) compared with Western controls. From these epidemiological observations, the benefits of fatty fish consumption have been explored in cell culture and animal studies, as well as randomized controlled trials investigating the cardioprotective effects of omega-3 fatty acids. Dietary omega-3 fatty acids seem to stabilize the myocardium electrically, resulting in reduced susceptibility to ventricular arrhythmias, thereby reducing the risk of sudden death. These fatty acids also have potent anti-inflammatory effects, and may also be antithrombotic and anti-atherogenic. Furthermore, the recent GISSI-Prevention study of 11 324 patients showed a marked decrease in risk of sudden cardiac death as well as a reduction in all-cause mortality in the group taking a highly purified form of omega-3 fatty acids, despite the use of other secondary prevention drugs, including beta-blockers and lipid-lowering therapy. The use of omega-3 fatty acids should be considered as part of a comprehensive secondary prevention strategy post-myocardial infarction.


Single-stage surgery for cholesteatoma: an actuarial analysis.
Single-stage surgery was used for 215 operations for cholesteatoma. The results were analyzed using months at risk (actuarial) statistics. The methods of data collection and of creating a life-table for cholesteatoma follow-up are described. Ninety-one canal-down procedures are compared with 124 canal-up procedures as to the recidivism rate as well as hearing results. The actuarial tables showed a 45% cumulative success rate for canal-up procedures versus a 90% rate for canal-down operations. The successful canal-up procedures demonstrated slightly better hearing results, however. These success rates seemed to be comparable to those using planned staged surgery. It was concluded that, if single-stage canal-up procedures were used with larger mastoids and canal-down procedures with smaller mastoids, 80% of patients could be controlled without either residual or recurrent disease appearing. For the others, it was felt safe to wait for the disease to reappear rather than to do planned two-stage procedures for all patients. It was further urged that actuarial statistics be employed when reporting the results of surgery for cholesteatoma.


[Concerning the crisis of the West German politics of limit values in the 1970s: the transformation of cancer at the workplace from a toxicological into a socioeconomic problem].
The paper tackles the changes that occurred in the political culture and the episteme of risk in the Federal Republic of Germany in the 1970s. The objects of observation are limit values for hazardous industrial materials, especially for carcinogens. At the forefront of the production of such values in Germany was the German Research Society's Senate Commission for the Examination of Hazardous Industrial Materials. Limit values bring economy, politics, and science together and they mediate different interests. This makes limit values an ideal object of study to bring together changes in different parts of society. In 1972, a new category of limit values for carcinogenic substances is introduced, the so called "Technische Richtkonzentration" (TRK). This category of values does not assume that complete safety can be reached, as do limit values for hazardous industrial materials, so called "Maximale Arbeitsplatzkonzentrationen" (MAK). This means an important rupture in toxicological thinking. Until the 1970s, Paracelsus' dictum about dosage and poison still served as starting point for toxicologists. The innovation of TRK marks an important rupture in the episteme of regulating dangerous matters. Whereas until the 1970s there existed, at least as an ideal, the myth of "no risk" or "zero tolerance" even in the case of carcinogens, since the beginning of the 1970s, certainty is no more guaranteed by epistemically, but by socially robust knowledge. This also means the return of the risk society at the beginning of the 1970s, whereby cancer at the workplace becomes--in the view of the regulatory bodies--out of a medical problem a socioeconomic illness. The paper argues that these changes are connected to a general feeling of disorientation.


Influence of mechanical and TGF-β3 stimulation on the tenogenic differentiation of tonsil-derived mesenchymal stem cells.
Organogenesis from tonsil-derived mesenchymal cells (TMSCs) has been reported, wherein tenogenic markers are expressed depending on the chemical stimulation during tenogenesis. However, there are insufficient studies on the mechanical strain stimulation for tenogenic cell differentiation of TMSCs, although these cells possess advantages as a cell source for generating tendinous tissue. The purpose of this study was to investigate the effects of mechanical strain and transforming growth factor-beta 3 (TGF-β3) on the tenogenic differentiation of TMSCs and evaluate the expression of tendon-related genes and extracellular matrix (ECM) components, such as collagen. mRNA expression of tenogenic genes was significantly higher when the mechanical strain was applied than under static conditions. Moreover, mRNA expression of tenogenic genes was significantly higher with TGF-β3 treatment than without. mRNA expression of osteogenic and chondrogenic genes was not significantly different among different mechanical strain intensities. In cells without TGF-β3 treatment, double-stranded DNA concentration decreased, while the amount of normalized collagen increased as the intensity of mechanical strain increased. Mechanical strain and TGF-β3 have significant effects on TMSC differentiation into tenocytes. Mechanical strain stimulates the differentiation of TMSCs, particularly into tenocytes, and cell differentiation, rather than proliferation. However, a combination of these two did not have a synergistic effect on differentiation. In other words, mechanical loading did not stimulate the differentiation of TMSCs with TGF-β3 supplementation. The effect of mechanical loading with TGF-β3 treatment on TMSC differentiation can be manipulated according to the differentiation stage of TMSCs. Moreover, TMSCs have the potential to be used for cell banking, and compared to other mesenchymal stem cells, they can be procured from patients via less invasive procedures.


Validated modified Lycopodium spore method development for standardisation of ingredients of an ayurvedic powdered formulation Shatavaryadi churna.
Validated modified lycopodium spore method has been developed for simple and rapid quantification of herbal powdered drugs. Lycopodium spore method was performed on ingredients of Shatavaryadi churna, an ayurvedic formulation used as immunomodulator, galactagogue, aphrodisiac and rejuvenator. Estimation of diagnostic characters of each ingredient of Shatavaryadi churna individually was carried out. Microscopic determination, counting of identifying number, measurement of area, length and breadth of identifying characters were performed using Leica DMLS-2 microscope. The method was validated for intraday precision, linearity, specificity, repeatability, accuracy and system suitability, respectively. The method is simple, precise, sensitive, and accurate, and can be used for routine standardisation of raw materials of herbal drugs. This method gives the ratio of individual ingredients in the powdered drug so that any adulteration of genuine drug with its adulterant can be found out. The method shows very good linearity value between 0.988-0.999 for number of identifying character and area of identifying character. Percentage purity of the sample drug can be determined by using the linear equation of standard genuine drug.


Passive K+-Cl- fluxes in low-K+ sheep erythrocytes: modulation by A23187 and bivalent cations.
A fraction of the ouabain-resistant (OR) K+ flux of low-K+ (LK) sheep erythrocytes is Cl- dependent (K+-Cl- transport) and is activated reversibly by cell swelling or irreversibly by treatment with N-ethylmaleimide (NEM). The effect of the ionophore A23187 plus bivalent cations (Me2+) or ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid (EGTA) was studied on K+-Cl- transport in control or NEM-treated LK cells. The following observations were made. 1) A23187 (6 microM), at a hematocrit of 10% (vol/vol) and in the presence of 1 mM EGTA, activated severalfold OR K+-Cl- transport in shrunken or swollen cells but failed to stimulate further K+-Cl- flux in NEM-treated cells. 2) In the absence of EGTA, but at very low external Ca2+ concentrations [( Ca2+]o = 10(-7) M), A23187 stimulated OR K+-Cl- flux in controls less than with EGTA and inhibited it slightly in NEM-treated cells. 3) When [Ca2+]o was raised to 10(-3) M, an almost complete inhibition of OR K+-Cl- fluxes occurred in shrunken, swollen, or NEM-treated cells. 4) Other Me2+ inhibited OR K+-Cl- flux in the presence of A23187 in the following order of decreasing potency: Mn2+ much greater than Ca2+ greater than Mg2+ greater than Sr2+ much much greater than Ba2+. 5) Stimulation of OR K+-Cl- flux by A23187 +/- EGTA and inhibition by A23187 + Ca2+ were reversible and did not alter significantly cellular ATP. 6) The stimulatory effect of A23187 plus EGTA, perhaps by Me2+ removal, on K+-Cl- flux and its inhibition by Ca2+ were reversibly abolished in metabolically depleted cells.(ABSTRACT TRUNCATED AT 250 WORDS)


[MRI in the diagnosis of tumors of the parotid gland].
Tumors of the parotid gland are easily depicted with magnetic resonance imaging. Their exact site, and extension in the case of a malignant tumor, are correctly predicted. The histologic nature of the lesion remains to be verified by histologic examination. MRI is invaluable for the detection of recurrent pleomorphic adenomas.


In situ characterization and mapping of iron compounds in Alzheimer's disease tissue.
There is a well-established link between iron overload in the brain and pathology associated with neurodegeneration in a variety of disorders such as Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases [1]. This association was first discovered in AD by Goodman in 1953 [2], where, in addition to abnormally high concentrations of iron in autopsy brain tissue, iron has also been shown to accumulate at sites of brain pathology such as senile plaques [3]. However, since this discovery, progress in understanding the origin, role and nature of iron compounds associated with neurodegeneration has been slow. Here we report, for the first time, the location and characterisation of iron compounds in human AD brain tissue sections. Iron fluorescence was mapped over a frontal-lobe tissue section from an Alzheimer's patient, and anomalous iron concentrations were identified using synchrotron X-ray absorption techniques at 5 mum spatial resolution. Concentrations of ferritin and magnetite, a magnetic iron oxide potentially indicating disrupted brain-iron metabolism, were evident. These results demonstrate a practical means of correlating iron compounds and disease pathology in-situ and have clear implications for disease pathogenesis and potential therapies.


Bowel injury following gynecological laparoscopic surgery.
Bowel injury remains a serious complication of gynecological laparoscopic surgery. We aimed to review the literature on this topic, combined with personal experiences, so as to give recommendations on how to avoid and manage this complication. We performed a narrative review on bowel injury following gynecological laparoscopic surgery using PubMed covering prevention, diagnosis, and management. Search terms used were laparoscopy, gynaecology, injury, bowel, prevention, treatment. Important principles of prevention include proper pre-operative evaluation and increased laparoscopic surgical skills and knowledge. High clinical suspicion is crucial for early diagnosis. Diagnostic workup of suspected cases includes serial abdominal examination, measuring inflammatory markers, and performing imaging studies including abdominal ultrasound and CT scan. When bowel injury is recognized during the first laparoscopic procedure then laparoscopic primary suturing could be tried although laparotomy may be needed. When diagnosis is delayed, then laparotomy is the treatment of choice. The role of robotic surgery and three-dimensional laparoscopic gynecological surgery on bowel injury needs to be further assessed. Early recognition of bowel injury is crucial for a favorable clinical outcome. A combined collaboration between gynecologists and general surgeons is important for timely and proper decisions to be made.


Theoretical study of mechanism and stereoselectivity of catalytic Kinugasa reaction.
The mechanism of the catalytic Kinugasa reaction is investigated by means of density functional theory calculations. Different possible mechanistic scenarios are presented using phenanthroline as a ligand, and it is shown that the most reasonable one in terms of energy barriers involves two copper ions. The reaction starts with the formation of a dicopper-acetylide that undergoes a stepwise cycloaddition with the nitrone, generating a five-membered ring intermediate. Protonation of the nitrogen of the metalated isoxazoline intermediate results in ring opening and the formation of a ketene intermediate. This then undergoes a copper-catalyzed cyclization by an intramolecular nucleophilic attack of the nitrogen on the ketene, affording a cyclic copper enolate. Catalyst release and tautomerization gives the final β-lactamic product. A comprehensive study of the enantioselective reaction was also performed with a chiral bis(azaferrocene) ligand. In this case, two different reaction mechanisms, involving either the scenario with the two copper ions or a direct cycloaddition of the parent alkyne using one copper ion, were found to have quite similar barriers. Both mechanisms reproduced the experimental enantioselectivity, and the current calculations can therefore not distinguish between the two possibilities.


Modeling of multiple-optical-axis pattern-integrated interference lithography systems.
The image quality and collimation in a multiple-optical-axis pattern-integrated interference lithography system are evaluated for an elementary optical system composed of single-element lenses. Image quality and collimation are individually and jointly optimized for these lenses. Example images for a jointly optimized system are simulated using a combination of ray tracing and Fourier analysis. Even with these nonoptimized components, reasonable fidelity is shown to be possible.


[A dimensional diagnostic approach using the "Assessment of DSM-IV Personality Disorders (ADP-IV)" Questionnaire].
The ADP-IV is a self-assessment instrument of personality disorders providing categorical as well as dimensional diagnoses. The German translation of the Dutch original has already shown sufficient reliability as well as a rather weak convergent validity of categorical diagnoses. This study investigates the validity of the dimensional assessment of personality disorders. Four hundred patients and a community sample of 385 subjects completed the ADP-IV. A SCID-II interview and an expert consensus rating were also performed in 210 patients. Norms for patients and the community sample were calculated by using z-transformation. Receiver operator curves (ROC) were employed for the determination of cut-offs for categorical diagnoses on the basis of the dimensional scores. The ROC analyses resulted in negative predictive values of 99 % for the five most frequent personality disorders in the sample; in contrast, positive predictive values were low. The instrument is well suited for screening purposes, allowing for a reliable exclusion of personality disorders. For diagnosing personality disorders, however, clinical interviewing remains necessary. Norms and a dimensional personality disorder profile provide hints concerning the presence of pathological personality traits with respect to the reference group. The ADP-IV represents the only German-language questionnaire for the assessment of DSM-IV personality disorders which has been sufficiently validated. It is freely available on the internet at http://zmkweb.uni-muenster.de/einrichtungen/proth/dienstleistungen/psycho/diag/index.html.


Salmonella serotypes isolated from the aquatic environment (Wabash River, Indiana, 1973-1976).
During 1973-1976, 833 isolations of salmonellae were made from the aquatic biosphere of the Wabash River, Lafayette, Ind. Of the isolants, 643 were definitively serotyped. Salmonella typhimurium represented 34.4% of the cultures. Salmonella eimsbuettel previously had not been recognized in Indiana. A total of 35 serotypes and 1 untypable group C1 was obtained from the aquatic samples, ie, river water, river bottom sediment, fish, and mussels. Most of the isolants were presumed to be of human origin, because many samplings were made in close proximity to sewage treatment plant outfalls. During the survey period, epidemic salmonellosis had not been reported for the Lafayette-West Lafayette metropolitan area.


Pro-inflammatory variants of DRB1 and RAGE genes are associated with susceptibility to pediatric type 1 diabetes: a new hypothesis on the adaptive role of autoimmunity.
Functional polymorphisms of two MHC genes (DRB1 and RAGE) were analysed in Italian pediatric patients with Type 1 diabetes and in a control group. The diabetic condition is related positively to the positive electric charge of the pocket 4 of pro-inflammatory DRB1 alleles (R = 0.5072, P = 0.0001) and negatively to at least one anti-inflammatory RAGE allele (R = -0.2200, P = 0.0106). The association DRB1-disease decreases from high risk positively charged alleles to low risk negatively ones. A multiple regression model including the effect of electric charges at positions 70 and 74 of the DRB1 explains more than 31% of the variability of our data. The addition of the RAGE dependent variables does not increase the significance of the model. Our results confirm that the interaction between a negatively charged amino acid of insulin autoantigenic peptides and a positively charged DRB1 is the key event triggering the autoimmune process. The linkage disequilibrium between RAGE and DRB1 is the main cause of the association between the variants of RAGE and the initial outcome of the disease. However, since RAGE ligands increase during the disease progression, the observed association suggests that the proinflammatory RAGE and DRB1 polymorphisms synergize to activate the immune response which leads to the complications of diabetes. These evidences support a new hypothesis that considers the largely unexplored role of the MHC genes in genetic adaptation to a variable environment and in the maintenance of the metabolic biodiversity. A mechanism based on the maternal immunization against the negatively charged autoantigens, such as the insulin peptide B9-23, and on the fetal-maternal interaction might transform the physiological adaptation into adaptive changes of the genetic population structure. According to the "thrifty-genotype" hypothesis, "thrifty DRB alleles" with a positive charge are responsible for the susceptibility to diabetes and for an efficient storage of caloric intake in arctic climates with scarce food availability while "non-thrifty DRB alleles" with a negative or neutral charge are advantaged in tropical climates with constant food supply.


Umeclidinium bromide/vilanterol combination in the treatment of chronic obstructive pulmonary disease: a review.
Chronic obstructive pulmonary disease (COPD) is a common disease among the elderly that could be prevented by smoking cessation. As it is characterized by airflow limitation that is not fully reversible, bronchodilator therapy is the first choice of treatment. Symptomatic COPD patients with or without risk for future exacerbations have a strong indication for the permanent use of long- and ultralong-acting β2-agonists and/or long-acting muscarinic antagonists. Combining bronchodilators is an effective approach, as they demonstrate synergic action at a cellular level and have additive clinical benefits and fewer adverse events compared with increased doses of the monocomponents. Novel fixed-dose combinations of long-acting β2-agonists/long-acting muscarinic antagonists in one inhaler have been approved for clinical use by the US Food and Drug Administration and the European Medicines Agency. This review focuses on published clinical trials about the fixed-dose combination of umeclidinium/vilanterol trifenatate in patients with COPD. Results from six studies (five of them of 12 weeks' duration and one that lasted 1 year, including more than 6,000 patients in total) showed that umeclidinium/vilanterol trifenatate improved lung function, dyspnea, and health-related quality of life and decreased the exacerbation rate with no serious adverse events. More longstanding trials are needed to evaluate the effect of the drug on disease progression and compare it directly with other fixed-dose combinations.


[Experiences with a new vacuum-accelerated microwave histoprocessor].
Methods of microwave and vacuum accelerated fixation, dehydration and paraffin embedding are described. They can be carried out in a new type of vacuum and temperature stabilizable microwave histoprocessor: MFX-800. The whole histoprocessing lasts 3.5-5.5 hours depending on the thickness of the tissue blocks. Preserved structural detail, intensive staining and good antigen preservation were achieved with various tissues. This new histoprocessing facility can be highly recommended for pathology laboratories interested in speeding up the processing procedure, as well as in immunohistochemistry.


Delayed nerve regeneration in streptozotocin diabetic rats.
Nerve regeneration across a 10-mm gap was delayed in streptozotocin diabetic rats 3 and 4 weeks after transecting the sciatic nerve. Opposite ends of each cut nerve were introduced into a silicone tube, leaving a 10-mm gap. Electron microscopy was used to evaluate the progress of regeneration in sections at 2-mm intervals across the 10-mm gap. After 3 weeks, control axons had bridged the 10-mm gap, and myelin sheaths extended for 6-8 mm. By contrast, axons and their myelin sheaths were seen no further than 2 mm from the proximal stump in diabetic animals. By 4 weeks, axons had bridged the gap in diabetics; however, they appeared immature and showed dystrophic changes. The findings suggest that although regeneration does occur in diabetic nerves, it is significantly delayed and qualitatively impaired.


Polyethylenimine-based Formulations for Delivery of Oligonucleotides.
Polyethyleneimine (PEI) is well-known as a non-viral gene delivery vector, especially for oligonucleotide delivery. However, its clinical applications are significantly limited due to its high cationic charge, lack of specificity, and interaction with the proteins and nontarget cells in the biological fluids, resulting in high cytotoxicity, poor stability and low transfection efficiency for oligonucleotides transporting. It has been shown that the molecular weight (MW) of PEI, degree of branching, N/P ratio, buffer capacity, oligonucleotide structure, culture medium pH, serum, presence or absence of and method of preparation make a significant difference in the cytoxicity, stability, and transfection efficiency for the PEI-based oligonucleotides delivery systems. Ligands, hydrophobic, hydrophilic, and amphiphilic modification of PEI have been investigated to reduce the cytoxicity and improve the stability, the transfection efficiency, and therapeutic effect. Moreover, various intelligent modifications of PEI, such as pH-responsive (hydrazone bond) and redox sensitive linkers (disulfide bond) can control oligonucleotides release and have attracted much attention. In general, more efficient oligonucleotide delivery can be achieved by the introduction of modifications to PEI and by optimization of parameters of PEI or PEI-based formulations.


Matching molecular diversity and ecophysiology of benthic cyanobacteria and diatoms in communities along a salinity gradient.
The phylogenetic diversity of oxygenic phototrophic microorganisms in hypersaline microbial mats and their distribution along a salinity gradient were investigated and compared with the halotolerances of closely related cultivated strains. Segments of 16S rRNA genes from cyanobacteria and diatom plastids were retrieved from mat samples by DNA extraction and polymerase chain reaction (PCR), and subsequently analysed by denaturing gradient gel electrophoresis (DGGE). Sequence analyses of DNA from individual DGGE bands suggested that the majority of these organisms was related to cultivated strains at levels that had previously been demonstrated to correlate with characteristic salinity responses. Proportional abundances of amplified 16S rRNA gene segments from phylogenetic groupings of cyanobacteria and diatoms were estimated by image analysis of DGGE gels and were generally found to correspond to abundances of the respective morphotypes determined by microscopic analyses. The results indicated that diatoms accounted for low proportions of cells throughout, that the cyanobacterium Microcoleus chthonoplastes and close relatives dominated the communities up to a salinity of 11% and that, at a salinity of 14%, the most abundant cyanobacteria were related to highly halotolerant cultivated cyanobacteria, such as the recently established phylogenetic clusters of Euhalothece and Halospirulina. Although these organisms in cultures had previously demonstrated their ability to grow with close to optimal rates over a wide range of salinities, their occurrence in the field was restricted to the highest salinities investigated.


Genomic analysis of Pseudomonas putida phage tf with localized single-strand DNA interruptions.
The complete sequence of the 46,267 bp genome of the lytic bacteriophage tf specific to Pseudomonas putida PpG1 has been determined. The phage genome has two sets of convergently transcribed genes and 186 bp long direct terminal repeats. The overall genomic architecture of the tf phage is similar to that of the previously described Pseudomonas aeruginosa phages PaP3, LUZ24 and phiMR299-2, and 39 out of the 72 products of predicted tf open reading frames have orthologs in these phages. Accordingly, tf was classified as belonging to the LUZ24-like bacteriophage group. However, taking into account very low homology levels between tf DNA and that of the other phages, tf should be considered as an evolutionary divergent member of the group. Two distinguishing features not reported for other members of the group were found in the tf genome. Firstly, a unique end structure--a blunt right end and a 4-nucleotide 3'-protruding left end--was observed. Secondly, 14 single-chain interruptions (nicks) were found in the top strand of the tf DNA. All nicks were mapped within a consensus sequence 5'-TACT/RTGMC-3'. Two nicks were analyzed in detail and were shown to be present in more than 90% of the phage population. Although localized nicks were previously found only in the DNA of T5-like and phiKMV-like phages, it seems increasingly likely that this enigmatic structural feature is common to various other bacteriophages.


Explanatory Versus Pragmatic Trials: An Essential Concept in Study Design and Interpretation.
Randomized clinical trials often represent the highest level of clinical evidence available to evaluate the efficacy of an intervention in clinical medicine. Although the process of randomization serves to maximize internal validity, the external validity, or generalizability, of such studies depends on several factors determined at the design phase of the trial including eligibility criteria, study setting, and outcomes of interest. In general, explanatory trials are optimized to demonstrate the efficacy of an intervention in a highly selected patient group; however, findings from these studies may not be generalizable to the larger clinical problem. In contrast, pragmatic trials attempt to understand the real-world benefit of an intervention by incorporating design elements that allow for greater generalizability and clinical applicability of study results. In this article we describe the explanatory-pragmatic continuum for clinical trials in greater detail. Further, a well-accepted tool for grading trials on this continuum is described, and applied, to 2 recently published trials pertaining to the surgical management of lumbar degenerative spondylolisthesis.


Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.


Death, mode of death, morbidity, and rehospitalization after coronary artery bypass grafting in relation to occurrence of and time since a previous myocardial infarction.
To describe the prognosis during 2 years after coronary artery bypass grafting (CABG) in relation to occurrence of and time since a previous acute myocardial infarction (AMI), data of all patients in western Sweden who underwent CABG without simultaneous valve surgery in the period June 1988-June 1991 were evaluated. In all, 2120 patients were included in the analyses. Of these, 1296 (61%) had a history of AMI and 127 (6%) had suffered an AMI within the last month before CABG. Mortality during the first 30 days after CABG was for patients with no previous AMI, previous AMI > 30 days prior to CABG, and previous AMI < or = 30 days prior to CABG 2.4%, 4.1%, and 5.5%, respectively (p < 0.05). The corresponding figures for the period between 30 days and 2 years after CABG were 3.6%, 4.4%, and 3.4% respectively (NS). In a multivariate analysis among patients with a previous AMI, a recent infarction (< or = 30 days prior to CABG) did not turn out as an independent predictor of death during 2 years of follow-up. A history of AMI was associated with increased mortality during the first 30 days but not thereafter, but recent AMI was not an independent predictor of total 2-year mortality.


Vitamin D in North-East Asian clinical nutrition practice.
Sound clinical nutrition practice is grounded in evidence and stimulated by research. Yet, there are unanswered questions about food-health relationships. Clinical nutrition involves the identification of nutritional disorders and the motivation to rectify them with all required care. Vitamin D health exemplifies the biomedical, societal and environmental dimensions of clinical nutrition, its science and practice. It depends most of all on access to sunshine and food and probably represents a paradigm in human health which is still at its beginning. Nevertheless, the problem of its deficiency is much more widespread and common than has been thought since it was first identified as a cause of rickets and osteomalacia. It is now known to spare no body organ or system. The problem in North-East Asia is comparable to much of the rest of the world, but the risk profile for it is exaggerated by atmospheric pollution, cultures with sun-avoidance on account of skin colour and potentially mitigated by foodstuffs like fish, eggs, organ meats and mushrooms which can partially offset sunshine-deficiency. Diagnosis requires a high index of suspicion and confirmation by biochemistry which may not be affordable. Therefore a close working relationship between public health and clinical nutritionist is essential.


I can't play ball anymore.
The case material from the treatments of four older individuals suffering from late-life depressions reveal that their conditions were precipitated by the presence of physical problems that led to an interference with long-standing athletic skills. Since the skills in question had developed in the context of a tie with an important early object, the loss of the athletic function led to a double loss, that of the object tie as well. In addition, it was seen that the tie with the original object also served as a protection for patients against the specter of the imminence of their own deaths. The loss of this protective function intensified feelings of castration and of vulnerability to death.


Proteomic analysis of putative heme-binding proteins in Streptococcus pyogenes.
Streptococcus pyogenes is an important human bacterium with high pathogenicity. Heme is a major source of iron that plays a critical role in bacterial survival and virulence. In this study, heme-affinity chromatography, two-dimensional-electrophoresis and mass spectrometry were combined to identify putative heme-binding proteins and heme-regulatory proteins. In total, 68 heme-regulatory proteins and 284 putative heme-binding proteins were identified, among which 37 proteins showed expression alterations in response to heme deficiency. Bioinformatics analysis revealed that several key metabolic pathways had changed in the absence of heme, among which glycolysis was a major pathway impaired under heme-deficient conditions. New potential heme-binding proteins were successfully identified in this study providing novel clues for the study of the heme transport mechanism. Heme-binding proteins may play fundamental roles in many important biological pathways and thus contribute to bacterial pathogenicity.


Ester production by Pseudomonas fragi. IV. Demonstration of esterase activity.
Assay of the esterase activity of sonically treated cell-free extracts, whole cell suspensions, and supernatant fluid of Pseudomonas fragi cultures with a differential respirometer revealed that the esterases were intracellular. Polyacrylamide-gel electrophoresis demonstrated six bands of esterase activity, which revealed substrate specificity differences. Band 1 exhibited slow mobility, bands 2, 3, and 4 moderate mobility, and bands 5 and 6 rapid mobility. Six bands were active with alpha-naphthyl acetate, four bands with alpha-naphthyl propionate, and 5 bands with alphanaphthyl butyrate. These esterases appeared to be more active with aromatic esters than with aliphatic esters.


Clinical Impact of T1 Slope Minus Cervical Lordosis After Multilevel Posterior Cervical Fusion Surgery: A Minimum 2-Year Follow Up Data.
Retrospective study. To assess the long-term relationship between sagittal alignment of the cervical spine and patient-reported health-related quality-of-life (HRQOL) scores after multilevel posterior cervical fusion, and to explore whether an analog of T1 slope minus C2-C7 lordosis ('T1S-CL') impacts on patients' clinical outcomes. A 6-month follow-up study demonstrated that, similar to the thoracolumbar spine, the severity of disability increases with sagittal malalignment after cervical reconstruction surgery. From 2007 to 2014, 31 consecutive patients having multilevel posterior cervical fusion for cervical stenosis, myelopathy, and deformities met inclusion criteria. To determine the true impact of the alignment on HRQOL, patients who have pseudarthrosis, a misplaced screw, junctional pathologies, or adjacent level disc herniation were excluded. Radiographic measurements included: C0-C2 lordosis, C2-C7 lordosis, C2-C7 sagittal vertical axis (SVA), T1 slope, and T1S-CL. Pearson correlation coefficients were calculated between pairs of radiographic measures and HRQOL. C2-C7 SVA positively correlated with neck disability index (NDI) scores (r = 0.550). For significant correlations between C2-C7 SVA and NDI scores, regression models predicted a threshold C2-C7 SVA value of 43.5 mm, beyond which correlations were most significant. The T1S-CL also correlated positively with C2-C7 SVA and NDI scores (r = 0.827 and r = 0.618, respectively). Results of the regression analysis indicated that a C2-C7 SVA value of 43.5 mm corresponded to a T1S-CL value of 22.2°. This minimum 2-year follow-up study showed that disability of the neck increased with cervical sagittal malalignment after surgical reconstruction and a greater T1S-CL mismatch was associated with a greater degree of cervical malalignment. Specifically, a T1S-CL mismatch greater than 22.2° corresponded to severe disability (NDI>25) and positive cervical sagittal malalignment, defined as C2-C7 SVA greater than 43.5 mm. 4.


Promising use of immune cell-derived exosomes in the treatment of SARS-CoV-2 infections.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is persistently threatening the lives of thousands of individuals globally. It triggers pulmonary oedema, driving to dyspnoea and lung failure. Viral infectivity of coronavirus disease 2019 (COVID-19) is a genuine challenge due to the mutagenic genome and mysterious immune-pathophysiology. Early reports highlighted that extracellular vesicles (exosomes, Exos) work to enhance COVID-19 progression by mediating viral transmission, replication and mutations. Furthermore, recent studies revealed that Exos derived from immune cells play an essential role in the promotion of immune cell exhaustion by transferring regulatory lncRNAs and miRNAs from exhausted cells to the active cells. Fortunately, there are great chances to modulate the immune functions of Exos towards a sustained repression of COVID-19. Engineered Exos hold promising immunotherapeutic opportunities for remodelling cytotoxic T cells' function. Immune cell-derived Exos may trigger a stable epigenetic repression of viral infectivity, restore functional cytokine-producing T cells and rebalance immune response in severe infections by inducing functional T regulatory cells (Tregs). This review introduces a view on the current outcomes of immunopathology, and immunotherapeutic applications of immune cell-derived Exos in COVID-19, besides new perspectives to develop novel patterns of engineered Exos triggering novel anti-SARS-CoV-2 immune responses.


Diagnosis of cholangiocarcinoma.
Cholangiocarcinoma is suspected based on signs of biliary obstruction, abnormal liver function tests, elevated tumor markers (carbohydrate antigen 19-9 and carcinoembryonic antigen), and ultrasonography showing a bile stricture or a mass, especially in intrahepatic cholangiocarcinoma. Magnetic resonance imaging (MRI) or computed tomography (CT) is performed for the diagnosis and staging of cholangiocarcinomas. However, differentiation of an intraductal cholangiocarcinoma from a hypovascular metastasis is limited at imaging. Therefore, reasonable exclusion of an extrahepatic primary tumor should be performed. Differentiating between benign and malignant bile duct stricture is also difficult, except when metastases are observed. The sensitivity of fluorodeoxyglucose positron emission tomography is limited in small, infiltrative, and mucinous cholangiocarcinomas. When the diagnosis of a biliary stenosis remains indeterminate at MRI or CT, endoscopic imaging (endoscopic or intraductal ultrasound, cholangioscopy, or optical coherence tomography) and tissue sampling should be carried out. Tissue sampling has a high specificity for diagnosing malignant biliary strictures, but sensitivity is low. The diagnosis of cholangiocarcinoma is particularly challenging in patients with primary sclerosing cholangitis. These patients should be followed with yearly tumor markers, CT, or MRI. In the case of dominant stricture, histological or cytological confirmation of cholangiocarcinoma should be obtained. More studies are needed to compare the accuracy of the various imaging methods, especially the new intraductal methods, and the imaging features of malignancy should be standardized.


Implications of transcriptional factor, OCT-4, in human bladder malignancy and tumor recurrence.
OCT-4, which is also known as POU5f1, is a key regulator of self-renewal in embryonic stem cells. The new cancer stem cell concept proposes that the expression of such genes is potentially correlated with tumorigenesis and can affect some aspects of the cancer behavior, such as recurrence or metastasis. This study investigated the association between OCT-4 expression in cancer tissues obtained by transurethral surgery and the clinical data to clarify the involvement of OCT-4 in human bladder malignancy. Immunohistochemical analysis demonstrated that a positive rate of OCT-4 expression was significantly associated with the higher-grade cancer (G2 and G3) in comparison with that of the lower grade (G1). In addition, positive OCT-4 expression was significantly associated with the intra-bladder tumor recurrence after the operation. The staining intensity of OCT-4 expression was also correlated with tumor recurrence. These data indicate that positive OCT-4 expression may be involved in the development of high-grade bladder cancer and with the bladder cancer recurrence. This is the first study showing a correlation between the expression of OCT-4 and bladder cancer recurrence. OCT-4 may be a valuable clinical marker for the progression of bladder cancer and may be an attractive therapeutic target for the development of new medicines for the treatment of malignancy.


Delay in commencement of palliative care service episodes provided to Indigenous and non-Indigenous patients: cross-sectional analysis of an Australian multi-jurisdictional dataset.
Rapid effective responsiveness to patient needs is pivotal to high quality palliative care. Aboriginal and Torres Strait Islander (Indigenous) people are susceptible to life-limiting illnesses at younger ages than other Australians and experience inequity of health service provision. The Palliative Care Outcomes Collaboration collects Australia-wide health service data on patient care, and has established performance benchmarks for specialist palliative care services. We investigated whether the benchmark for timely commencement of palliative care episodes (occurrence of delay >1 day after being designated 'ready for care' in <10% instances) is being met for Indigenous Australians in participating services. Additionally, we investigated the association between identification as Indigenous and delay. Using multi-jurisdictional Palliative Care Outcomes Collaboration data, this cross-sectional analytical study investigated all episodes of care (n = 84,238) provided to patients ≥18 years (n = 61,073: Indigenous n = 645) in hospital and community settings commenced and completed during the period 01/07/2013-30/06/2015. Proportions of episodes resulting in delay were determined. Crude and adjusted odds of delay among Indigenous compared with non-Indigenous patients were investigated using multiple logistic regression, with missing data handled by multiple imputation. The benchmark was met for both Indigenous and non-Indigenous patients (delay in 8.3 and 8.4% episodes respectively). However, the likelihood of delay was modestly higher in episodes provided to Indigenous than non-Indigenous patients (adjusted odds ratio [aOR], 1.41; 95% confidence interval [CI] 1.07-1.86). Excess delay among Indigenous patients was accentuated in first episodes (aOR, 1.53; 95% CI 1.14-2.06), in patients aged < 65 years (aOR, 1.66; 95% CI 1.14-2.41), and among those residing in Inner Regional areas (aOR, 1.97; 95% CI 1.19-3.28), and also approached significance among those in outer regional, remote and very remote areas collectively (aOR, 1.72; CI 0.97-3.05). Although the timeliness benchmark is being met for Indigenous Australians in palliative care, they may experience delayed initiation of care episodes, particularly if younger, and especially at first encounter with a service. Qualitative research is required to explore determinants of delay in initiating palliative care episodes. The timeliness of initial referral for specialist palliative care in this population remains to be determined.


The L protein of vesicular stomatitis virus modulates the response of the polyadenylic acid polymerase to S-adenosylhomocysteine.
TsG16(I) is a temperature-sensitive (ts) mutant of vesicular stomatitis virus, Indiana serotype, which overproduces polyadenylic acid [poly(A)] in an in vitro transcription system due to a mutation in the L protein. Others have reported that L-S-adenosylhomocysteine (S-Ado-Hcy) causes wild-type (wt) virus to overproduce poly(A) in vitro. The possibility that tsG16(I) constitutively expresses a property induced by S-Ado-Hcy in the case of wt virus was found not to be so since polyadenylation by the mutant was still sensitive to S-Ado-Hcy. Indeed, S-Ado-Hcy caused tsG16(I) to overproduce poly(A) in vitro to a greater extent than its parental wt virus. The increase in polyadenylation observed in response to saturating levels of S-Ado-Hcy differed for tsG16(I), for its parental wt virus and for another wt strain. To characterize which viral protein modulated the polyadenylation response to S-Ado-Hcy, purified virions were fractionated and their phenotypes in homologous and heterologous reconstitution assays were examined. The results indicated that the viral L protein modulated the response in all three stocks of virus. These data provide further evidence to suggest that the L protein of vesicular stomatitis virus plays a role in polyadenylation of the viral mRNA.


Effects of pyrimidine antagonists on sialic acid regeneration in HL-60 cells.
Because alterations in cell membrane sialoglycoconjugates can affect the behavior of neoplastic cells, we investigated the effects of in vitro treatment with antimetabolites used in cancer therapy on the expression of membrane sialic acid in cultured HL-60 leukemic cells. In these studies, cells were incubated with Vibrio cholerae neuraminidase to remove surface sialic acid. Reappearance of membrane sialic acid during drug treatment was followed (a) by measuring changes in radioactive surface labeling of viable cells with sodium metaperiodate-sodium[3H]-borohydride, (b) by measuring the decline in accessible surface galactosyl receptor sites which occurred coincident with membrane sialic acid replacement, and (c) by measuring the incorporation of [3H]glucosamine into membrane-associated neuraminidase-labile sialic acid. We were especially interested in learning whether drugs that affect intracellular pools of cytidine triphosphate (CTP), an important nucleotide intermediate in sialylation reactions, could inhibit regeneration of membrane sialic acid. 3-Deazauridine, a competitive inhibitor of CTP synthetase, depleted CTP pools and curtailed surface membrane resialylation with little or no effect on synthesis of de novo sialic acid from precursor sugars. The addition of cytidine restored CTP pools and sialic acid regeneration. Acivicin, a glutamine antagonist, also depleted CTP pools and curtailed surface membrane resialylation. In addition, it retarded de novo synthesis of sialic acid. The addition of cytidine restored intracellular CTP pools and sialic acid regeneration. However, both cytidine and guanosine were required to restore sialic acid synthesis from precursor sugars. 1-beta-D-Arabinofuranosylcytosine, a competitive inhibitor of sialic acid synthetase and of sialyltransferase, inhibited both de novo sialic acid synthesis and membrane resialylation. Only the latter effect was reversed by the addition of exogenous cytidine. Hydroxyurea, an agent shown previously to inhibit glycoconjugate production in hamster fibroblasts, curtailed membrane resialylation and de novo synthesis of sialic acid without depleting CTP pools. Doxorubicin, at levels that caused marked arrest of cell proliferation, had no effect on sialic acid synthesis or expression on the membrane surface. These data suggest that antimetabolites, apart from their cytotoxic effects or effects on cellular growth, may directly inhibit the expression of membrane sialic acid.(ABSTRACT TRUNCATED AT 400 WORDS)


Improved lung function by means of retrograde flush in canine lung transplantation with non-heart-beating donors.
Use of lungs from non-heart-beating donors would increase the pulmonary donor pool. The aim of this study was to evaluate the effects of retrograde flush in canine lung transplantation from non-heart-beating donors. Left lung transplantation was performed in 12 weight-matched pairs of dogs. Donors were killed without heparinization, left at room temperature for 2 hours, and then randomized into 2 groups. In group AF (n = 6) lung retrieval was performed after flushing the lung block with low potassium dextran glucose (50 mL/kg) solution through the pulmonary artery. In group AF+RF (n = 6) additional retrograde flushing (low potassium dextran glucose, 25 mL/kg) was performed through the left atrium before retrieval. Flushed solution was sampled at intervals to measure hemoglobin concentrations. The lungs were preserved at 4 degrees C for 2 hours, and the left lung was implanted to the recipient being subjected to a total ischemic time of 5 hours. After left lung transplantation, the right pulmonary artery and main bronchus were ligated. Lung function, including arterial blood gas and pulmonary hemodynamics, was measured for 3 hours. For lung function study, statistical analyses were performed by using 1-way analysis of variance with repeated measures. Group AF+RF had significantly better gas exchange and lower wet/dry weight ratio of the transplanted lung than group AF. Changes of hemoglobin concentration in the flushed solution indicated that additional retrograde flush could remove residual microthrombi after antegrade flush. This study supports the theory that additional retrograde flush improves lung function after lung transplantation by removing residual pulmonary microthrombi in the lungs of non-heart-beating donors.


Effect of teleost GnRH on reinitiation of oocyte meiosis in goldfish, in vitro.
The effects of native and an agonist analogue of teleost gonadotropin-releasing hormone (GnRH) [(D-Arg6, Trp7, Leu8, Pro9-NHEt)-GnRH; tGnRH-A] on the hormone-induced meiotic maturation of goldfish oocytes were investigated. Incubation of follicle-enclosed goldfish oocytes with either carp gonadotropin (GtH) or meiogenic progestogens, including 17 alpha-hydroxyprogesterone (HP) and 17 alpha,20 beta-dihydroxyprogesterone (DHP), reinitiated oocyte meiosis in vitro, as indicated by germinal vesicle dissolution (GVD). Addition of tGnRH-A (10(-7) M) significantly attenuated the GVD response to GtH, HP, and DHP in a dose-related fashion; tGnRH-A reduced the magnitude of progestogen-induced GVD response without significantly affecting the sensitivity of the oocytes to the meiogenic steroids. Similarly, administration of native teleost GnRH (tGnRH) significantly attenuated GtH-induced GVD response, although the 50% maximal response of the native peptide was significantly higher than that of tGnRH-A (380.9 +/- 125 and 2.72 +/- 0.94 nM, respectively). The present results provide the first demonstration of an inhibitory action of a GnRH agonist on the process of progestogen-induced oocyte meiosis and support the hypothesis that GnRH or a GnRH-like peptide might play a modulating role in the control of oocyte meiosis at the ovarian level in goldfish.


Low birth weight babies. Preterm and small: the obstetric challenge.
Preterm labour is of unexpected origin, closely related to social class and a history of similar earlier obstetric situations. If maturity is more than 34 weeks the hazards are not great and can be comfortably cared for by paediatricians. Stopping labour can cause harm, either to the fetus which is in distress or to the mother who may not benefit from the drugs used to stop it. Thus not only can we both harm the fetus by stopping labour, even if the drugs are totally safe, but also with present methods we cannot be assured of absolute intrauterine fetal wellbeing. A decision to stop labour should therefore be confined to two groups of patients. First, the patients who would be better transferred to an appropriate intensive care neonatal unit (and there is no doubt that intrauterine transfer is preferable to extrauterine transfer because of the importance in hypoxia of the first 20 minutes). Secondly, to patients who are in preterm labour without any good cause, where the mother is totally healthy, the fetus is healthy, alive, and not at evident risk, the gestation is less than 35 weeks, the baby weighs less than 1500 g or more than 600 g, the membranes are intact, the cervix is less than 3 cm dilated, and there is no obvious intrauterine growth retardation.


Unilateral Erythema Nodosum following Norethindrone Acetate, Ethinyl Estradiol, and Ferrous Fumarate Combination Therapy.
Erythema nodosum is a septal panniculitis that typically presents as symmetric, tender nodules on the anterior aspects of bilateral lower extremities. Nearly half of cases are due to secondary causes, with oral contraceptive pills being the leading pharmaceutical cause. However, to our knowledge, there has yet to be a published association with norethindrone acetate, ethinyl estradiol, and ferrous fumarate. We report our experience with a 30-year-old woman who developed unilateral tender nodules within a month of starting 1 mg norethindrone acetate and 20 mcg ethinyl estradiol daily. Of note, she had previously taken oral contraceptives with the same estrogen agent but different progesterone, without problems. We conclude that systemically triggered erythema nodosum can present with lesions localized to one extremity. When a patient presents with tender, firm nodules, clinicians should consider the possibility of erythema nodosum and its triggers, such as oral contraceptives. Additionally, should a patient on hormonal therapy develop erythema nodosum, changing the progesterone agent may allow the patient to continue similar therapy without developing symptoms.


The physiology of exercise and its clinical implications in coronary heart disease.
Exercise conditioning is a safe, effective therapeutic weapon in coronary heart disease (CHD) if correctly applied. This correct application presupposes, as would be the case in other forms of medical or surgical management, that the prescriber has a thorough knowledge of the underlying pathophysiology, both of the disease and of the cure. The physiology of exercise in normal persons is described in some detail, since similar effects apply in CHD patients. The training phenomenon, too, is similar in CHD sufferers, although it is less extensive than in athletes. Lastly, the alterations in physiology by which the patient can expect to benefit, are discussed.


lncRNA JPX-Enriched Chromatin Microenvironment Mediates Vascular Smooth Muscle Cell Senescence and Promotes Atherosclerosis.
Senescence is a series of degenerative changes in the structure and physiological function of an organism. Whether JPX-a newly identified age-related noncoding RNA by us-is associated with atherosclerosis is still unknown. Our study was to investigate the role of JPX and provide insights into potential therapies targeting atherosclerosis. We analyzed clinical data from multiple tissues including meniscus tissue, leukemia cells, and peripheral blood monocytes to identify age-related noncoding RNAs in senescent vascular smooth muscle cells (VSMCs). The molecular mechanism of JPX was investigated by capture hybridization analysis of RNA targets and chromatin immunoprecipitation. IGVTools and real-time quantitative polymerase chain reaction were used to evaluate the JPX expression during phenotype regulation in age-related disease models. The therapeutic potential of JPX was evaluated after establishing an atherosclerosis model in smooth muscle-specific JPX knockout mice. JPX expression was upregulated in Ras-induced senescent VSMCs and atherosclerotic arteries. JPX knockdown substantially reduced the elevation of senescence-associated secretory phenotype (SASP) genes in senescent VSMCs. Cytoplasmic DNA leaked from mitochondria via mitochondrial permeability transition pore formed by VDAC1 (voltage-dependent anion channel 1) oligomer activates the STING (stimulator of interferon gene) pathway. JPX could act as an enhancer for the SASP genes and functions as a scaffold molecule through interacting with phosphorylated P65 and BRD4 (bromodomain-containing protein 4) in chromatin remodeling complex, promoting the transcription of SASP genes via epigenetic regulation. Smooth muscle knockout of JPX in ApoeKO mice resulted in a decrease in plaque area, a reduction in SASP gene expression, and a decrease in senescence compared with controls. As an enhancer RNA, JPX can integrate P65 and BRD4 to form a chromatin remodeling complex, activating SASP gene transcription and promoting cellular senescence. These findings suggest that JPX is a potential therapeutic target for the treatment of age-related atherosclerosis.


New Insights in Autoimmune Hemolytic Anemia: From Pathogenesis to Therapy Stage 1.
Autoimmune hemolytic anemia (AIHA) is a highly heterogeneous disease due to increased destruction of autologous erythrocytes by autoantibodies with or without complement involvement. Other pathogenic mechanisms include hyper-activation of cellular immune effectors, cytokine dysregulation, and ineffective marrow compensation. AIHAs may be primary or associated with lymphoproliferative and autoimmune diseases, infections, immunodeficiencies, solid tumors, transplants, and drugs. The direct antiglobulin test is the cornerstone of diagnosis, allowing the distinction into warm forms (wAIHA), cold agglutinin disease (CAD), and other more rare forms. The immunologic mechanisms responsible for erythrocyte destruction in the various AIHAs are different and therefore therapy is quite dissimilar. In wAIHA, steroids represent first line therapy, followed by rituximab and splenectomy. Conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine) are now considered the third line. In CAD, steroids are useful only at high/unacceptable doses and splenectomy is uneffective. Rituximab is advised in first line therapy, followed by rituximab plus bendamustine and bortezomib. Several new drugs are under development including B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), or neonatal Fc receptor. Here, a comprehensive review of the main clinical characteristics, diagnosis, and pathogenic mechanisms of AIHA are provided, along with classic and new therapeutic approaches.


Carbon Supply and Photoacclimation Cross Talk in the Green Alga Chlamydomonas reinhardtii.
Photosynthetic organisms are exposed to drastic changes in light conditions, which can affect their photosynthetic efficiency and induce photodamage. To face these changes, they have developed a series of acclimation mechanisms. In this work, we have studied the acclimation strategies of Chlamydomonas reinhardtii, a model green alga that can grow using various carbon sources and is thus an excellent system in which to study photosynthesis. Like other photosynthetic algae, it has evolved inducible mechanisms to adapt to conditions where carbon supply is limiting. We have analyzed how the carbon availability influences the composition and organization of the photosynthetic apparatus and the capacity of the cells to acclimate to different light conditions. Using electron microscopy, biochemical, and fluorescence measurements, we show that differences in CO2 availability not only have a strong effect on the induction of the carbon-concentrating mechanisms but also change the acclimation strategy of the cells to light. For example, while cells in limiting CO2 maintain a large antenna even in high light and switch on energy-dissipative mechanisms, cells in high CO2 reduce the amount of pigments per cell and the antenna size. Our results show the high plasticity of the photosynthetic apparatus of C. reinhardtii This alga is able to use various photoacclimation strategies, and the choice of which to activate strongly depends on the carbon availability.


Neuroimaging contrast across the cortical hierarchy is the feature maximally linked to behavior and demographics.
An essential task of neuroscience is to elucidate the relationship between brain activity, brain structure, and human behavior. This study aims to understand this 3-way relationship by studying the population covariance of resting-state functional connectivity, cortical thickness, and behavioral/demographic measures in a large cohort of individuals. Using a data-driven canonical correlation analysis, we found that maximal pairwise correlations between the three modalities are approximately along the same direction across subjects, which is characterized by the change of the overall positive-negative trait of human behavior. More importantly, this behavioral change is associated with a divergent modulation of both resting-state connectivity and cortical thickness across cortical hierarchies between the higher-order cognitive networks and lower-order sensory/motor regions. The findings suggest that the cross-hierarchy contrast of structural and functional brain measures is tightly linked to the overall positive-negative trait of human behavior/demographics.


Risk Perception and Media in Shaping Protective Behaviors: Insights From the Early Phase of COVID-19 Italian Outbreak.
In the absence of target treatments or vaccination, the SARS-CoV-2 pandemic can be impeded by effectively implementing containment measures and behaviors. This relies on individuals' adoption of protective behaviors, their perceived risk, and the use and trust of information sources. During a health emergency, receiving timely and accurate information enables individuals to take appropriate actions to protect themselves, shaping their risk perception. Italy was the first western country plagued by COVID-19 and one of the most affected in the early phase. During this period, we surveyed 2,223 Italians before the national lockdown. A quarter of the sample perceived COVID-19 less threatening than flu and would not vaccinate, if a vaccine was available. Besides, most people perceived containment measures, based on social distancing or wearing masks, not useful. This perceived utility was related to COVID-19 threat perception and efficacy beliefs. All these measures were associated with the use of media and their truthfulness: participants declared to mainly use the Internet, while health organizations' websites were the most trusted. Although social networks were frequently used, they were rated lower for trustfulness. Our data differ from those obtained in other community samples, suggesting the relevance to explore changes across different countries and during the different phases of the pandemic. Understanding these phenomena, and how people access the media, may contribute to improve the efficacy of containment measures, tailoring specific policies and health communications.


Hydrologic and atrazine simulation of the Cedar Creek Watershed using the SWAT model.
One of the major factors contributing to surface water contamination in agricultural areas is the use of pesticides. The Soil and Water Assessment Tool (SWAT) is a hydrologic model capable of simulating the fate and transport of pesticides in an agricultural watershed. The SWAT model was used in this study to estimate stream flow and atrazine (2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine) losses to surface water in the Cedar Creek Watershed (CCW) within the St. Joseph River Basin in northeastern Indiana. Model calibration and validation periods consisted of five and two year periods, respectively. The National Agricultural Statistics Survey (NASS) 2001 land cover classification and the Soil Survey Geographic (SSURGO) database were used as model input data layers. Data from the St. Joseph River Watershed Initiative and the Soil and Water Conservation Districts of Allen, Dekalb, and Noble counties were used to represent agricultural practices in the watershed which included the type of crops grown, tillage practices, fertilizer, and pesticide application rates. Model results were evaluated based on efficiency coefficient values, standard statistical measures, and visual inspection of the measured and simulated hydrographs. The Nash and Sutcliffe model efficiency coefficients (E(NS)) for monthly and daily stream flow calibration and validation ranged from 0.51 to 0.66. The E(NS) values for atrazine calibration and validation ranged from 0.43 to 0.59. All E(NS) values were within the range of acceptable model performance standards. The results of this study indicate that the model is an effective tool in capturing the dynamics of stream flow and atrazine concentrations on a large-scale agricultural watershed in the midwestern USA.


Interaction of Mg-2+ with peptidoglycan and its relation to the prevention of lysis of a marine pseudomonad.
Intact cells of marine pseudomonad B-16 (ATCC 19855) which have been washed with a solution of NaCl require only 0.001 M MgSO4 and 100 to 300 times this concentration of NaCl or KCl to prevent lysis. Conversion of intact cells to mureinoplasts, a process involving removal of the outer double-track layer (outer membrane) and the periplasmic space layer of the cell wall, approximately doubled the requirement for the three salts to prevent lysis. The formation of protoplasts from mureinoplasts by removing the peptidoglycan layer again doubled the requirement for Na+ and K+ salts but increased the requirement for the Mg-2+ salt 200- to 300-fold. Cells of the marine pseudomonad suspended in solutions containing Mg-2+ salts failed to lyse on subsequent repeated suspension in distilled water, whereas cells presuspended in NaCl lysed immediately. Isolated envelope layers including the peptidoglycan layer, when dialyzed against solutiions containing Mg-2+ salts, retained Mg-2+ after subsequent suspension in distilled water. Envelope layers exposed to solutions of Na+ or K+ salts failed to retain these ions after exposure to distilled water. Na+ displaced Mg-2+ from the cell envelope layers. The results obtained indicate that the capacity of Mg-2+ salts at very low concentration to prevent lysis of intact cells and mureinoplasts of this organism is due primarily to the interaction of Mg-2+ with the peptidoglycan layer of the cell wall. Ion interaction with the layers lying outside of the peptidoglycan layer contributes only a small amount to the mechanical strength of the wall.


Manipulation of the Pancharatnam phase in vectorial vortices.
Linearly polarized vectorial vortices are analyzed according to their Pancharatnam phase and experimentally demonstrated using a geometric phase element consisting of space-variant subwavelength gratings. It is shown that in the absence of a Pancharatnam phase, stable vectorial vortices that have no angular momentum arise. In contrast, if a Pancharatnam phase is present the vectorial vortices have orbital angular momentum and collapse upon propagation.


Ticks and tickborne bacterial diseases in humans: an emerging infectious threat.
Ticks are currently considered to be second only to mosquitoes as vectors of human infectious diseases in the world. Each tick species has preferred environmental conditions and biotopes that determine the geographic distribution of the ticks and, consequently, the risk areas for tickborne diseases. This is particularly the case when ticks are vectors and reservoirs of the pathogens. Since the identification of Borrelia burgdorferi as the agent of Lyme disease in 1982, 15 ixodid-borne bacterial pathogens have been described throughout the world, including 8 rickettsiae, 3 ehrlichiae, and 4 species of the Borrelia burgdorferi complex. This article reviews and illustrate various aspects of the biology of ticks and the tickborne bacterial diseases (rickettsioses, ehrlichioses, Lyme disease, relapsing fever borrelioses, tularemia, Q fever), particularly those regarded as emerging diseases. Methods are described for the detection and isolation of bacteria from ticks and advice is given on how tick bites may be prevented and how clinicians should deal with patients who have been bitten by ticks.


The acquisition of conditioned responding.
This report analyzes the acquisition of conditioned responses in rats trained in a magazine approach paradigm. Following the suggestion by Gallistel, Fairhurst, and Balsam (2004), Weibull functions were fitted to the trial-by-trial response rates of individual rats. These showed that the emergence of responding was often delayed, after which the response rate would increase relatively gradually across trials. The fit of the Weibull function to the behavioral data of each rat was equaled by that of a cumulative exponential function incorporating a response threshold. Thus, the growth in conditioning strength on each trial can be modeled by the derivative of the exponential--a difference term of the form used in many models of associative learning (e.g., Rescorla & Wagner, 1972). Further analyses, comparing the acquisition of responding with a continuously reinforced stimulus (CRf) and a partially reinforced stimulus (PRf), provided further evidence in support of the difference term. In conclusion, the results are consistent with conventional models that describe learning as the growth of associative strength, incremented on each trial by an error-correction process.


[Changes in the cyclic AMP level in the cells of murine sarcoma induced by monkey adenovirus SA7(C8) during tumor growth enhanced by lymphocytes from intact syngeneic mice].
Under consideration is the problem of changes in the cAMP level in sarcoma of mice CBA with routine and enhanced rate of growth. To this end the kinetics of sarcoma growth, induced by monkey adenovirus SA7 (C8), with common and stimulated by lymphocytes from intact syngeneic animals rates of growth was studied. Simultaneously, the kinetics of intracellular cAMP content in tumor cells was studied too. It was found that there is an inverse dependence between the cAMP content and the rate of sarcoma SA7 (C8) growth. Use of one type of tumor cells with the predetermined different rate of growth makes it possible to relate the changes in the content of intracellular tumor cell cAMP with changes being due to growth potentials.


A sparse orthogonal collimator for small animal intensity-modulated radiation therapy. Part II: hardware development and commissioning.
A dose-modulation device for small animal radiotherapy is required to use clinically analogous treatment techniques, which will likely increase the translatability of preclinical research results. Because the clinically used multileaf collimator (MLC) is impractical for miniaturization, we have developed a simpler, better-suited sparse orthogonal collimator (SOC) for delivering small animal intensity-modulated radiation therapy (IMRT) using a rectangular aperture optimization (RAO) treatment planning system. The SOC system was modeled in computer-aided design software and fabricated with machined tungsten leaves and three-dimensional (3D) printed leaf housing. A graphical user interface was developed for controlling and calibrating the SOC leaves, which are driven by Arduino-controlled stepper motors. A Winston-Lutz test was performed to assess mechanical alignment, and abutting field and grid dose patterns were created to analyze intra- and intercalibration leaf positioning error. Leaf transmission and penumbra were measured over the full range of gantry angles and leaf positions, respectively. Three SOC test plans were delivered, and film measurements were compared to the intended dose distributions. The differences in maximum, mean, and minimum, as well as pixelwise absolute dose differences, were compared for each structure, and a gamma analysis was performed for the target structures using criteria of 4% dose difference and 0.3 mm distance to agreement. The Winston-Lutz test revealed maximum directional offsets between the SOC and primary collimator axes of 0.53 mm at 0° and 0.68 mm over the full 360°. Upper and lower abutting field patterns had maximum dose deviations of 18.8 ± 3.1% and 15.5 ± 2.9%, respectively, and grid patterns showed intra- and intercalibration repeatability of 93% and 91%, respectively. Extremely low midleaf (0.15 ± 0.05%) and interleaf (0.27 ± 0.22%) transmission was measured, with no significant rotational variation. The average penumbra was ~0.8 mm for all leaves at field center, with a range of 0.17 mm for all leaf positions. A highly concave test plan was delivered with a ~ 95% gamma analysis pass rate, and a realistic mouse phantom liver irradiation plan achieved a pass rate of ~98%. A highly complex dose distribution was also created with 551 SOC apertures averaging 2.4 mm in size. A sparse orthogonal collimator was developed and commissioned, with promising preliminary dosimetry results. The SOC design, with its limited moving components and high dose-modulation resolution, is ideal for delivering high-quality small animal IMRT with our RAO-based treatment planning system.


Strasberg's Critical View: Strategy for a Safe Laparoscopic Cholecystectomy.
Every year, worldwide, the celebration for patient safety is carried out; since about 2.6 million people are documented who die each year from events that can potentially be avoided during their medical care, it is even estimated that around 15% of hospital costs can be attributed to treatment resulting in patient safety. As an important part of its dissemination in the medical-surgical community, we present the following article in relation to the critical vision of safety in the bile duct, promoted and published initially by Dr Steven Strasberg, which aims to reduce the number of complications during laparoscopic cholecystectomies. A bibliographic search was carried out in PubMed, Medline, Clinical Key, and Index Medicus. From May 2020 to July 2021 in Spanish and English with the following. Strasberg's critical view is a proposed strategy to minimize the risk to zero during laparoscopic gallbladder surgery. It consists of obtaining a plane in which the surgeon can visualize the anatomical structures that make up the bile duct, as well as its irrigation and drainage. Being able to clearly observe these structures allows the surgeon to cut freely and safely to avoid bile duct injuries which are not so uncommon during this procedure. Montalvo-Javé EE, Contreras-Flores EH, Ayala-Moreno EA, et al. Strasberg's Critical View: Strategy for a Safe Laparoscopic Cholecystectomy. Euroasian J Hepato-Gastroenterol 2022;12(1):40-44.


The Animal Welfare Act: from enactment to enforcement.
Originally enacted in 1966, the Laboratory Animal Welfare Act has been amended several times and renamed the Animal Welfare Act. Responsibility for administering the Animal Welfare Act was delegated within the United States Department of Agriculture to the Administrator of the Animal and Plant Health Inspection Service, and regulations and standards have been developed to implement the intent of Congress conveyed in the language of the Act. In our opinion, the key to compliance with the Animal Welfare Act and its regulations and standards is to have in place a proactive, progressive Animal Care and Use Program that uses the semiannual inspection and programmatic review process to improve the day-to-day management of the program. Successfully managing the inspection process has taken on new meaning in what has recently become known as the 'Age of Enforcement.' As part of this approach, the Animal and Plant Health Inspection Service made changes to the inspection process and issued an Enhanced Animal Welfare Enforcement Plan, which included the development of an Inspection Requirements Handbook. The Inspection Requirements Handbook provides inspectors with information on conducting inspections and includes as an attachment a flow chart for Enforcement Action Guidance. The chart describes 4 types of actions that may occur as part of the enforcement process and the steps that will be followed if noncompliant items are documented during an inspection.


Amphiphilic behavior of new cholesteryl cyclodextrins: a molecular study.
Amphiphilic cyclodextrins (CDs) are good candidates to functionalize natural membranes as well as synthetic vesicles. In this paper, we describe the synthesis of the amphiphilic permethylated monocholesteryl α-CD (TASC). Its interfacial behavior is compared with that of the permethylated mono- and dicholesteryl β-CD analogues (TBSC and TBdSC). Langmuir isotherms suggest a reorganization upon compression for all compounds, which is quantified using neutron as well as X-ray reflectivity. The in-plane structure is characterized by atomic force microscopy (AFM) on monolayers deposited on solid substrates. A model involving a reorientation of the CD with respect to the interface to adjust its conformation to the available area per molecule is proposed. Although we observe for TBSC a rearrangement similar to TASC and TBdSC, it is already achieved at lower surface pressures compared with its disubstituted derivative. This specific behavior is explained by an increased structural flexibility and compressibility compared with TBdSC and TASC. The average number of water molecules per CD was determined using the neutron data and validated from X-ray data, which also allows the determination of the CD's molecular volume. The permethylated CD molecules are strongly hydrated in the film, but the α-CD analogue is less hydrated than the β-CD derivatives, and hydration decreases with compression.


Kindergarten Predictors of Third Grade Writing.
The primary goal of the present study was to examine the relations of kindergarten transcription, oral language, word reading, and attention skills to writing skills in third grade. Children (N = 157) were assessed on their letter writing automaticity, spelling, oral language, word reading, and attention in kindergarten. Then, they were assessed on writing in third grade using three writing tasks - one narrative and two expository prompts. Children's written compositions were evaluated in terms of writing quality (the extent to which ideas were developed and presented in an organized manner). Structural equation modeling showed that kindergarten oral language and lexical literacy skills (i.e., word reading and spelling) were independently predicted third grade narrative writing quality, and kindergarten literacy skill uniquely predicted third grade expository writing quality. In contrast, attention and letter writing automaticity were not directly related to writing quality in either narrative or expository genre. These results are discussed in light of theoretical and practical implications.


Tissue engineering of bovine articular cartilage within porous poly(ether ester) copolymer scaffolds with different structures.
The potential of porous poly(ether ester) scaffolds made from poly(ethylene glycol) terephthalate: poly(butylene terephthalate) (PEGT:PBT) block copolymers produced by various methods to enable cartilaginous tissue formation in vitro was studied. Scaffolds were fabricated by two different processes: paraffin templating (PT) and compression molding (CM). To determine whether PEGT:PBT scaffolds are able to support chondrogenesis, primary bovine chondrocytes were seeded within cylindrical scaffolds under dynamic seeding conditions. On day 3, constructs were transferred to six-well plates and evaluated for glycosaminoglycan (GAG) distribution (3, 10, and 24 days), type II collagen distribution, cellularity, and total collagen and GAG content (10 and 24 days). It was observed that better cell distribution during infiltration within PT scaffolds allowed greater chondrogenesis, and at later time points, than in CM scaffolds. The amount of GAG remained constant for all groups from 10 to 24 days, whereas collagen content increased significantly. These data suggest that PEGT:PBT scaffolds are suitable for cartilage tissue engineering, with the PT process enabling greater chondrogenesis than CM.


Emission color variation of (Ba,Sr)3BP3O12:Eu2+ phosphors for white light LEDs.
A series of alkaline earth borophosphate phosphors, (Ba,Sr)(3)BP(3)O(12) doped with Eu(2+) ions, were synthesized by a solid state reaction. Two emission bands at 465 nm and 520 nm were attributed to the f-d transitions of doped Eu(2+) ions occupying in two different cation sites in host lattices and emission color variation was observed by substituting the M(2+) sites, which was rationalized in terms of two competing factors of the crystal field strength and bond covalence. Green and bluish-white pc-LEDs were fabricated by combination of a 370 nm near-UV chip and composition-optimized Ba(3)BP(3)O(12):Eu(2+) and (Ba,Sr)(3)BP(3)O(12):Eu(2+) phosphors, respectively. The series of phosphors may serve as a promising green and bluish-white luminescent materials used in fabrication of near UV-based white pc-LEDs.


Coping with the threat of severe acute respiratory syndrome: Role of threat appraisals and coping responses in health behaviors.
The present study examines the psychological impact of severe acute respiratory syndrome (SARS) by exploring the coping strategies and health behaviors enacted in response to the SARS epidemic. Hierarchical linear regression indicated that the use of wishful thinking in response to the threat of SARS was related to both avoiding public places and avoiding people perceived to be possible carriers of the SARS virus, but was not associated with the use of more adaptive health behaviors, such as using disinfectants and hand washing. Conversely, those who reported engaging in empathic responding in response to the threat of SARS were both less likely to report avoiding people perceived as being at a high risk for SARS and more likely to report engaging in effective health behaviors. Support seeking was not a significant predictor of the health behaviors examined in the present study. Results are discussed in terms of coping with health threats and health promotion.


[The frequency of anemia in children with newly diagnosed Crohn's disease in children].
The aim of the study was to analyze the occurrence of anemia in children with newly diagnosed Crohn's disease and 3 months after the initiation of treatment depending on location and activity of the disease. 36 children aged from 2 to 18 years with newly diagnosed Crohn's disease treated in the years 2005-2011. According to the classification of Paris children were divided into 2 groups: II - 9 children (0-10 years); II - 27 children (11-17 years). We analyzed RBC, Hb, HCT, MCV, Fe, PCDAI at diagnosis and 3 months after the treatment, depending on the location and phenotype of the disease. Anemia was defined according to WHO criteria. Children were treated in accordance with the standards and activity of the disease. During the observation period supplementation of iron was not used. We analyzed the potential factors that could affect on the incidence of anemia. In the group I mean activity of the disease was lower than in group II in both observed periods. No statistically significant differences in hemoglobin, red blood cell count, hematocrit and volume of erythrocytes at diagnosis and after 3 months were noted. The average iron concentration increased from 6.98 microg/dl to 9.95 microg/dl (p < 0.05) after the treatment. A statistically significant higher incidence of iron deficit in group II in both analyzed periods was observed, respectively, 66.7% vs 92.59% and 55.5% vs 77.77% (p < 0.05). Anemia was more frequent in group II (p > 0.05). After 3 months of treatment the incidence of anemia reduced from 63.88% to 44.4% (p < 0.05) and iron deficit from 83.3% to 72.2% (p > 0.05). Inflammatory changes in upper gastrointestinal tract were found in 61.1% of children with Helicobacter pylori infection in 8.3% of cases. Ileal location was observed in 52.7% of children, more often in group II than I, 62.9% vs 22.22% (p < 0.05). Isolated location of inflammatory lesions in the colon more frequently observed in group I than II, respectively 55.5% vs 29.6% (p < 0.05). Thiopurine were used in 38.8% of children more often in group II than I, respectively 48.1% vs 11.1% (p < 0.05). Corticosteroids were used in 50.0% of children, often in group II than I, respectively 55.5% vs. 33.3% (p > 0.05). In children with newly diagnosed Crohn's disease anemia was diagnosed in 63.88% of the children and in 47.2% of children after 3 months of treatment (p < 0.05), iron deficiencies, respectively, in 83.3% and 72.2% of children (p > 0.05). 3-month treatment period of Crohn's disease has increased the iron concentration from 6.98 microg/dl to 9.95 mg/dl although the absence of supplementation (p < 0.05). In group II more often than in group I risk factors of anemia like changes in the upper gastrointestinal tract, the location of the ileum, intestinal villous atrophy and the use of immunosuppressive drugs were observed (p < 0.05). Anemia and iron deficiency were more often observed in the ileocolonic location than when the upper gastrointestinal tract was involved (adquately 55.5% vs 30.5%; p < 0.05 and 75.0% vs 41.6%; p < 0.05).


Does the mean platelet volume have any importance in patients with acute pulmonary embolism?
To determine whether an association exists between a known marker of platelet activation, mean platelet volume (MPV), and the severity of acute pulmonary embolism (APE), and to test whether it can be used as prognostic indicator in patients with high-risk pulmonary embolism (PE). The study included 209 consecutive patients with APE (106 male, 103 female, mean age 62.4 ± 15.4 years) and 162 controls (86 male, 76 female) matched for age (60.5 ± 14.3 years) and concomitant diseases. Contrast-enhanced spiral computerized tomography or ventilation-perfusion scintigraphy, echocardiography, and lower extremity venous Doppler ultrasound were performed on the patients with APE. D-dimer level, troponin, arterial blood gases, platelet count, and MPV were measured in serum. The MPV did not differ between the patients with APE and the controls (8.0 ± 1.1 fL, 7.9 ± 0.59 fL, p = 0.22). There were no significant differences in the value of MPV among the groups of patients with massive, submassive, and nonmassive PE (MPV: 8.3 ± 0.9 fL, 8.1 ± 1.0 fL, 7.9 ± 1.1 fL, p = 0.08, respectively). The MPV was higher in non-survivors than survivors (8.6 ± 1.1 vs. 7.9 ± 1.1 fL, p = 0.02). There was a statistically weak correlation between MPV and mean pulmonary arterial pressure (r = 0.25, p < 0.001) and also between MPV and right ventricle diameter (r = 0.11, p = 0.045). Our results suggest that a simple baseline determination of MPV at a single time point is not a reliable indicator to determine the severity of PE or for the diagnosis of APE, but it is possible that the MPV increases in nonsurvivors.


Neuroprotective potency of mangiferin against 3-nitropropionic acid induced Huntington's disease-like symptoms in rats: possible antioxidant and anti-inflammatory mechanisms.
Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of psychiatric disturbances, cognitive and motor dysfunction. The daily performances and life quality of HD patients have been severely interfered by these clinical signs and symptoms until the last stage of neuronal cell death. To the best of our knowledge, no treatment is available to completely mitigate the progression of HD. Mangiferin, a naturally occurring potent glucoxilxanthone, is mainly isolated from the Mangifera indica plant. Considerable studies have confirmed the medicinal benefits of mangiferin against memory and cognitive impairment in neurodegenerative experimental models such as Alzheimer's and Parkinson's diseases. Therefore, this study aims to evaluate the neuroprotective effect of mangiferin against 3-nitropropionic acid (3-NP) induced HD in rat models. Adult Wistar rats (n = 32) were randomly allocated equally into four groups of eight rats each: normal control (Group I), disease control (Group II) and two treatment groups (Group III and Group IV). Treatment with mangiferin (10 and 20 mg/kg, p. o.) was given for 14 days, whereas 3-NP (15 mg/kg, i. p.) was given for 7 days to induce HD-like symptoms in rats. Rats were assessed for cognitive functions and motor coordination using open field test (OFT), novel object recognition (NOR) test, neurological assessment, rotarod and grip strength tests. Biochemical parameters such as oxidative stress markers and pro-inflammatory markers in brain hippocampus, striatum and cortex regions were evaluated. Histopathological study on brain tissue was also conducted using hematoxylin and eosin (H&E) staining. 3-NP triggered anxiety, decreased recognition memory, reduced locomotor activity, lower neurological scoring, declined rotarod performance and grip strength were alleviated by mangiferin treatment. Further, a significant depletion in brain malondialdehyde (MDA) level, an increase in reduced glutathione (GSH) level, succinate dehydrogenase (SDH), superoxide dismutase (SOD) and catalase (CAT) activities, and a decrease in tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) levels were observed in mangiferin treated groups. Mangiferin also mitigated 3-NP induced histopathological alteration in the brain hippocampus, striatum and cortex sections. It could be inferred that mangiferin protects the brain against oxidative damage and neuroinflammation, notably via antioxidant and anti-inflammatory activities. Mangiferin, which has a good safety profile, may be an alternate treatment option for treating HD and other neurodegenerative disorders. The results of the current research of mangiferin will open up new avenues for the development of safe and effective therapeutic agents in diminishing HD.


Renal function during and after a temporary complete unilateral ureter obstruction in rats.
We studied changes in the glomerular filtration rate (GFR) and in the distribution of the renal blood flow over the left and right kidney during and after unilateral ureteral obstruction in rats. The fraction of the total renal blood flow to the obstructed kidney slowly decreased with the duration of obstruction. The fraction of the total GFR decreased at a much faster rate. After the removal of an obstruction of 7, 14, or 21 days, the kidney resumed glomerular filtration with or without an intact contralateral kidney. The degree of recovery diminished with the duration of the obstruction. We conclude that recovery of the GFR, in the case of a complete unilateral ureteral obstruction, depends upon the duration of the obstruction and not on the presence of the intact contralateral kidney.


Diminished AHR Signaling Drives Human Acute Myeloid Leukemia Stem Cell Maintenance.
Eliminating leukemic stem cells (LSC) is a sought after therapeutic paradigm for the treatment of acute myeloid leukemia (AML). While repression of aryl hydrocarbon receptor (AHR) signaling has been shown to promote short-term maintenance of primitive AML cells in culture, no work to date has examined whether altered AHR signaling plays a pathologic role in human AML or whether it contributes at all to endogenous LSC function. Here, we show AHR signaling is repressed in human AML blasts and preferentially downregulated in LSC-enriched populations within leukemias. A core set of AHR targets are uniquely repressed in LSCs across diverse genetic AML subtypes. In vitro and in vivo administration of the specific AHR agonist FICZ significantly impaired leukemic growth, promoted differentiation, and repressed self-renewal. Furthermore, LSCs suppressed a set of FICZ-responsive AHR target genes that function as tumor suppressors and promoters of differentiation. FICZ stimulation did not impair normal hematopoietic stem and progenitor (HSPC) function, and failed to upregulate a prominent LSC-specific AHR target in HSPCs, suggesting that differential mechanisms govern FICZ-induced AHR signaling manifestations in HSCs versus LSCs. Altogether, this work highlights AHR signaling suppression as a key LSC-regulating control mechanism and provides proof of concept in a preclinical model that FICZ-mediated AHR pathway activation enacts unique transcriptional programs in AML that identify it as a novel chemotherapeutic approach to selectively target human LSCs. SIGNIFICANCE: The AHR pathway is suppressed in leukemic stem cells (LSC), therefore activating AHR signaling is a potential therapeutic option to target LSCs and to treat acute myeloid leukemia.


[Study of antiarrhythmic activity and duration of action of quaternidine].
The results of experiments on dogs showed that quaternidine, a quaternary ammonium derivative of trimecaine, produces a significant antiarrhythmogenic effect in cases of rhythm disorders in the late stage of a model myocardial infarction. For drugs administered in a single isotoxic dose, the therapeutic effect of quaternidine in animals with acute myocardial ischemia considerably exceeds the duration of action of lidocaine and trimecaine.


Gene Expression Noise Enhances Robust Organization of the Early Mammalian Blastocyst.
A critical event in mammalian embryo development is construction of an inner cell mass surrounded by a trophoectoderm (a shell of cells that later form extraembryonic structures). We utilize multi-scale, stochastic modeling to investigate the design principles responsible for robust establishment of these structures. This investigation makes three predictions, each supported by our quantitative imaging. First, stochasticity in the expression of critical genes promotes cell plasticity and has a critical role in accurately organizing the developing mouse blastocyst. Second, asymmetry in the levels of noise variation (expression fluctuation) of Cdx2 and Oct4 provides a means to gain the benefits of noise-mediated plasticity while ameliorating the potentially detrimental effects of stochasticity. Finally, by controlling the timing and pace of cell fate specification, the embryo temporally modulates plasticity and creates a time window during which each cell can continually read its environment and adjusts its fate. These results suggest noise has a crucial role in maintaining cellular plasticity and organizing the blastocyst.