An association study of polymorphisms in the H19 imprinted gene in an Iranian population with the risk of polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies that causes problems in female fertility at the reproductive age. PCOS is a multifactorial disease, with genetic factors playing a crucial role in its development. H19 is a long non-coding RNA (lncRNA) expressed from the maternal chromosome, which is correlated with PCOS. In this study, 115 women suffering from PCOS and 130 healthy women with regular menstrual cycles were recruited as case and control groups, respectively. After the extraction of genomic DNA, the restriction fragment length polymorphism polymerase chain reaction was employed for genotyping of rs2067051G>A and rs3741219T>C. Statistical analysis was done using SPSS package V.22 for Windows. In silico analysis was recruited to determine the effects of SNPs on the secondary structure of gene transcript as well as miRNA binding sites. The obtained data showed that the A allele of rs2067051G>A was associated with the high risk of PCOS (OR = 2.00, 95%CI = 1.38-2.91, P = 0.00). AG and AA genotypes led to a 3.64- and (about) a five-fold increase in the risk of PCOS, respectively (95%CI = 2.02-6.54, P = 0.00, and 95%CI = 1.51-16.52, P = 0.00, respectively). These variants caused a significant increase in the risk of this disorder in all genotype models except in the recessive model. However, no association was found between rs3741219T>C and the increased risk of PCOS, either in the allele or in the genotype models. According to the findings, rs2067051G>A is associated with an increased risk of PCOS in the Iranian population.


[Influencing Factors for Hydrolysis of Sewage Sludge Pretreated by Microwave-H2O2-Alkaline Process].
Pretreatment can improve carbon source utilization of sludge. In this study, influencing factors of hydrolysis including hydrolysis time, ratio of seed sludge and temperature were investigated for sewage sludge pretreated by microwave-H2O2-alkaline process through batch experiments. Meanwhile, effects of hydrolysis and releasing characteristics of organic matters were also investigated under the optimized conditions. The results showed that the optimal hydrolysis time was 12 h and the optimized inoculum to substrate ratio (I/S) was 0.07. Under optimized conditions (12 h, I/S =0.07), SCOD, soluble proteins, soluble sugars and total VFAs content increased with increasing temperature, reaching the maximum at 65 degrees C. Acetic, propionic and iso-valeric acids were the dominant VFAs produced, and the percentage of acetic acid accounting for total VFAs was between 42.7% and 59.7%. In terms of carbon source composition, SCOD accounted for 37.8%-40.8% of total COD, soluble proteins accounted for 38.3%-41.3% of SCOD, soluble sugars accounted for 9.0%-9.3% of SCOD and total VFAs accounted for 3.3%-5.5% of SCOD. The COD/TN watio was between 15.79 and 16.50 in the sludge supernatant. The results of the three-dimensional fluorescence spectra and apparent molecular weight distributions showed that the fluorescence intensity of tyrosine-like substances in the soluble microbial products was the highest and increased with the increasing temperature in the sludge supernatant. After the sewage sludge was pretreated by microwave-H2O2-OH process, a lot of organic matters were released, including small molecule organics (M 100-350), while after hydrolysis, M, 3000-60,000 organics were degraded.


How to grow great leaders.
Few leaders excel at both the unit and enterprise levels. More than ever, though, corporations need people capable of running business units, functions, or regions and focusing on broader company goals. It's up to organizations to develop leaders who can manage the inherent tensions between unit and enterprise priorities. Take the example of RBC Financial Group, one of the largest, most profitable companies in Canada. In the mid-1990's, RBC revamped its competitive strategy in a couple of ways. After the government announced that the Big Six banks in Canada could neither merge with nor acquire one another, RBC decided to grow through cross-border acquisitions. Additionally, because customers were starting to seek bundled products and services, RBC reached across its traditional stand-alone businesses to offer integrated solutions. These changes in strategy didn't elicit immediate companywide support. Instinctively, employees reacted against what would amount to a delicate balancing act: They would have to lift their focus out of their silos while continuing to meet unit goals. However, by communicating extensively with staff members, cross-fertilizing talent across unit boundaries, and targeting rewards to shape performance, RBC was able to cultivate rising leaders with the unit expertise and the enterprise vision to help the company fulfill its new aims. Growing such well-rounded leaders takes sustained effort because unit-enterprise tensions are quite real. Three common conditions reinforce these tensions. First, most organizational structures foster silo thinking and unimaginative career paths. Second, most companies lack venues for airing and resolving conflicts that arise when there are competing priorities. Third, many have misguided reward systems that pit unit performance against enterprise considerations. Such long-established patterns of organizational behavior are tough to break. Fortunately, as RBC discovered, people can be trained to think and work differently.


Quantifying streams of thought during cognitive task performance using sequence analysis.
Streams of thought vary in content from one moment to the next, and these temporal patterns have been argued to be critical to understanding the wandering mind. But few analytic methods have been proposed that can account for both the content and temporal ordering of categorical experience sampling thought probes over time. In the present study, I apply sequence analytic methods to quantify the dynamics of thought from time series sequences of categorical experience sampling thought probes delivered across five different cognitive tasks in the same individuals (N = 545). Analyses revealed some patterns of consistency in streams of thought within individuals, but also demonstrated considerable variability within and between task sessions. Hierarchical clustering of sequence dissimilarities further revealed common typologies of mind wandering across individuals. These findings demonstrate the application of sequence analytic methods for quantifying the dynamics of thought over the course of task performance and show that contextual task constraints are associated with how streams of thought unfold over time. More broadly, sequence analysis provides a valuable framework for investigation of time ordered cognitive and behavioral processes across psychological domains.


[Vascularization of the human embryonic neocortex in the rat anterior chamber under cyclosporine A immunosuppression].
Fragments of 9 weeks hyman embryo neocortex were grafted into the rat eye anterior chamber. To prevent rejection cyclosporin A was introduced to the animals. Vascular network forming in transplants was studied for 5 weeks 3 days endothelial buds from the iris vessels appeared in transplants. After 10 days capillaries with erythrocytes appeared in the graft on the border with iris. 3 weeks later vascular network achieved its maximal development, occupying almost the entire graft thickness. The vessels developed diverged from the norm: they had variceal widenings, and focal distribution with significant non-vascular gaps.


Use of oral stable strontium to provide an index of intestinal calcium absorption in chronic ambulatory peritoneal dialysis patients.
Recent interest in the role of oral calcium carbonate and low calcium dialysate has emphasised the need for a simple, safe and inexpensive test of intestinal calcium absorption. The stable, non-radioactive, strontium absorption test fits these requirements. Stable strontium and calcium-45 were administered simultaneously to 19 fasting CAPD patients and their serum levels were subsequently measured. There was a close correlation between the absorption of calcium and strontium at both 60 and 120 min post-ingestion. The two markers resulted in the same classification of patients as normal or malabsorbers in 18 of 19 cases (95%), suggesting that strontium could be substituted for calcium-45 in a 60-min test of absorption enabling safe, simple and repeated measurements in renal failure patients.


Evaluating the Impact of the Diabetes Mellitus Strategy for the National Health System: An Interrupted Time Series Analysis.
(1) Background: Diabetes mellitus is a significant public health problem. Macrovascular complications (stroke, acute myocardial infarction (AMI) and lower limb amputations (LLAs) represent the leading cause of morbi-mortality in DM. This work aims to evaluate the impact of the approval of the Diabetes Mellitus Strategy of the National Health System (SDM-NHS) on hospitalizations for those macrovascular complications related to DM; (2) Methods: Interrupted time series applying segmented regression models (Negative Binomial) adjusted for seasonality to data from hospital discharge records with a primary or secondary diagnosis of DM (code 250 ICD9MC); (3) Results: Between 2001 and 2015, there have been 7,302,750 hospital discharges with a primary or secondary diagnosis of DM. After the approval of the SDM-NHS, all the indicators showed a downward trend, modifying the previous trend in the indicators of AMI and LLA. The indicators of stroke and AMI also showed an immediate reduction in their rates; (4) Conclusions: After the approval of the SDM-NHS, an improvement has been observed in all the indicators of macrovascular complications of DM evaluated, although it is difficult to establish a causal relationship between the strategy and the effects observed. Interrupted time series is applicable for evaluating the impact of interventions in public health when experimental designs are not possible.


Comparison of adolescent, young adult, and adult women's maternity experiences and practices.
Pregnant adolescents face unique challenges. Understanding the experiences, knowledge, and behaviors of adolescents during the pregnancy and postpartum periods may contribute to improvement of their maternity care. The purpose of this study was to compare the maternity experiences, knowledge, and behaviors of adolescent, young adult, and adult women by using a nationally representative sample. This study used data from the Canadian Maternity Experiences Survey (N = 6421). The weighted proportions of each variable were calculated by using survey sample weights. Logistic regression was used to estimate odds ratios. Bootstrapping techniques were used to calculate variance estimates for prevalence and 95% confidence intervals. Adolescents and young adults were more likely to experience physical abuse in the previous 2 years, initiate prenatal care late, not take folic acid before or during pregnancy, have poor prenatal health behaviors, have a lower cesarean delivery rate, have lower breastfeeding initiation and duration rates, experience more stressful life events, experience postpartum depression symptoms, and rate their infant's health as suboptimal than adult women. Adolescents were more likely to rate their own health as suboptimal. Adolescents have unique needs during pregnancy and postpartum. Health care professionals should seek to provide care in a manner that acknowledges these needs.


Stimulation of erythrocyte phospholipid scrambling by enniatin A.
Enniatin A, a peptide antibiotic and common food contaminant, triggers mitochondrial dysfunction and apoptosis. Even though lacking mitochondria, erythrocytes may similarly undergo suicidal cell death or eryptosis. Eryptosis is characterized by cell shrinkage and cell membrane phospholipid scrambling. Triggers of phospholipid scrambling include energy depletion and increase in cytosolic Ca(2+) activity ([Ca(2+) ](i) ). The present study explored whether enniatin A triggers phospholipid scrambling. Phospholipid scrambling was estimated from annexin-V-binding, cell volume from forward scatter (FSC), [Ca(2+) ](i) from Fluo3-fluorescence, cytosolic ATP-concentration ([ATP](i) ) using a luciferase assay and hemolysis from hemoglobin release. Exposure of erythrocytes for 48 h to enniatin A (≥ 2.5 μM) significantly increased [Ca(2+) ](i) , decreased [ATP](i) , decreased FSC, triggered annexin-V-binding and elicited hemolysis. Annexin-V-binding affected 25%, and hemolysis 2% of treated erythrocytes. Decreased [ATP](i) by glucose depletion for 48 h was similarly followed by increased [Ca(2+) ](i) , decreased FSC and annexin-V-binding. Enniatin A augmented the effect on [Ca(2+) ](i) and annexin-V-binding, but not on FSC. Annexin-V-binding was blunted by Ca(2+) removal, by the cation channel inhibitor amiloride (1 mM), by the protein kinase C inhibitor staurosporine (500 nM) but not by the pancaspase inhibitor zVAD (10 μM). The food contaminant enniatin A triggers ATP depletion and increases cytosolic Ca(2+) activity, effects resulting in suicidal erythrocyte death.


Continued production of drug-sensitive human immunodeficiency virus type 1 in children on combination antiretroviral therapy who have undetectable viral loads.
Highly active antiretroviral therapy (HAART) can suppress plasma human immunodeficiency virus type 1 (HIV-1) levels to below the detection limit of ultrasensitive clinical assays. However, HIV-1 persists in cellular reservoirs, and in adults, persistent low-level viremia is detected with more sensitive assays. The nature of this viremia is poorly understood, and it is unclear whether viremia persists in children on HAART, particularly those who start therapy shortly after birth. We therefore developed a reverse transcriptase PCR (RT-PCR) assay that allows genotyping of HIV-1 protease even when viremia is present at levels as low as 5 copies of HIV-1 RNA/ml. We demonstrated that viremia persists in children with plasma virus levels below the limit of detection of clinical assays. Viremia was detected even in children who began HAART in early infancy and maintained such strong suppression of viremia that HIV-1-specific antibody responses were absent or minimal. The low-level plasma virus lacked protease inhibitor resistance mutations despite the frequent use of nelfinavir, which has a low mutational barrier to resistance. Protease sequences resembled those of viruses in the latent reservoir in resting CD4(+) T cells. Thus, in most children on HAART with clinically undetectable viremia, there is continued virus production without evolution of resistance in the protease gene.


Regulating tobacco retail outlets in Bangladesh: retailers' views and implications for tobacco control advocacy.
Tobacco products are ubiquitously available in Bangladesh. There are currently no restrictions on who can sell tobacco products and where they are allowed to be sold. The objective of this study was to explore tobacco retailers' views regarding tobacco retail licensing (TRL) in Bangladesh. A two-stage cluster sampling procedure was used to collect data from a representative sample of 472 tobacco retailers (97% response rate) in Dhaka city in 2018 through face-to-face interviews using a semistructured questionnaire. Data were analysed using descriptive statistics, X2 tests and logistic regression. The majority (79%) of the retailers reported that they would support TRL, and 68% were interested in applying for TRL if adopted. Support for TRL was higher among those with a university degree (OR 2.1, 95% CI 0.8 to 5.3) and among those with knowledge about existing tobacco control regulations (OR 1.8, 95% CI 1.1 to 2.8). Furthermore, support for TRL was significantly higher among those who believed that it would restrict tobacco retailing locations (AOR 1.9, 95% CI 1.3 to 3.0) and prevent tobacco sales to minors (AOR 3.5, 95% CI 2.2 to 5.5). This sample of tobacco retailers in Bangladesh supported TRL. TRL advocacy efforts could draw on this support.


Mechanical behavior of closed lamellar membranes as a possible common mechanism for the establishment of developmental shapes.
The mechanical behavior of a closed membrane composed of two layers in contact is described as it is obtained by finding the minimum of the membrane bending energy at constant membrane area, constant difference between the areas of the two layers, and constant enclosed volume. It is shown that the membrane bending energy is a discontinuous function of the volume (v) and difference between the layer areas (delta a) defined relative to the volume and area difference of a sphere with the same membrane area, respectively. However, for different classes of shapes it is possible to obtain regions in the v/delta a diagram within which the shapes change continuously with v and delta a. These regions are shown for the egg, dumbbell and cup shape classes, respectively. The results of the shape analysis are used in the discussion of cell polarity, cytokinesis and gastrulation. Cell polarity is related to the decrease in symmetry during the transition from the radially symmetrical spherical shape to the asymmetrical shapes of the egg class. It is proposed that symmetrical cytokinesis occurs within the dumbbell class and that asymmetrical cytokinesis occurs within the egg class. Gastrulation is described as shape transformations within the class of cup shapes.


Success of interventions in mastitis problems with Staphylococcus aureus after the introduction of an automatic milking system.
Staphylococcus aureus (S. aureus) is often the cause of mastitis problems in dairy herds and causes great economic losses. In this study, isolates from a dairy herd with a known S. aureus mastitis problem were examined by means of molecular methods (spa typing, PFGE, and DNA microarray) to investigate their epidemiological relationship and the success of intervention measures. The investigated dairy farm has a herd size of 60 cows and uses a fully automated milking system for milk production. A S. aureus strain, which contaminated the automated milking system and was subsequently spread among the herd through the latter, was suspected to be the origin of the mastitis problem within the herd. Thanks to the applied molecular methods, the common origin of the S. aureus isolates from the collected milk and swab samples could be shown. By culling chronically infected cows, optimising dry cow management and ensuring reliable intermediate cluster disinfection, the bulk milk somatic cell count improved.


Contract cholangiography.
Clinical, operative, and conventional radiological criteria may provide insufficient indications for exploration of the common bile duct. The technique of contact cholangiography improves the radiographic definition, especially in the obese, and has resulted in more positive choledochotomies and in fewer negative explorations.


Changes in serum 25-hydroxyvitamin D and cholecalciferol after one whole-body exposure in a commercial tanning bed: a randomized study.
We wanted to evaluate the cutaneous synthesis of 25OHD and cholecalciferol after one whole-body exposure to ultraviolet radiation type B (UVB) in a randomized setup. Healthy volunteers were randomized to one whole-body exposure in a commercial tanning bed with UVB emission (UVB/UVA ratio 1.8-2.0%) or an identical placebo tanning bed without UVB. The output in the 280-320 nm range was 450 µW/cm². Blood samples were analyzed for 25OHD and cholecalciferol at baseline and during 7 days after treatment. We included 20 volunteers, 11 to UVB and 9 to placebo treatment. During the first 6 h, no significant differences in 25OHD between the groups were found. At the end of the study, we found a mean increase of 25OHD in the UVB group of 4.5 nmol/l (SD 7 nmol/l) compared to a decline of -1.2 nmol/l (SD 7 nmol/l) in the placebo group (p = 0.1). A linear mixed model yielded an increase of 25OHD in the UVB group of 1.0 nmol/l per 24 h (p < 0.01). For cholecalciferol, we found a near significant increase of 1 pmol/l per hour in the UVB group compared to the placebo group during the first 6 h (p = 0.052). One tanning bed session had significant, but modest impact on the level of 25OHD during 7 days after exposure to UVB.


Gastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis.
The composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and microbiome alteration. Here, we analyze data from two longitudinal studies of tuberculosis (TB) therapy (35 and 20 individuals) and a cross sectional study from 55 healthy controls, in which we collected fecal samples (for microbiome analysis), sputum (for determination of Mycobacterium tuberculosis (Mtb) bacterial load), and peripheral blood (for transcriptomic analysis). We decouple microbiome effects from pathogen sterilization by comparing standard TB therapy with an experimental TB treatment that did not reduce Mtb bacterial load. Random forest regression to the microbiome-transcriptome-sputum data from the two longitudinal datasets reveals that renormalization of the TB inflammatory state is associated with Mtb pathogen clearance, increased abundance of Clusters IV and XIVa Clostridia, and decreased abundance of Bacilli and Proteobacteria. We find similar associations when applying machine learning to peripheral gene expression and microbiota profiling in the independent cohort of healthy individuals. Our findings indicate that antibiotic-induced reduction in pathogen burden and changes in the microbiome are independently associated with treatment-induced changes of the inflammatory response of active TB, and the response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation.


A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics.
The neurotransmitter serotonin has been implicated in the pathophysiology of psychosis. The serotonin transporter (5-HTT) plays a critical role in regulation of serotonergic function. A recently identified polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) produces significant differences in 5-HTT expression and function and was found to be associated with anxiety-related traits in healthy volunteers. We investigated whether 5-HTTLPR is associated with psychosis in neuroleptic-free schizophrenic or schizoaffective patients. Fifty patients with schizophrenia or schizoaffective disorder by DSM-III-R criteria were genotyped at 5-HTTLPR and underwent double-blind Brief Psychiatric Rating Scale (BPRS) ratings while neuroleptic-free for approximately 4 weeks. Patients with the 5-HTTLPR II genotype (n = 19) had significantly higher BPRS ratings for psychosis than patients with the Is (n = 25) or ss (n = 6) genotypes. Examination of individual items revealed a specific significant increase in intensity of hallucinations in patients with the 5-HTTLPR II genotpe. These data provide preliminary evidence for a role of serotonin in the pathophysiology of hallucinations and may represent the identification of an allelic variant that modifies the complex clinical presentation of schizophrenia.


Glycosome assembly in trypanosomes: variations in the acceptable degeneracy of a COOH-terminal microbody targeting signal.
Trypanosomes compartmentalize most of their glycolytic enzymes in a peroxisome-like microbody, the glycosome. The specificity of glycosomal targeting was examined by expression of chloramphenicol acetyltransferase fusion proteins in trypanosomes and monkey cells. Compartmentalization was assessed by cell fractionation, differential detergent permeabilization, and immunofluorescence. The targeting signal of trypanosome phosphoglycerate kinase resides in the COOH-terminal hexapeptide, NRWSSL; a basic amino acid is not required. The minimal targeting signal is, as for mammalian cells, a COOH-terminal tripeptide related to -SKL. However, the acceptable degeneracy of the signal for glycosomal targeting in trypanosomes is considerably greater than that for peroxisomal targeting in mammals, with particularly relaxed requirements in the penultimate position.


Linear dichroism of acrylodan-labeled tropomyosin and myosin subfragment 1 bound to actin in myofibrils.
Muscle contraction can be activated by the binding of myosin heads to the thin filament, which appears to result in thin filament structural changes. In vitro studies of reconstituted muscle thin filaments have shown changes in tropomyosin-actin geometry associated with the binding of myosin subfragment 1 to actin. Further information about these structural changes was obtained with fluorescence-detected linear dichroism of tropomyosin, which was labeled at Cys 190 with acrylodan and incorporated into oriented ghost myofibrils. The fluorescence from three sarcomeres of the fibril was collected with the high numerical aperture objective of a microscope and the dichroic ratio, R (0/90 degrees), for excitation parallel/perpendicular to the fibril, was obtained, which gave the average probe dipole polar angle, Theta. For both acrylodan-labeled tropomyosin bound to actin in fibrils and in Mg2+ paracrystals, Theta congruent to 52 degrees +/- 1.0 degrees, allowing for a small degree of orientational disorder. Binding of myosin subfragment 1 to actin in fibrils did not change Theta; i.e., the orientation of the rigidly bound probe on tropomyosin did not change relative to the actin axis. These data indicate that myosin subfragment 1 binding to actin does not appreciably perturb the structure of tropomyosin near the probe and suggest that the geometry changes are such as to maintain the parallel orientation of the tropomyosin and actin axes, a finding consistent with models of muscle regulation. Data are also presented for effects of MgADP on the orientation of labeled myosin subfragment 1 bound to actin in myofibrils.


Expression and maturation of human cathepsin D in baby-hamster kidney cells.
In medium and in homogenates from baby-hamster kidney cells (BHK) transfected with human cathepsin D cDNA, an elevated activity of cathepsin D was found as compared to non-transfected cells. The elevated activity was removed by titrating the homogenates with an anti-(human cathepsin D) antibody. Metabolic labelling and immunoprecipitation revealed that, in the transfected cells, human cathepsin D was synthesized as a 53-kDa precursor indistinguishable from that found in human cells. A portion of the precursor was secreted and the remainder was processed to intermediate and mature chains within a few hours of synthesis. The precursor that was released from the transfected cells had a slightly smaller apparent size than that from cultured human fibroblasts. This difference was abrogated when the precursors were treated with glycopeptidase F. In the intracellular small chain a difference was observed in the size of carbohydrate chains that were cleavable with endo-beta-N-acetylglucosaminidase H. Sequence analysis of the N-termini of mature intracellular cathepsin D indicated a N-terminal trimming in both large and small chains from both human and transfected hamster cells. The proteolytic maturation of human cathepsin D in BHK cells closely resembles that in human cells, whereas a portion of the carbohydrate side chains is processed differently. The trimming of the N-termini in mature cathepsin D is proposed to be a part of the maturation and aging of this protein.


Unusual arteritis causing myocardial infarction in a child.
A 5-year-old girl presented with a diffuse inflammatory disease that consisted of fever, lymphadenopathy, splenomegaly, and anterior uveitis. A chest x-ray film indicated an apparently nodular infiltrate. Her condition deteriorated abruptly, and she died of acute myocardial infarction. Autopsy revealed an extensive vasculitis that involved the aorta, pulmonary arteries, and coronary vessels. An aneurysm of the left coronary artery was noted. We present and discuss this case as an unusual arteritis in childhood, closely resembling Takayasu's disease. The presence of extensive erythrophagocytosis in sinus histiocytes hinted at a viral or immunologic origin for this child's disease.


Rates of GDP-induced and GTP-induced depolymerization of glutamate dehydrogenase: a possible factor in metabolic regulation.
The rate of the depolymerization of beef liver glutamate dehydrogenase induced by coenzyme and the purine nucleotides guanosine 5'-diphosphate and guanosine 5'-triphosphate, which are potent inhibitors of enzymatic activity, has been measured by rapid light scattering techniques and by absorbancy changes with stop flow. It is shown that the rate constant for this process may vary from several milliseconds to several seconds depending upon the nucleotides used. The widely varying rate constants for the nucleotide-induced depolymerization may serve a role in determining the nature of the regulation of enzyme activity by nucleotides. Depolymerization induced by guanosine 5'-diphosphate in the presence of diphosphopyridine nucleotide is slower than in the presence of triphosphopyridine nucleotide as coenzyme, and this difference is apparently due to the isomerization of the enzyme as a result of diphosphopyridine nucleotide binding to a second, nonactive site. This binding, as well as binding of the coenzyme to the active site, may be conveniently measured by a purine nucleotide-induced spectral shift in the coenzyme absorption spectrum. It is also shown that complete depolymerization of the enzyme in the presence of guanosine 5'-triphosphate is accomplished by about half saturation of the coenzyme active sites (6-8 active "monomer").


[The Buzzati Traverso archive].
The life and activity of Adriano Buzzati-Traverso are significantly linked to the birth and development of genetics in Italy, as well as to the achievements and the shortcomings of the creation of a 'modern' notion and policy of science in our country. His archive sheds light on public and private aspects of his activity, especially the creation of important research centers.


The effect of exercise on pulpal and gingival blood flow in physically active and inactive subjects as assessed by laser Doppler.
The effects of exercise on pulpal and gingival blood flow are undefined. The autonomic nervous system response suggests that they could increase or decrease with exercise, and they may be independent of each other. This study attempts to answer these questions. 15 "physically active" subjects and 15 "physically inactive" subjects exercised on a treadmill. Laser Doppler recordings of pulpal and gingival blood flow were taken before and after exercise. There was a mean increase of approximately 50% in both pulpal (range -66%-+509%) and gingival (-72%- +1022%) blood flow after exercise, with wide variations, with no significant differences between the two groups of subjects. Exercise could increase pulpal and/or gingival blood flow as part of the overall increase in cardiac output with exercise, or could decrease pulpal and/or gingival blood flow due to diversion of blood to the somatic muscles during exercise. This study suggests that the former physiological phenomenon usually takes place at both sites,though there were some contradictory results.


[Clinical mycoplasmosis outbreak due to Mycoplasma ovis in sheep from Shalta, Argentina. Clinical, microbiological and molecular diagnosis].
Mycoplasma ovis is an obligatory parasite of the erythrocytes from small ruminants (sheep, goat), wherein it causes chronic or acute anaemia. This agent shows worldwide distribution. However, its dispersion is still unknown in Argentina. This work describes an outbreak of mycoplasmosis occurred in January 2007 in a sheep flock from Rosario de la Frontera, Salta, Argentina. Adult sheep became ill with a mortality rate of 17.8%. All blood smears (n = 11) examined by Giemsa stain showed the presence of small basophile bodies characteristic of M. ovis infection, indicating a high prevalence of the infection in the flock. The molecular diagnosis (n = 9) confirmed the findings through the amplification of two fragments from the 16S rRNA gene. This is the third report of M. ovis in Argentina and the first one concomitant with clinical signs at flock level.


Thought-based interaction: Same data, same methods, different results?
Restoration of communication in people with complete motor paralysis-a condition called complete locked-in state (CLIS)-is one of the greatest challenges of brain-computer interface (BCI) research. New findings have recently been presented that bring us one step closer to this goal. However, the validity of the evidence has been questioned: independent reanalysis of the same data yielded significantly different results. Reasons for the failure to replicate the findings must be of a methodological nature. What is the best practice to ensure that results are stringent and conclusive and analyses replicable? Confirmation bias and the counterintuitive nature of probability may lead to an overly optimistic interpretation of new evidence. Lack of detail complicates replicability.


A low inflammatory, Langerhans cell-targeted microprojection patch to deliver ovalbumin to the epidermis of mouse skin.
In a low inflammatory skin environment, Langerhans cells (LCs) - but not dermal dendritic cells (dDCs) - contribute to the pivotal process of tolerance induction. Thus LCs are a target for specific-tolerance therapies. LCs reside just below the stratum corneum, within the skin's viable epidermis. One way to precisely deliver immunotherapies to LCs while remaining minimally invasive is with a skin delivery device such as a microprojection arrays (MPA). Today's MPAs currently achieve rapid delivery (e.g. within minutes of application), but are focussed primarily at delivery of therapeutics to the dermis, deeper within the skin. Indeed, no MPA currently delivers specifically to the epidermal LCs of mouse skin. Without any convenient, pre-clinical device available, advancement of LC-targeted therapies has been limited. In this study, we designed and tested a novel MPA that delivers ovalbumin to the mouse epidermis (eMPA) while maintaining a low, local inflammatory response (as defined by low erythema after 24 h). In comparison to available dermal-targeted MPAs (dMPA), only eMPAs with larger projection tip surface areas achieved shallow epidermal penetration at a low application energy. The eMPA characterised here induced significantly less erythema after 24 h (p = 0.0004), less epidermal swelling after 72 h (p < 0.0001) and 52% less epidermal cell death than the dMPA. Despite these differences in skin inflammation, the eMPA and dMPA promoted similar levels of LC migration out of the skin. However, only the eMPA promoted LCs to migrate with a low MHC II expression and in the absence of dDC migration. Implementing this more mouse-appropriate and low-inflammatory eMPA device to deliver potential immunotherapeutics could improve the practicality and cell-specific targeting of such therapeutics in the pre-clinical stage. Leading to more opportunities for LC-targeted therapeutics such as for allergy immunotherapy and asthma.


Food deprivation and hypothermia in desynchronized sleep-deprived rats.
Reports of the effect of desynchronized sleep (DS) deprivation on body temperature (Tb) of rats in the literature are contradictory. Since conspicuous body weight loss is common in such deprivation, the effect of food plus DS deprivation on Tb of adult male Wistar rats was studied. DS deprivation carried out by the small platform method with food ad libitum (N = 8) induced hyperthermia (Tb above 38.5 degrees C) in 1 to 3 rats daily until the 8th day, when a case of discrete hypothermia (Tb below 36.9 degrees C) appeared. Food deprivation alone started to induce hypothermia on the third day in one (20%) out of five rats. Fasting imposed from the 5th to the 8th day of DS deprivation (N = 12) caused hypothermia in 33% and 67% of the animals on the second and third day of starvation, respectively. DS compensatory manifestations in 6 starved rats intensified (N = 2) or precipitated (N = 2) hypothermia after the end of sleep deprivation. It is concluded that the hypothermia is not a primary effect of DS deprivation, and this state of sleep seems to have its particular functional role which is independent of thermoregulation.


Childhood blindness and low vision in Uganda.
To examine the causes and outcome of subnormal vision starting in childhood in Uganda, to aid in planning for its avoidance and for rehabilitation. All those seen having subnormal vision with onset from birth to 15 years (total 1135) (schools 1983-97; community 1988-97) were included in the study. Clinical examination was performed and a World Health Organisation (WHO) form completed, with analysis by its computer program. Main outcome measures were visual acuity, signs of eye pathology, outcome of treatment and refraction and low vision assessment. By WHO category 14.8% had visual impairment, 6.5% severe visual impairment, 63.2% were blind and 15.2% were too young to test. The acuities and causes were similar in school and community groups, excepting cortical visual impairment and multiple impairment, which are much commoner in the community. Cataract was the largest cause of visual impairment (30.7%) and surgical outcome was unsatisfactory. Visual loss following corneal ulceration was the second commonest cause of subnormal vision (22.0%). Cataract and corneal damage cause half of all subnormal vision, which is avoidable for both. Cataract surgery needs to be upgraded. To prevent corneal visual loss, primary health care should continue to be expanded, especially measles immunisation and nutrition care; rubella immunisation should be added. Special education needs to be greatly expanded. Public perceptions need changing if results are to be improved and help offered to more than the present minority.


Incontinent ileo-vesicostomy urinary diversion in the treatment of lower urinary tract dysfunction.
The combination of high spinal cord injury and neurovesical dysfunction can present formidable problems in urological management. The lack of upper extremity function often prevents intermittent catheterization and leads to alternative methods. A total of 23 patients underwent incontinent ileo-vesicostomy in an effort to gain a low pressure bladder and control of urinary soiling: 17 had been previously treated by catheter drainage, 9 had bladder and/or renal calculi, 9 experienced recurrent sepsis, and 7 had urethrocutaneous fistula and total urinary incontinence. Most patients had poorly compliant bladder dysfunction associated in 9 cases with poor urethral continence function. At a mean followup of 45 months (range 3 to 240 months) 22 of 23 patients had a low pressure reservoir with low pressure degrees of urine into a collection device. Complications included stomal stenosis in 3 patients and poor drainage across the ileovesical junction requiring revision in 2. One of these patients ultimately underwent ileal loop diversion. Upper tract function improved or remained stable in all patients.


Highly sensitive detection of nanoparticles with a self-referenced and self-heterodyned whispering-gallery Raman microlaser.
Optical whispering-gallery-mode resonators (WGMRs) have emerged as promising platforms for label-free detection of nano-objects. The ultimate sensitivity of WGMRs is determined by the strength of the light-matter interaction quantified by quality factor/mode volume, Q/V, and the resolution is determined by Q. To date, to improve sensitivity and precision of detection either WGMRs have been doped with rare-earth ions to compensate losses and increase Q or plasmonic resonances have been exploited for their superior field confinement and lower V. Here, we demonstrate, for the first time to our knowledge, enhanced detection of single-nanoparticle-induced mode splitting in a silica WGMR via Raman gain-assisted loss compensation and WGM Raman microlaser. In particular, the use of the Raman microlaser provides a dopant-free, self-referenced, and self-heterodyned scheme with a detection limit ultimately determined by the thermorefractive noise. Notably, we detected and counted individual nanoparticles with polarizabilities down to 3.82 × 10(-6) μm(3) by monitoring a heterodyne beatnote signal. This level of sensitivity is achieved without exploiting plasmonic effects, external references, or active stabilization and frequency locking. Single nanoparticles are detected one at a time; however, their characterization by size or polarizability requires ensemble measurements and statistical averaging. This dopant-free scheme retains the inherited biocompatibility of silica and could find widespread use for sensing in biological media. The Raman laser and operation band of the sensor can be tailored for the specific sensing environment and the properties of the targeted materials by changing the pump laser wavelength. This scheme also opens the possibility of using intrinsic Raman or parametric gain for loss compensation in other systems where dissipation hinders progress and limits applications.


Coagulation in Brain Tumors: Biological Basis and Clinical Implications.
Cancer patients commonly show abnormal laboratory coagulation tests, indicating a subclinical hypercoagulable condition that contribute to morbidity and mortality. The hypercoagulation status not only increases the risk of thromboembolic events but also influences the tumor biology promoting its growth and progression by stimulating intracellular signaling pathways. Recent molecular studies characterized the role of oncogene and suppressor gene in activating clotting pathways, as an integral feature of the neoplastic transformation. It is now clear how haemostatic processes, activated by cancer cells harboring oncogenic mutations, rely on the molecular profile of a particular malignancy, an aspect particularly evident in the differential coagulome profiles showed by different molecular subtypes of brain tumors, such as glioblastoma and medulloblastoma. This review focuses on the biological and clinical aspects of haemostasis in cancer with particular regard on brain tumors.


Quantitative accuracy of (177)Lu SPECT reconstruction using different compensation methods: phantom and patient studies.
In targeted radionuclide therapy (TRT), accurate quantification using SPECT/CT images is important for optimizing radiation dose delivered to both the tumour and healthy tissue. Quantitative SPECT images are regularly reconstructed using the ordered subset expectation maximization (OSEM) algorithm with various compensation methods such as attenuation (A), scatter (S) and detector and collimator response (R). In this study, different combinations of the compensation methods are applied during OSEM reconstruction and the effect on the (177)Lu quantification accuracy is studied in an anthropomorphic torso phantom. In addition, the phantom results are reflected to (177)Lu-DOTA-Tyr3-octreotate ((177)Lu-DOTATATE)-treated patient data and kidney absorbed dose estimates. The torso phantom was imaged with nine various sized (0.4-104.4 cm(3)) spherical inserts, filled with known (177)Lu activity ranging from 0.5 to 105.5 MBq. Images were reconstructed using OSEM algorithm using A, AR and ARS compensation method combinations. The compensation method combinations were compared by calculating the concentration recovery coefficient (cRC) for each insert. In addition, ten (177)Lu-DOTATATE-treated patient's post-therapy dosimetry acquisitions were reconstructed, and the absorbed dose to kidneys was estimated. cRC values depend on the insert size for all compensation methods. AR and ARS produced significantly higher cRC values than attenuation correction alone. There were no cRC value differences between the methods for the smallest 1-cm-diameter insert, cRC being 0.18. However, the collimator and detector response compensation method (R) made the 1.3-cm-diameter insert clearly visible and improved cRC estimate from 0.19 to 0.43. ARS produced slightly higher cRC values for small- and medium-sized inserts than AR. On the patient data, a similar trend could be seen. AR and ARS produced higher kidney activities than using attenuation correction alone; the total absorbed doses to the right and left kidneys were on average 15 and 20 % higher for AR and 19 and 25 % higher for ARS, respectively. The effective half-life decay estimated from time-activity curves however showed no notable difference between the compensation methods. The highest cRC values were achieved by applying ARS compensation during reconstruction. The results were notably higher than those using attenuation correction alone. Similarly, higher activity estimates and thus higher absorbed dose estimates were found in patient data when all compensation methods were applied. ARS improved cRC especially in small-sized sources, and it thus might aid tumour dosimetry for (177)Lu PRRT treatments.


Lactate-enhanced-qSOFA (LqSOFA) score is superior to the other four rapid scoring tools in predicting in-hospital mortality rate of the sepsis patients.
The rising prevalence of early therapy for sepsis has led to the demand for rapid risk-stratification tools that can estimate the risk of in-hospital mortality for sepsis patients and the need for intensive care unit (ICU) admission. A robust risk-stratification tool is crucial for in-time sepsis treatment. This study aimed to compare the abilities of five rapid scoring systems, i.e., LqSOFA score, qSOFA score, SIRS, MEDS, and MEWS, in predicting the mortality in hospital and ICU admission for sepsis patients. A retrospective observational clinical study was conducted in West China Hospital. Our cases included all patients admitted to the hospital with a diagnosis of sepsis (sepsis-3). We calculated five rapid prediction scores for the enrolled cases. We then compared each rapid score's ability to predict in-hospital mortality and ICU admission. A total of 821 of mixed sepsis patients by sepsis-3 definition were included. The all-cause hospital mortality rate was 21.1%. The LqSOFA score presented the most significant discrimination with an area under the receiver operating characteristic curve (AUC) of 0.751. The AUC of the LqSOFA score for mortality in the hospital was significantly higher than qSOFA (AUC 0.717), SIRS (AUC 0.704), MEDS (AUC 0.670), and MEWS (AUC 0.685). LqSOFA is a superior prognostic tool for predicting mortality in the hospital. It may provide more exact information for hospital mortality than the other 4 rapid scores in treating sepsis patients.


Effects of Interfacial Molecular Structures on Pressure-Driven Brine Flow in Silica Mesopores.
In this work, we conduct molecular dynamics simulations to investigate pressure-driven brine flow in silica mesopores under typical reservoir conditions (323 K and 20 MPa). While surface counterions accumulate strongly in the vicinity of fully deprotonated silica surfaces, water forms multilayer structures due to hydrogen bonding, counterion hydration, and excluded-volume effect. Brine flow behaviors exhibit adsorption, transition, and bulk-like regions in fully deprotonated silica mesopores, while the transition region is negligible in fully protonated ones. In the adsorption region, strong surface hydrogen bonding and a high degree of counterion hydration collectively hinder water mobility. Even without surface hydrogen bonding, persistent ion hydration impedes water flow, leading to the transition region in fully deprotonated silica mesopores and higher viscosity of brine (with 10 wt % NaCl) in the bulk region. This work elucidates the collective effects of surface chemistry and interfacial water structures on brine flow behaviors in silica mesopores from molecular perspectives.


A systematic approach to evaluate the influence of environmental conditions on eDNA detection success in aquatic ecosystems.
The use of environmental DNA (eDNA) to determine the presence and distribution of aquatic organisms has become an important tool to monitor and investigate freshwater communities. The successful application of this method in the field, however, is dependent on the effectiveness of positive DNA verification, which is influenced by site-specific environmental parameters. Factors affecting eDNA concentrations in aquatic ecosystems include flow conditions, and the presence of substances that possess DNA-binding properties or inhibitory effects. In this study we investigated the influence of different environmental parameters on the detection success of eDNA using the invasive goby Neogobius melanostomus. In a standardized laboratory setup, different conditions of flow, sediment-properties, and fish density were compared, as well as different potential natural inhibitors such as algae, humic substances, and suspended sediment particles. The presence of sediment was mainly responsible for lower eDNA detection in the water samples, regardless of flow-through or standing water conditions and a delayed release of eDNA was detected in the presence of sediment. Humic substances had the highest inhibitory effect on eDNA detection followed by algae and siliceous sediment particles. The results of our study highlight that a successful application of eDNA methods in field surveys strongly depends on site-specific conditions, such as water flow conditions, sediment composition, and suspended particles. All these factors should be carefully considered when sampling, analyzing, and interpreting eDNA detection results.


Templated fabrication of hierarchically porous metal-organic frameworks and simulation of crystal growth.
Hierarchically porous metal-organic frameworks (MOFs) have recently emerged as a novel crystalline hybrid material with tunable porosity. Many efforts have been made to develop hierarchically porous MOFs, yet their low-energy fabrication remains a challenge and the underlying mechanism is still unknown. In this study, the rapid fabrication of two hierarchically porous MOFs (Cu-BTC and ZIF-8) was carried out at room temperature and ambient pressure for 10 min using a novel surfactant as the template in a (Cu, Zn) hydroxy double salt (HDS) solution, where the (Cu, Zn) HDS accelerated the nucleation of crystals and the anionic surfactants served as templates to fabricate mesopores and macropores. The growth mechanism of hierarchically porous MOFs was analyzed via mesodynamics (MesoDyn) simulation, and then the synthetic mechanism of hierarchically porous MOFs at the molecular level was obtained. The as-synthesized hierarchically porous Cu-BTC showed a high uptake capacity of 646 mg g-1, which is about 25% higher as compared with microporous Cu-BTC (516 mg g-1) for the capture of toluene. This study provides a theoretical basis for the large-scale fabrication of hierarchically porous MOFs and offers a reference for the understanding of their synthetic mechanism.


Are psychedelics the answer to chronic pain: A review of current literature.
We aim to provide an evidence-based overview of the use of psychedelics in chronic pain, specifically LSD and psilocybin. Chronic pain is a common and complex problem, with an unknown etiology. Psychedelics like lysergic acid diethylamide (LSD) and psilocybin, may play a role in the management of chronic pain. Through activation of the serotonin-2A (5-HT2A) receptor, several neurophysiological responses result in the disruption of functional connections in brain regions associated with chronic pain. Healthy reconnections can be made through neuroplastic effects, resulting in sustained pain relief. However, this process is not fully understood, and evidence of efficacy is limited and of low quality. In cancer and palliative related pain, the analgesic potential of psychedelics was established decades ago, and the current literature shows promising results on efficacy and safety in patients with cancer-related psychological distress. In other areas, patients suffering from severe headache disorders like migraine and cluster headache who have self-medicated with psychedelics report both acute and prophylactic efficacy of LSD and psilocybin. Randomized control trials are now being conducted to study the effects in cluster headache Furthermore, psychedelics have a generally favorable safety profile especially when compared to other analgesics like opioids. In addition, psychedelics do not have the addictive potential of opioids. Given the current epidemic use of opioids, and that patients are in desperate need of an alternative treatment, it is important that further research is conducted on the efficacy of psychedelics in chronic pain conditions.


Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells.
Aberrant epigenetic repression of gene expression has been implicated in most cancers, including breast cancer. The nuclear amine oxidase, lysine-specific demethylase 1 (LSD1) has the ability to broadly repress gene expression by removing the activating mono- and di-methylation marks at the lysine 4 residue of histone 3 (H3K4me1 and me2). Additionally, LSD1 is highly expressed in estrogen receptor α negative (ER-) breast cancer cells. Since epigenetic marks are reversible, they make attractive therapeutic targets. Here we examine the effects of polyamine analog inhibitors of LSD1 on gene expression, with the goal of targeting LSD1 as a therapeutic modality in the treatment of breast cancer. Exposure of the ER-negative human breast cancer cells, MDA-MB-231 to the LSD1 inhibitors, 2d or PG11144, significantly increases global H3K4me1 and H3K4me2, and alters gene expression. Array analysis indicated that 98 (75 up and 23 down) and 477 (237 up and 240 down) genes changed expression by at least 1.5-fold or greater after treatment with 2d and PG11144, respectively. The expression of 12 up-regulated genes by 2d and 14 up-regulated genes by PG11144 was validated by quantitative RT-PCR. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that up-regulated gene expression by polyamine analogs is associated with increase of the active histone marks H3K4me1, H3K4me2 and H3K9act, and decrease of the repressive histone marks H3K9me2 and H3K27me3, in the promoter regions of the relevant target genes. These data indicate that the pharmacologic inhibition of LSD1 can effectively alter gene expression and that this therapeutic strategy has potential.


High-Throughput flaA Short Variable Region Sequencing to Assess Campylobacter Diversity in Fecal Samples From Birds.
Current approach to identify sources of human pathogens is largely dependent on the cultivation and isolation of target bacteria. For rapid pathogen source identification, culture-independent strain typing method is necessary. In this study, we designed new primer set that broadly covers flaA short variable region (SVR) of various Campylobacter species, and applied the flaA SVR sequencing method to examine the diversity of Campylobacter spp. in geese fecal samples (n = 16) with and without bacteria cultivation. Twenty-three Campylobacter strains isolated from the 16 geese fecal samples were grouped similarly by conventional flaA restriction fragment length polymorphism (RFLP) method and by the flaA SVR sequencing method, but higher discriminant power was observed in the flaA SVR sequencing approach. For culture-independent flaA SVR sequencing analysis, we developed and optimized the sequence data analysis pipeline to identify as many genotypes as possible, while minimizing the detection of genotypes generated by sequencing errors. By using this pipeline, 51,629 high-quality flaA sequence reads were clustered into 16 operational taxonomic units (=genotypes) by using 98% sequence similarity and >50 sequence duplicates. Almost all flaA genotypes obtained by culture-dependent method were also identified by culture-independent flaA SVR MiSeq sequencing method. In addition, more flaA genotypes were identified probably due to high throughput nature of the MiSeq sequencing. These results suggest that the flaA SVR sequencing could be used to analyze the diversity of Campylobacter spp. without bacteria isolation. This method is promising to rapidly identify potential sources of Campylobacter pathogens.


Artifacts in slab average-intensity-projection images reformatted from JPEG 2000 compressed thin-section abdominal CT data sets.
The objective of our study was to assess the effects of compressing source thin-section abdominal CT images on final transverse average-intensity-projection (AIP) images. At reversible, 4:1, 6:1, 8:1, 10:1, and 15:1 Joint Photographic Experts Group (JPEG) 2000 compressions, we compared the artifacts in 20 matching compressed thin sections (0.67 mm), compressed thick sections (5 mm), and AIP images (5 mm) reformatted from the compressed thin sections. The artifacts were quantitatively measured with peak signal-to-noise ratio (PSNR) and a perceptual quality metric (High Dynamic Range Visual Difference Predictor [HDR-VDP]). By comparing the compressed and original images, three radiologists independently graded the artifacts as 0 (none, indistinguishable), 1 (barely perceptible), 2 (subtle), or 3 (significant). Friedman tests and exact tests for paired proportions were used. At irreversible compressions, the artifacts tended to increase in the order of AIP, thick-section, and thin-section images in terms of PSNR (p < 0.0001), HDR-VDP (p < 0.0001), and the readers' grading (p < 0.01 at 6:1 or higher compressions). At 6:1 and 8:1, distinguishable pairs (grades 1-3) tended to increase in the order of AIP, thick-section, and thin-section images. Visually lossless threshold for the compression varied between images but decreased in the order of AIP, thick-section, and thin-section images (p < 0.0001). Compression artifacts in thin sections are significantly attenuated in AIP images. On the premise that thin sections are typically reviewed using an AIP technique, it is justifiable to compress them to a compression level currently accepted for thick sections.


Central motor deficits of the deltoid muscle in patients with chronic rotator cuff tears.
Previous surface EMG studies have shown that chronic rotator cuff tears (RCT) may be associated with a altered activation of adjacent shoulder muscles. The effect of RCT on central neuromuscular control mechanisms of the shoulder girdle muscles such as the deltoideus muscle (MD), a key muscle of shoulder function, has as yet not been studied in detail. This study investigated the cortico-spinal excitability of the MD to assess the effects of RCT on the central neuromuscular function of upper limb muscles. The motor evoked potentials (MEP) in response to transcranial magnetic stimulation of MD and first dorsal interosseus muscle (FDI) on both sides were obtained of six right-handed men with chronic, symptomatic, full-thickness RCT on the dominant sides. Stimulus response curves at four different levels were measured at two tasks (MD at rest and during activity). Different interactions were found between stimulus intensity, task and side for MEP of the MD (F = 3.9, P = 0.03), indicating that MD excitability on the affected side were lower when compared with the non-affected side. No correlation was found between the correspondent MEP amplitudes of MD and FDI at rest (r = 0.1, P = 0.44) and MD activation (r = 0.3, P = 0.05) on the affected side whereas a correlation existed on the non-affected side at rest (r = 0.5, P = 0.007) and during activation (r = 0.8, P < 0.001). These decreased cortico-motoneuronal excitability of the MD on the affected side seems to related to adaptive chan- ges in motor cortex as a consequence of chronic RCT. The data suggest an involvement of central mechanisms and seem to precede severe changes of osteoarthritis of the shoulder.


[Multichannel infant reflex audiometry (MIRA)].
A new method for evaluation of hearing threshold in babies is presented. The method does not require much time, cost or personnel and is practicable for infants up to about 12 months. It is based on synchronous electrical registration of sucking and breathing activities as well as of eye movements evoked by acoustic stimuli. Sucking and breathing are reduced by supra-threshold stimuli, preparing the baby for attentive listening. Eye movements are directed towards localizing the site of the stimulus.


Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells.
Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, maintains bone mass in adulthood. We now report that IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differentiation of recruited mesenchymal stem cells (MSCs) by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. Mice with knockout of the IGF-1 receptor (Igf1r) in their pre-osteoblastic cells showed lower bone mass and mineral deposition rates than wild-type mice. Further, MSCs from Igf1rflox/flox mice with Igf1r deleted by a Cre adenovirus in vitro, although recruited to the bone surface after implantation, were unable to differentiate into osteoblasts. We also found that the concentrations of IGF-1 in the bone matrix and marrow of aged rats were lower than in those of young rats and directly correlated with the age-related decrease in bone mass. Likewise, in age-related osteoporosis in humans, we found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis. Notably, injection of IGF-1 plus IGF binding protein 3 (IGFBP3), but not injection of IGF-1 alone, increased the concentration of IGF-1 in the bone matrix and stimulated new bone formation in aged rats. Together, these results provide mechanistic insight into how IGF-1 maintains adult bone mass, while also providing a further rationale for its therapeutic targeting to treat age-related osteoporosis.


Detection and Elimination of Signal Errors Due to Unintentional Movements in Biomedical Magnetic Induction Tomography Spectroscopy (MITS).
In biomedical MITS, slight unintentional movements of the patient during measurement can contaminate the aimed images to a great extent. This study deals with measurement optimization in biomedical MITS through the detection of these unpredictable movements during measurement and the elimination of the resulting movement artefacts in the images to be reconstructed after measurement. The proposed detection and elimination (D&E) methodology requires marking the surface of the object under investigation with specific electromagnetically perturbing markers during multi-frame measurements. In addition to the active marker concept already published, a new much simpler passive marker concept is presented. Besides the biological signal caused by the object, the markers will perturb the primary magnetic field inducing their own signals. The markers' signals will be used for the detection of any unwanted object movements and the signal frames corrupted thereby. The corrupted signal frames will be then excluded from image reconstruction in order to prevent any movement artefacts from being imaged with the object. In order to assess the feasibility of the developed D&E technique, different experiments followed by image reconstruction and quantitative analysis were performed. Hereof, target movements were provoked during multifrequency, multiframe measurements in the β-dispersion frequency range on a saline phantom of physiological conductivity. The phantom was marked during measurement with either a small single-turn coil, an active marker, or a small soft-ferrite plate, a passive marker. After measurement, the erroneous phantom signals were corrected according to the suggested D&E strategy, and images of the phantom before and after correction were reconstructed. The corrected signals and images were then compared to the erroneous ones on the one hand, and to other true ones gained from reference measurements wherein no target movements were provoked on the other hand. The obtained qualitative and quantitative measurement and image reconstruction results showed that the erroneous phantom signals could be accurately corrected, and the movement artefacts could be totally eliminated, verifying the applicability of the novel D&E technique in measurement optimization in biomedical MITS and supporting the proposed aspects.


[The applied anatomy of human right posterior hepatic veins].
The right posterior hepatic veins (RPHV) were investigated using the stripped specimens of 55 cadaver adult livers and the corrosion casts of portal and hepatic venous system of 45 embryos and newborns. RPHV were found in 88 livers (88%). RPHV of 6 livers (6%) was thicker than the right hepatic vein. There were 4 types of RP-HV and they could be grouped under three anatomical locations: superior, intermedial and inferior RPHV. According to our observation, RPHV with calibre more than 0.50 cm was mainly in the group of inferior RPHV (72%). RPHV in 23 (41.82%) adult livers had extrahepatic course with a Length of 1.72 +/- 0.88 cm. The application of RPHV in hepatectomy and image diagnosis was also discussed.


3D QSAR, Docking, Molecular Dynamics Simulations and MM-GBSA studies of Extended Side Chain of the Antitubercular Drug (6S) 2-Nitro-6- {[4-(trifluoromethoxy) benzyl] oxy}-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine.
PA-824 analogues have been proposed on a promising approach for treating MDR/XDR tuberculosis. In order to understand the structural requirement of reported extended side chain analogues were studied to get insight into their structural requirements responsible for high affinity as a ligand-based pharmacophore, 3D-QSAR model have been developed. Docking and molecular dynamics studies revealed the better binding interaction of inhibitor binding pocket of deazaflavin dependent nitroreductase (Ddn) with cofactor F420 crystal. For pharmacophore generation and atom-based 3D-QSAR analysis, a dataset of 84 compounds were selected which were carried out using PHASE. The docking studies were performed using Glide module consists of five steps protein preparation, ligand preparation, receptor grid generation, actual docking procedure and finally viewing the docking results using the poseviewer. QikProp provides ranges for comparing a particular molecule's properties with those of 95% of known drugs. Molecular dynamics (MD) simulations for docking complex of deazaflavin dependent nitroreductase (Ddn) with molecule 63 were performed using Desmond. Prime Molecular Mechanics/Generalized-Born/Surface Area (MM-GBSA) was used for the calculation of binding free energy for the docked complexes. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R2 = 0.8988 for training set compounds, higher variance ratio F= 127.3 and the model generated showed excellent predictive power, with a correlation coefficient of structure to analyses Q2= 0.8543 for a randomly chosen test set of 17 compounds. The binding position of most active molecule 63 is shown in figure 4. Several favorable interactions between ligand and enzyme clearly observed; H-bond showed between O atom presence as spacer in C-6- 2-Nitro-6-{[4-(trifluoromethoxy) benzyl] oxy}-6,7-dihydro-5H-imidazo[2,1-b] [1,3] oxazine and Asn 62. Weak hydrogen bonding observed between N1 atom in imidazole ring and Asn91. The binding of imidazole nucleus occurs at site, which has extensive hydrophobic interaction with Arg60 residues. All these pharmacokinetic parameters within the acceptable range defined for human use, thereby indicating their potential as drug- like molecule. Stability of deazaflavin dependent nitroreductase (Ddn) with molecule 63 complex was evaluated through 100 ns molecular dynamic simulations. Main contributions to the tight binding of molecule 63 to Ddn are the exceptionally electrostatics (dG_bind_Coulomb) and enhance hydrogen bond interactions (dG_bind_Hbond). Docking, MM-GBSA, MD stimulation, pharmacophore model and 3D-QSAR studies as well as QikProp pharmacokinetic analysis presented in this paper is hoped to be a primer towards the development of various novel PA-824 with different chemical scaffolds and further its biological activity predictions to invent novel, potent, selective and safe PA-824 analogues for the treatment of MDR/XDR tuberculosis. Moreover, further use of contemporary experimental and computational techniques to data presented here may widen its scope and applicability.


Volumetric gray matter measures of amygdala and accumbens in childhood overweight/obesity.
Neuroimaging data suggest that pediatric overweight and obesity are associated with morphological alterations in gray matter (GM) brain structures, but previous studies using mainly voxel-based morphometry (VBM) showed inconsistent results. Here, we aimed to examine the relationship between youth obesity and the volume of predefined reward system structures using magnetic resonance (MR) volumetry. We also aimed to complement volumetry with VBM-style analysis. Fifty-one Caucasian young subjects (32 females; mean age: 13.8±1.9, range: 10.2-16.5 years) were included. Subjects were selected from a subsample of the I.Family study examined in the Hungarian center. A T1-weighted 1 mm3 isotropic resolution image was acquired. Age- and sex-standardized body mass index (zBMI) was assessed at the day of MRI and ~1.89 years (mean±SD: 689±188 days) before the examination. Obesity related GM alterations were investigated using MR volumetry in five predefined brain structures presumed to play crucial roles in body weight regulation (hippocampus, amygdala, accumbens, caudate, putamen), as well as whole-brain and regional VBM. The volumes of accumbens and amygdala showed significant positive correlations with zBMI, while their GM densities were inversely related to zBMI. Voxel-based GM mass also showed significant negative correlation with zBMI when investigated in the predefined amygdala region, but this relationship was mediated by GM density. Overweight/obesity related morphometric brain differences already seem to be present in children/adolescents. Our work highlights the disparity between volume and VBM-derived measures and that GM mass (combination of volume and density) is not informative in the context of obesity related volumetric changes. To better characterize the association between childhood obesity and GM morphometry, a combination of volumetric segmentation and VBM methods, as well as future longitudinal studies are necessary. Our results suggest that childhood obesity is associated with enlarged structural volumes, but decreased GM density in the reward system.


Use of KW-2189, a DNA minor groove-binding agent, in patients with hepatocellular carcinoma: a north central cancer treatment group (NCCTG) phase II clinical trial.
Hepatocellular carcinoma (HCC) is a common cancer in certain portions of the world. Currently no effective therapies exist for patients with advanced or metastatic HCC. KW-2189, a DNA minor groove-binding agent, has shown promising activity against HCC in preclinical evaluations. A phase II study was conducted to evaluate the activity of KW-2189 in patients with histologic or cytologic confirmed advanced or metastatic HCC who had no prior systemic therapy. Patients received KW-2189 at a dose of 0.5 mg/m2 administered on day 1 of a 6-week cycle. The primary endpoint of the trial was objective regression. Other endpoints included toxicity, disease-free survival, and overall survival. Due to hematologic toxicity the dose of KW-2189 was reduced to 0.375 mg/m2 after 11 patients had been enrolled into the trial. Due to continued significant hematologic toxicity in the next five patients enrolled at the lower dose the trial was closed to accrual. Two responses were seen in patients enrolled at the higher dose, including one sustained CR. KW-2189 showed evidence of anti-tumor activity in HCC. However, because of significant and prolonged hematologic toxicity, when given as a single dose every 6 weeks, further development of this drug in HCC is not possible. Further exploration of DNA minor groove-binding agents in the treatment of HCC appears warranted.


Clinical and radiological characteristics in multiple sclerosis patients with large cavitary lesions.
Large cavitary lesions are not typical for multiple sclerosis (MS). Cavitary white matter changes may be seen in megalencephalic leukoencephalopathy with subcortical cysts, Alexander disease, mitochondrial leukoencephalopathies, vanishing white matter disease, leukoencephalopathy with calcifications and cysts, cytomegalovirus infection, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. To analyze clinical and radiological characteristics in MS patients with large cavitary lesions. We studied MS patients with large cavitary brain lesions. Patient characteristics, disease onset/duration/subtype, expanded disability status scale (EDSS), mini mental state (MMS), corpus callosum lesions, history of segmental myelitis, CSF oligoclonal bands (OCB), visual evoked potentials (VEP), vanishing white matter disease genetic analysis, and characteristics of the cavitary lesions were analyzed. Nine patients were analyzed, 1 man and 8 women. Mean age of disease onset was 38.5 years. Mean disease duration was 9 years. Three patients had initial relapsing-remitting MS and 6 patients had primary-progressive MS. Mean EDSS was 4.5. Mean MMS was 20/30. Segmental myelitis was present in 6 cases. OCB were found in 6 patients. VEP was performed in 6 patients, and pathological in all but one. Vanishing white matter disease genetic analysis was performed and negative in 5 patients. Inferior corpus callosum lesions were seen in all patients with available sagittal FLAIR sequences. Cavitary lesions were strictly supratentorial, and located inside the diffuse leukoencephalopathy, with often a posterior predominance. MS patients with large cavitary lesions seem to represent an MS subgroup, predominantly women, with relatively late disease onset, predominantly primary-progressive type, relatively high EDSS scores, and severe cognitive dysfunction.


Diameter of coronary arteries in 36 species of mammalian from mouse to giraffe.
Systematic quantitative investigations were performed in the coronary arteries of 102 hearts of 36 mammal species with an overall more than tenthousandfold difference of their heart weight. After postmortem coronary angiography with a filling pressure of 100 mm Hg x-rays were taken, and the widest diameters of the coronary artery stems were determined. We found a nearly linear correlation between diameter of a standardized coronary artery and virtual diameter of heart, but the increase in diameter of coronary arteries exceeded somewhat that of the diameter of heart especially for heart weights surmounting 100 g. Perhaps relative enlargement of coronary arteries in the bigger hearts contributes to the prevention of large increase of blood flow velocity.


Gypenosides attenuate the development of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rat model of Parkinson's disease.
Gypenosides (GPS) and ethanol extract of Gynostemma pentaphyllum (GP-EX) show anxiolytic effects on affective disorders in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD). Long-term administration of L-3,4-dihydroxyphenylalanine (L-DOPA) leads to the development of severe motor side effects such as L-DOPA-induced-dyskinesia (LID) in PD. The present study investigated the effects of GPS and GP-EX on LID in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD. Daily administration of L-DOPA (25 mg/kg) in the 6-OHDA-lesioned rat model of PD for 22 days induced expression of LID, which was determined by the body and locomotive AIMs scores and contralateral rotational behaviors. However, co-treatments of GPS (25 and 50 mg/kg) or GP-EX (50 mg/kg) with L-DOPA significantly attenuated the development of LID without compromising the anti-parkinsonian effects of L-DOPA. In addition, the increases in ∆FosB expression and ERK1/2 phosphorylation in 6-OHDA-lesioned rats induced by L-DOPA administration were significantly reduced by co-treatment with GPS (25 and 50 mg/kg) or GP-EX (50 mg/kg). These results suggest that GPS (25 and 50 mg/kg) and GP-EX (50 mg/kg) effectively attenuate the development of LID by modulating the biomarker activities of ∆FosB expression and ERK1/2 phosphorylation in the 6-OHDA-lesioned rat model of PD. GPS and GP-EX will be useful adjuvant therapeutics for LID in PD.


Describing Natural History and Exploring Risk Factors for Kidney Function Decline in Persons With CKD of Uncertain Etiology in Sri Lanka.
Chronic kidney disease of uncertain etiology (CKDu) is a leading cause of death of adults in Sri Lanka's dry region. We initiated the Kidney Progression Project (KiPP) to prospectively follow 292 persons with Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) 20 to 60 ml/min per 1.73 m2 living in a CKDu endemic area. Using data from 3-year follow-up, we assessed kidney function decline (>30% from baseline eGFR), and the composite outcome of >30% eGFR decline, eGFR <15 ml/min or death, and explored the association of the 2 outcomes with baseline demographic, residential, and clinical parameters accounting for baseline eGFR. Median eGFR at enrollment was 28 ml/min among 71 women; 30 ml/min among 221 men; 91% to 99% had trace or no proteinuria during follow-up. At enrollment, median serum sodium, uric acid, and potassium were 143 mmol/l, 6.3 mg/dl, 4.5 meq/l, respectively among women; and 143 mmol/l, 6.9 mg/dl, 4.3 meq/l among men. Mean slope of eGFR decline was -0.5 (SD 4.9) ml/min/yr. In exploratory analyses, men with greater years of education and those living in northern region of the study area experienced lower likelihood of disease progression (hazard ratios [HR] 0.87 [0.77-0.98] per additional year and 0.33 [0.12-0.89] for northern versus other subregions, respectively). There was a suggestion that men drinking well water had higher likelihood and men living further away from reservoirs had lower likelihood of >30% decline in eGFR (HR 2.07 [0.95-4.49] for drinking well water versus not, and HR 0.58 [0.32-1.05] per kilometer distance, respectively). The overall rate of kidney function decline was slow in this CKDu cohort, similar to other nonalbuminuric CKD, and event rates were similar among men and women. Further etiologic investigations could focus on specific residence locale and water use.


Parent-Infant Interaction Tasks Adapted for Remote Testing: Strengths, Challenges, and Recommendations.
The closure of in-person laboratories and decreased safety of face-to-face interactions resulting from the COVID-19 pandemic jeopardized the ability of many developmental researchers to continue data collection during this time. Disruptions in data collection are particularly damaging to longitudinal studies, in which the testing of different age groups occurs on a continuous basis, and data loss at one time point can have cascading effects across subsequent time points and threaten the viability of the study. In an effort to continue collecting data for a longitudinal study on emotion development started in-person pre-pandemic, we adapted two parent-infant interaction tasks (free-play task and toy removal task) for a remote testing framework. Our procedure for pivoting these tasks to a supervised, remote online testing framework is outlined and the associated strengths and challenges of testing in this format (e.g., feasibility and implementation, testing environment and task setup validity, and accessibility, recruitment, and diversity) are critically evaluated. Considerations for applying this framework to other behavioral tasks are discussed and recommendations are provided.


Associations between Neighborhood Deprivation Index, Parent Perceptions and Preschooler Lifestyle Behaviors.
Parental perceptions and use of neighborhood facilities are important factors that are related to children's dietary intake and physical activity. The aim of this study was to examine the association between neighborhood deprivation index, parents' perceptions of their neighborhood environment, and healthy/unhealthy markers of child dietary intake, physical activity, and TV screen time. This cross-sectional study was conducted in Dublin, Ireland. The lifestyle behaviors among children and parental perceptions of their neighborhood environment were reported by the parents of 276 children aged 3-5 years by using parent-completed questionnaires. Deprivation index was assessed using the geographic information system (GIS). Data were analyzed using binary logistic regression, adjusting for socio-demographic confounders. In adjusted models, high deprivation index was associated with parental perception of the neighborhood as unsafe for walking and cycling due to crime (OR 1.59, 95% CI 1.04-2.43, p = 0.031) and children's low engagement in structured physical activity (OR 0.35, 95% CI 0.17-0.72, p = 0.004). Parental perceptions of an unsafe neighborhood due to heavy traffic were negatively correlated with children's active play (OR 0.73, 95% CI 0.55-0.95, p = 0.022). Children whose parents reported high satisfaction with the number of local sit-in and takeaway restaurants were 41% more likely to consume confectionary/sugar sweetened beverages (SSBs) weekly. In this age group, parents play an important role in children's lifestyle behaviors; therefore, a better understanding of parents' perceptions and their use of neighborhood facilities could contribute to creating a healthy environment for this age group.


Development of an obstetric vital sign alert to improve outcomes in acute care obstetrics.
Maternal morbidity and mortality is a national health problem. Causal analysis of near-miss and actual serious patient safety events, including those resulting in maternal death, within obstetric units often highlights a failure to promptly recognize and treat women who were exhibiting signs of decompensation/deterioration. The Obstetric Vital Sign Alert (OBVSA) is an early warning tool that leverages discrete data points in the electronic health record, calculating a risk score that is displayed as a visual cue for acute care obstetric staff. When studied in a cohort of women with postpartum hemorrhage, use of the OBVSA reduced symptom-to-response time and intervention time, as well as key process and outcome measures.


Effect of ultraviolet radiation on microorganisms as a principal extremal factor of space environment.
1. The problem of the transport of viable germs through interplanetary space has recently acquired special interest arising from the necessity of sterilization of space ships. 2. Of all cosmic extremal factors ultraviolet solar radiation is the most dangerous for microorganisms. The intensity of the most bactericidal region of ultraviolet radiation at a distance of one astronomical unit from the sun is 2 x 10(3) erg per cm2. 3. Sensitivity of microorganisms to ultraviolet rays varies in a large range. For the most resistant forms the lethal dose is approximately 440000 erg per cm2. 4. The penetrating capacity of ultraviolet radiation is very low, and therefore, even insignificant amounts of organic or mineral substances may protect the bacterial cell. 5. Dust particles of terrestrial origin carrying on themselves bacterial spores exert upon the latter a protective effect against ultraviolet radiation.


Human endogenous retrovirus K (HML-2) elements in the plasma of people with lymphoma and breast cancer.
Actively replicating endogenous retroviruses entered the human genome millions of years ago and became a stable part of the inherited genetic material. They subsequently acquired multiple mutations, leading to the assumption that these viruses no longer replicate. However, certain human tumor cell lines have been shown to release endogenous retroviral particles. Here we show that RNA from human endogenous retrovirus K (HERV-K) (HML-2), a relatively recent entrant into the human genome, can be found in very high titers in the plasma of patients with lymphomas and breast cancer as measured by either reverse transcriptase PCR or nucleic acid sequence-based amplification. Further, these titers drop dramatically with cancer treatment. We also demonstrate the presence of reverse transcriptase and viral RNA in plasma fractions that contain both immature and correctly processed HERV-K (HML-2) Gag and envelope proteins. Finally, using immunoelectron microscopy, we show the presence of HERV-K (HML-2) virus-like particles in the plasma of lymphoma patients. Taken together, these findings demonstrate that elements of the endogenous retrovirus HERV-K (HML-2) can be found in the blood of modern-day humans with certain cancers.


Stimulus-secretion coupling of glucose-induced insulin release. XXIX. Regulation of 86Rb+ efflux from perfused islets.
Glucose provokes a dose-related, rapid, sustained, and rapidly reversible reduction in the fractional outflow rate of 86Rb+ from perfused pancreatic islets. This efflux probably corresponds to a passive movement driven by the electrochemical gradient of K+ across the plasma membrane and mediated by a native ionphoretic system. Indeed, it is facilitated by valinomycin or cell membrane depolarization, little affected by ouabain, and inhibited by verapamil or omission of extracellular K+. The effect of glucose upon 86Rb+ efflux does not appear to be directly attributable to changes in either glucose transport, plasma cell polarization, Na+ influx, cyclic AMP concentration, or insulin secretion. Although a modulatory role of intracellular Ca2+ on K+ conductance cannot be ruled out, the experimental data suggest rather that the glucose-induced modification of 86Rb+ fractional outflow rate is directly linked, for its major part, to metabolic events such as an increase in the rate of glycolysis and/or generation of reduced pyridine nucleotides.


Genetic ablation of SOX18 function suppresses tumor lymphangiogenesis and metastasis of melanoma in mice.
The lymphatic vasculature provides a major route for tumor metastasis and inhibiting neolymphangiogenesis induced by tumors can reduce metastasis in animal models. Developmental biology studies have identified the transcription factor SOX18 as a critical switch for lymphangiogenesis in the mouse embryo. Here, we show that SOX18 is also critical for tumor-induced lymphangiogenesis, and we show that suppressing SOX18 function is sufficient to impede tumor metastasis. Immunofluorescence analysis of murine tumor xenografts showed that SOX18 is reexpressed during tumor-induced neolymphangiogenesis. Tumors generated by implantation of firefly luciferase-expressing B16-F10 melanoma cells exhibited a reduced rate of metastasis to the regional draining lymph node in Sox18-deficient mice, as assessed by live bioluminescence imaging. Lower metastatic rates correlated with reduced tumoral lymphatic vessel density and diameter and with impaired drainage of peritumoral injected liposomes specific for lymph vessels from the sentinel lymph nodes. Overall, our findings suggested that SOX18 induction is a key step in mediating tumor lymphangiogenesis and metastasis, and they identify SOX18 as a potential therapeutic target for metastatic blockade.


A national project to evaluate and reduce high sound pressure levels from music.
The highest recommended sound pressure levels for leisure sounds (music) in Sweden are 100 dB LAeq and 115 dB LAFmax for adults, and 97 dB LAeq and 110 dB LAFmax where children under the age of 13 have access. For arrangements intended for children, levels should be consistently less than 90 dB LAeq. In 2005, a national project was carried out with the aim of improving environments with high sound pressure levels from music, such as concert halls, restaurants, and cinemas. The project covered both live and recorded music. Of Sweden's 290 municipalities, 134 took part in the project, and 93 of these carried out sound measurements. Four hundred and seventy one establishments were investigated, 24% of which exceeded the highest recommended sound pressure levels for leisure sounds in Sweden. Of festival and concert events, 42% exceeded the recommended levels. Those who visit music events/establishments thus run a relatively high risk of exposure to harmful sound levels. Continued supervision in this field is therefore crucial.


[The sensitivity of a number of cell cultures to different types of influenza viruses and their reassortants].
The study of reproductive activity of human and animal influenza A, B, and C viruses as well as influenza A virus reassortants in some cell cultures allowed one to determine the range of cells susceptible for each type (subtype) of the viruses. Differences in the range of cells were demonstrated for different strains of influenza viruses of the same antigenic subtype. It was noted that reassortants of influenza A viruses with the same hemagglutinin subtypes as the parental strains had a wider range of susceptible cell lines and a higher reproductive capacity in these cells.


Application of CRISPR/Cas9 Tools for Genome Editing in the White-Rot Fungus Dichomitus squalens.
Dichomitus squalens is an emerging reference species that can be used to investigate white-rot fungal plant biomass degradation, as it has flexible physiology to utilize different types of biomass as sources of carbon and energy. Recent comparative (post-) genomic studies on D. squalens resulted in an increasingly detailed knowledge of the genes and enzymes involved in the lignocellulose breakdown in this fungus and showed a complex transcriptional response in the presence of lignocellulose-derived compounds. To fully utilize this increasing amount of data, efficient and reliable genetic manipulation tools are needed, e.g., to characterize the function of certain proteins in vivo and facilitate the construction of strains with enhanced lignocellulolytic capabilities. However, precise genome alterations are often very difficult in wild-type basidiomycetes partially due to extremely low frequencies of homology directed recombination (HDR) and limited availability of selectable markers. To overcome these obstacles, we assessed various Cas9-single guide RNA (sgRNA) ribonucleoprotein (RNP) -based strategies for selectable homology and non-homologous end joining (NHEJ) -based gene editing in D. squalens. We also showed an induction of HDR-based genetic modifications by using single-stranded oligodeoxynucleotides (ssODNs) in a basidiomycete fungus for the first time. This paper provides directions for the application of targeted CRISPR/Cas9-based genome editing in D. squalens and other wild-type (basidiomycete) fungi.


Neutropenia is not required for clinical remission during azathioprine therapy in inflammatory bowel disease.
Inflammatory bowel disease is an idiopathic chronic inflammatory process of the gastrointestinal tract. The aetiology remains unknown but probably involves a combination of genetic susceptibility, environmental triggers and abnormal immune regulation. Immunomodulators are effective in treating inflammatory bowel disease. Azathioprine and 6-mercaptopurine (6MP) are the most frequently used immunomodulator agents. These agents are probably underused by many clinicians because of concerns about myelosuppression, pancreatitis, allergic reactions and hepatotoxicity, which can occur in a fraction of patients taking these drugs. Therefore, clinicians have sought ways to optimize therapeutic response and limit toxic side effects. Neutropenia, although uncommon, can occur in patients taking azathioprine or 6MP. The question of neutropenia effecting clinical response has been raised as a possible indicator of therapeutic response. In the study from Campbell and Ghosh [7] in this issue of the European Journal of Gastroenterology and Hepatology, no difference in relapse rates was noted between neutropenic and non-neutropenic patients. In fact, severe life-threatening neutropenia was seen in four patients.


Molecular control of local translation in axon development and maintenance.
The tips of axons are often far away from the cell soma where most proteins are synthesized. Recent work has revealed that axonal mRNA transport and localised translation are key regulatory mechanisms that allow these distant outposts of the cell to respond rapidly to extrinsic factors and maintain axonal homeostasis. Here, we review recent evidence pointing to an increasingly broad role for local protein synthesis in controlling axon shape, synaptogenesis and axon survival by regulating diverse cellular processes such as vesicle trafficking, cytoskeletal remodelling and mitochondrial integrity. We further highlight current research on the regulatory mechanisms that coordinate the localization and translation of functionally linked mRNAs in axons.


E4orf1: a novel ligand that improves glucose disposal in cell culture.
Reducing dietary fat intake and excess adiposity, the cornerstones of behavioral treatment of insulin resistance (IR), are marginally successful over the long term. Ad36, a human adenovirus, offers a template to improve IR, independent of dietary fat intake or adiposity. Ad36 increases cellular glucose uptake via a Ras-mediated activation of phosphatidyl inositol 3-kinase(PI3K), and improves hyperglycemia in mice, despite a high-fat diet and without reducing adiposity. Ex-vivo studies suggest that Ad36 improves hyperglycemia in mice by increasing glucose uptake by adipose tissue and skeletal muscle, and by reducing hepatic glucose output. It is impractical to use Ad36 for therapeutic action. Instead, we investigated if the E4orf1 protein of Ad36, mediates its anti-hyperglycemic action. Such a candidate protein may offer an attractive template for therapeutic development. Experiment-1 determined that Ad36 'requires' E4orf1 protein to up-regulate cellular glucose uptake. Ad36 significantly increased glucose uptake in 3T3-L1 preadipocytes, which was abrogated by knocking down E4orf1 with siRNA. Experiment-2 identified E4orf1 as 'sufficient' to up-regulate glucose uptake. 3T3-L1 cells that inducibly express E4orf1, increased glucose uptake in an induction-dependent manner, compared to null vector control cells. E4orf1 up-regulated PI3K pathway and increased abundance of Ras--the obligatory molecule in Ad36-induced glucose uptake. Experiment-3: Signaling studies of cells transiently transfected with E4orf1 or a null vector, revealed that E4orf1 may activate Ras/PI3K pathway by binding to Drosophila discs-large (Dlg1) protein. E4orf1 activated total Ras and, particularly the H-Ras isoform. By mutating the PDZ domain binding motif (PBM) of E4orf1, Experiment-4 showed that E4orf1 requires its PBM to increase Ras activation or glucose uptake. Experiment-5: In-vitro, a transient transfection by E4orf1 significantly increased glucose uptake in preadipocytes, adipocytes, or myoblasts, and reduced glucose output by hepatocytes. Thus, the highly attractive anti-hyperglycemic effect of Ad36 is mirrored by E4orf1 protein, which may offer a novel ligand to develop anti-hyperglycemic drugs.


Near-Complete Genome Sequence of the Cellulolytic Bacterium Bacteroides (Pseudobacteroides) cellulosolvens ATCC 35603.
We report the single-contig genome sequence of the anaerobic, mesophilic, cellulolytic bacterium, Bacteroides cellulosolvens. The bacterium produces a particularly elaborate cellulosome system, wherein the types of cohesin-dockerin interactions are opposite of other known cellulosome systems: cell-surface attachment is thus mediated via type-I interactions, whereas enzymes are integrated via type-II interactions.


A single arginine to tryptophan interchange at beta-chain residue 458 of human complement component C4 accounts for the defect in classical pathway C5 convertase activity of allotype C4A6. Implications for the location of a C5 binding site in C4.
In general, C4A allotypes of human C4 show one-fourth to one-third the hemolytic activity of C4B allotypes. An exception to this rule is C4A6 which is almost totally deficient in hemolytic activity. Previous studies have localized the defect in C4A6 to the C5 convertase stage. Of the two critical events required for C5 cleavage, namely formation of a covalent adduct between C3b and the C4b subunit of the C3 convertase (C4b2a), and binding of C5 to this C4b-C3b complex, it is a defect in the latter step that accounts for the aberrant activity of C4A6. DNA sequencing studies described in a companion paper have suggested that the sole C4A6-specific difference was a Trp for Arg replacement at beta-chain residue 458. To directly ascertain whether this single substitution was responsible for the hemolytic defect in C4A6, we have used site-directed mutagenesis to introduce this change into both C4A and C4B cDNA expression plasmids. We found that the R to W replacement totally abrogated hemolytic activity. However, irrespective of the amino acid at residue 458, the mutant proteins behaved like their wild-type counterparts with respect to covalent binding to C1-bearing targets, i.e., the C4B recombinants displayed higher binding to sheep and human red cells than did the C4A counterparts. Furthermore, the mutants were able to form covalent C4b-C3b adducts. There was, however, substantially less C5 cleavage produced by cell-bound C4boxy23b complexes made with R458W mutant C4B than with wild-type C4B. These results are consistent with the sole defect in the mutants being at the C5 binding stage and strongly suggest that Arg 458 of the C4 beta-chain contributes to the C5 binding site of the molecule.