Genetic perturbation of AMP biosynthesis extends lifespan and restores metabolic health in a naturally short-lived vertebrate.
During aging, the loss of metabolic homeostasis drives a myriad of pathologies. A central regulator of cellular energy, the AMP-activated protein kinase (AMPK), orchestrates organismal metabolism. However, direct genetic manipulations of the AMPK complex in mice have, so far, produced detrimental phenotypes. Here, as an alternative approach, we alter energy homeostasis by manipulating the upstream nucleotide pool. Using the turquoise killifish, we mutate APRT, a key enzyme in AMP biosynthesis, and extend the lifespan of heterozygous males. Next, we apply an integrated omics approach to show that metabolic functions are rejuvenated in old mutants, which also display a fasting-like metabolic profile and resistance to high-fat diet. At the cellular level, heterozygous cells exhibit enhanced nutrient sensitivity, reduced ATP levels, and AMPK activation. Finally, lifelong intermittent fasting abolishes the longevity benefits. Our findings suggest that perturbing AMP biosynthesis may modulate vertebrate lifespan and propose APRT as a promising target for promoting metabolic health.


Factors Associated with Choice and Success of One- Versus Two-Stage Revision Arthroplasty for Infected Hip and Knee Prostheses.
Prosthetic joint infections (PJI) of hip and knee arthroplasties are becoming increasingly common with an aging population and an increasing demand for these procedures. Despite attempts at standardization, medical and surgical approaches vary widely among practitioners. We first sought to determine if there were specific factors associated with choice of one- versus two-stage revision. Then we investigated whether the type of revision approach influenced clinical treatment success. Finally, among two-stage revisions, we assessed if an antibiotic holiday prior to the second procedure affected clinical treatment success. We retrospectively reviewed patients who had revision surgery for infection of a hip or knee arthroplasty between January 1, 2000, and December 31, 2013, at the Sunnybrook Health Sciences Centre and the Holland Orthopedic and Arthritic Centre. PJI cases were identified using the Ontario Joint Replacement Registry. Infection was defined by gross intraoperative evidence of infection, positive intraoperative culture(s), and/or sinus tract prior to operation. The primary outcome was treatment failure at 1 year after revision surgery based on requirement for further surgery, ongoing infection, and/or continuous suppressive antibiotics. Of 110 eligible patients identified, 35 patients had a one-stage and 75 patients had a two-stage revision. Choice of a one-stage approach was most influenced by particular surgeon preference and was more likely for hip revision versus knee revision (OR 3.39 (95%CI 1.85-6.23). There was no statistical difference in clinical treatment success rate between one-stage (33/35; 94.2% success) and two-stage revision (63/75; 84%; p = 0.13). Enterococcus spp. (21 versus 3%; p = 0.027) and Peptostreptococcus spp. (14 versus 1%; p = 0.042) were more common among clinical treatment failures than successes, with a trend towards the same for Staphylococcus aureus (29 versus 9%; p = 0.06). Additionally, treatment success was not influenced by whether the patient had an antibiotic holiday with a two-stage revision. Our findings confirm the uncertainty of surgical strategy for treatment of PJI in hip and knee arthroplasty. Superiority of one- versus two-stage revision and the value of antibiotic-free periods prior to definitive revision remain unclear. Large prospective studies or randomized controlled trials are needed to inform best practice for treatment of these complex clinical problems.


Multicentric glioma: our experience in 25 patients and critical review of the literature.
Multicentric gliomas are interesting and well-recognised entities with a yet unknown rate of occurrence. Single cases or small series are reported in the literature accessible to us, and we think this is the first large series describing true multicentric gliomas. We reviewed 25 patients selected according to the criteria defined by Batzdorf and Malamud. Multicentricity was found in 2% of patients with malignant gliomas. Longer survival was observed in patients who underwent surgical excision of the multicentric lesions. Multicentric tumours are rare clinical entities. Our data suggest that they should be surgically removed whenever possible, and histopathologic examination of the lesions is always advisable if they are located in sites inaccessible to surgery. Stereotactic biopsy represents a safe and satisfactory method for achieving sure diagnosis.


Unusually Dispersed AgI Quantum Dots For Efficient HTL-Free CH3NH3PbI3 Photovoltaics.
The utilization of quantum dots (QDs) to improve the performance of perovskite solar cells is attracting much attention due to their unique optical and electronic properties. Most of QDs have to be prepared in advance and then incorporated into the perovskite hosts, which could not ensure the maintenance of their QD characteristics. In this work, we intelligently developed an in situ preparation strategy to disperse AgI QDs homogeneously in the perovskite host for the MAPbI3:AgI(QDs) cross-blended layer directly on indium tin oxide (ITO) via a common and convenient spin-coating process. We combine transmission electron microscopy, X-ray photoelectron spectroscopy, and Raman techniques to demonstrate the cross-blended MAPbI3:AgI(QDs) structure in the final perovskite devices. Furthermore, a series of simply inverted ITO/MAPbI3:AgI(QDs)/PCBM/Ag devices have been designed and fabricated. The photovoltaic performance of these solar cells shows significantly improved short-circuit current density (Jsc) and a champion power conversion efficiency of 16.41% even without a hole transport layer. The current technique induced the crystal growth toward high-quality perovskite films with a homogeneous structure, good crystallinity, less grain boundaries and defects, increased optical path length, and uniform thickness for better solar cell performance. Besides, the impact of the current strategy also lies in an accommodation effect of the hole collection at the ITO side induced by AgI QDs, which modifies the Fermi level of perovskite films, leading to significantly decreased level difference in the Fermi level/work function between the perovskite layer and ITO substrates by ultraviolet photoelectron spectra analysis. More importantly, the charge carrier dynamics of such novel MAPbI3:AgI(QDs) structures were also scrutinized by transient photovoltage analysis.


Safety and Efficacy of Bariatric Surgery in Cirrhosis Patients With Extreme Obesity.
To assess the safety and efficacy of bariatric surgery in patients with cirrhosis. Bariatric surgery may be a viable option for patients with cirrhosis and extreme obesity. However, the risk of liver decompensation after surgery is not thoroughly investigated. We conducted a case-controlled study with 106 obese patients with cirrhosis (cases) and 317 age, sex, body mass index-, and type of surgery-matched obese patients without cirrhosis (controls) who underwent bariatric surgery. Patients with cirrhosis were predominantly Child-Pugh class A (97%) with the diagnosis established prior to surgery in only 46%. In the cirrhosis group, there was no death in the first 30 days compared with 1 patient in the control group. At 90 days there was 1 death in the cirrhosis group but no additional deaths in the control group. In total, 12 months after the surgery, there were 3 deaths in the cirrhosis group and 1 in the control group (2.8% vs 0.6%, P = 0.056). The surgery-related length of stay was significantly longer in patients with cirrhosis (3.7 ± 4.0 vs 2.6 ± 2.4 d, P = 0.001), but the 30-day readmission rate was lower (7.5% vs 11.9%, P = 0.001). The percent of total weight loss at 30 and 90-days was not significantly different between the groups and remained that way even at 1 year (29.1 ± 10.9 vs 31.2 ± 9.4%, P = 0.096). Bariatric surgery in obese cirrhotic patients is not associated with excessive mortality compared with noncirrhotic obese patients.


Communications by professionals in palliative care.
In this article, the author first examines the ageist bias that is prevalent in clinics today. The author then reviews the basic communication principles and strategies that can help clinicians make their conversations with patients more focused and meaningful, thereby preparing patients and their family caregivers to make decisions in a crisis and to engage in planning for end-of-life care as early and intensively as possible.


Do people with a different goal-orientation or specific focus make different decisions about colorectal cancer-screening participation?
Previous studies have shown that having promotion-oriented goals (e.g. wanting to become healthy) or prevention-oriented goals (e.g. wanting to avoid getting ill) can affect people's health-related decisions and behaviour by emphasising aspects and information that seem relevant in light of what they want to achieve. However, this issue has not yet been researched regarding colorectal cancer (CRC) screening. With our study, we aimed to examine the relationship between people's goal-orientation or focus on advantages or disadvantages and their CRC screening participation, as this could provide insights for supporting people in making this complex decision. An online survey was carried out among a sample of first-time CRC screening invitees (1282 respondents, response rate 49%). We assessed people's goal-orientation (i.e. promotion-orientation and prevention-orientation), focus on the advantages or disadvantages of CRC screening, screening participation and main considerations (e.g. cancer is a serious illness) concerning their screening decision. Generally, CRC screening participants scored higher on both promotion-orientation and prevention-orientation than non-participants. Both CRC screening participation and non-participation were not associated with a dominant goal-orientation. CRC screening participants did show a dominant focus on the advantages of CRC screening. Mediation analysis showed support for our premise that the relationship between people's goal-orientation or focus on advantages or disadvantages and their screening participation could be (partially) mediated by people's main considerations concerning CRC screening. CRC screening participants and non-participants differed in their goal-orientation and focus on advantages or disadvantages. CRC screening participation appears to be associated with a focus on the advantages of CRC screening, which could impede the making of an informed decision. CRC screening non-participation appears not to be associated with any clear goal-orientation or focus, or we have not yet managed to capture this, which could be either beneficial or problematic for making an informed decision.


The Practice Patterns of American Association of Hip and Knee Surgeons for the Management of Chronic Periprosthetic Joint Infection After Total Knee Arthroplasty.
The management of periprosthetic joint infection (PJI) following total knee arthroplasty (TKA) has considerable variation. In order to better capture current preferences for the management of PJI, this study sought to poll the current members of American Association of Hip and Knee Surgeons (AAHKS) first to characterize the distribution of practice patterns. There were 32 questions in an online survey distributed to members of AAHKS. The questions were multiple choice regarding the management of PJI for TKA. There were 844 out of 2,752 members who completed the survey (response rate of 31%). Most of the members were in private practice (50%) compared to 28% being in an academic setting. On average, members were performing between 6 to 20 PJI cases per year. Two-stage exchange arthroplasty was performed in over 75% of the cases with either a cruciate retaining (CR) or posterior stabilized (PS) primary femoral component used in over 50% of the cases and 62% using an all-polyethylene tibial implant. Most of the members were using vancomycin and tobramycin. Typically, 2 to 3 grams of antibiotics were added per bag of cement regardless of the cement type. When indicated, amphotericin was the most often-used antifungal. Post-operative management had major variability with range of motion, brace use, and weight-bearing restrictions. There was variability in the responses from the members of AAHKS, but there was a preference toward performing a two-stage exchange arthroplasty with an articulating spacer using a metal femoral component and an all-polyethylene liner.


Coronary microvascular dysfunction is associated with baseline QTc prolongation amongst patients with chest pain and non-obstructive coronary artery disease.
Coronary microvascular dysfunction (CMD) causes ischemia and is linked to adverse cardiovascular events. Acute transmural ischemia is associated with QT prolongation, but whether CMD affects repolarization is unknown. The aim of this study was to determine if CMD is associated with prolongation of resting heart rate corrected QT interval (QTc). In patients presenting to the catheterization laboratory with chest pain and non-obstructive coronary artery disease (CAD) at angiography, coronary flow reserve (CFR) in response to intracoronary adenosine was measured and compared to baseline to give a CFR ratio. The Bazett's-derived QTc was manually derived from patients' 12-lead ECG obtained prior to the procedure. QTc was compared between patients with normal and abnormal (CFR ratio≤2.5) coronary microvascular function. Of the 926 patients included in this study, 281 patients (30%) had CMD (mean age 53.2 years [SD 12.7], 25% male). QTc was significantly longer in those with an abnormal CFR response to adenosine (median [Q1, Q3] ms: 420 [409, 438] vs. 416 [405, 432]; p value<0.001) and patients in the lowest quartile of CFR had a significantly longer QTc compared to those in the highest quartile (median [Q1, Q3] ms: 420 [409, 439] vs. 413 [402, 426]; p<0.001). In a linear regression model adjusting for age and sex, CMD was associated with an increase in QTc of 3.09 ms (p=0.055). Our data suggest that CMD may be associated with an increase in baseline QTc, however the precise clinical relevance of this finding needs to be better investigated in larger clinical studies.


Accidents in family forestry's firewood production.
Firewood is commonly used around the world, but little is known about the work involved in its production and associated accidents. The objectives were to identify relationships between accidents and time exposure, workers' age and sex, equipment used and work activities in family forestry's firewood production. Data from a postal survey in Northern Sweden were compared to a database of injuries in the same region. Most accidents occurred to 50-69 year old men, who also worked most hours. No significant differences in sex and age were found between expected and recorded accident frequencies when calculated from total work hours; however, when calculated using numbers of active persons significant differences were found for both age and sex. Frequency of accidents per unit worked time was higher for machine involving activities than for other activities. Accidents that occurred when using wedge splitter machines were responsible for most of this overrepresentation. Fingers were the most commonly injured body parts. Mean accident rate for the equipment used was 87 accidents per million work hours, and the rate was highest for wedge splitters (122 accidents per million work hours). Exposure to elevated risks due to violation of safety procedures is discussed, as well as possible preventative measures.


In vitro uptake of glutamate in GLAST- and GLT-1-transfected mutant CHO-K1 cells is inhibited by the ethylmercury-containing preservative thimerosal.
Thimerosal, also known as thimersal, Merthrolate, or sodiumethyl-mercurithiosalicylate, is an organic mercurial compound that is used in a variety of commercial as well as biomedical applications. As a preservative, it is used in a number of vaccines and pharmaceutical products. Its active ingredient is ethylmercury. Both inorganic and organic mercurials are known to interfere with glutamate homeostasis. Brain glutamate is removed mainly by astrocytes from the extracellular fluid via high-affinity astroglial Na+-dependent excitatory amino acid transporters, glutamate/ aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). The effects of thimerosal on glutamate homeostasis have yet to be determined. As a first step in this process, we examined the effects of thimerosal on the transport of [3H]-d-aspartate, a nonmetabolizable glutamate analog, in Chinese hamster ovary (CHO) cells transfected with two glutamate transporter subtypes, GLAST (EAAT1) and GLT-1 (EAAT2). Additionally, studies were undertaken to determine the effects of thimerosal on mRNA and protein levels of these transporters. The results indicate that thimerosal treatment caused significant but selective changes in both glutamate transporter mRNA and protein expression in CHO cells. Thimerosal-mediated inhibition of glutamate transport in the CHO-K1 cell line DdB7 was more pronounced in the GLT-1-transfected cells compared with the GLAST- transfected cells. These studies suggest that thimerosal accumulation in the central nervous system might contribute to dysregulation of glutamate homeostasis.


Proposal for a New Protocol for the Management of Immune Thrombocytopenia (ITP).
For many decades immune thrombocytopenia (ITP) was managed using therapies which had not undergone randomised clinical trials and included corticosteroids, immune suppression or splenectomy. These older therapies are associated with an increase in morbidity and mortality. These empirical therapies have variable efficacy and well-described side effects for many patients with minimal benefit to the patient. Over the past 10 years there has been a shift away from immune suppression and non-evidence-based therapies towards using treatments with reduced or no immune suppression with an increasing reliance on the recently developed and approved thrombopoietin receptor agonists. The recent COVID-19 pandemic has made it more urgent that we develop non-immune suppressive strategies for ITP. In this commentary we describe our proposal for a contemporary approach to the management of ITP in adults that is based on our hospital practices and published guidelines.


Developmental psychology: a precursor of moral judgment in human infants?
Human infants evaluate social interactions well before they can speak, and show a preference for characters that help others over characters that are not cooperative or are hindering.


Cytogenetic characterization of a bladder carcinoma cell line by fluorescence in situ hybridization.
A bladder carcinoma cell line, RT112/84, has been cytogenetically characterized by classical techniques and fluorescence in situ hybridization. The RHG banding and FISH analysis revealed a mixture of two clones and multiple chromosome rearrangements.


Proof-of-concept preparation and characterization of dual-drug amorphous nanoparticle complex as fixed-dose combination of poorly soluble drugs.
To carry out a proof-of-concept study on the development of dual-drug amorphous nanoparticle complex (nanoplex in short) as a potential formulation platform for fixed-dose combination (FDC) of poorly-soluble drugs. FDC has been proven effective in improving patient compliance for treatment that requires complex multidrug regimen. Currently, there is growing interest to develop FDC of poorly-soluble drugs due to the increased number of drugs exhibiting poor solubility thus low bioavailability. The dual-drug nanoplex was prepared by electrostatically-driven co-complexation of drug molecules with oppositely charged dextran sulfate, using ciprofloxacin (CIP) and itraconazole (ITZ) as the model poorly-soluble drugs. We first verified that the co-complexation products were dual-drug CIP-ITZ nanoplex, and not binary mixtures of the single-drug CIP and ITZ nanoplexes, by demonstrating their distinct thermal behaviors and dissolution characteristics. Depending on the preparation condition, the dual-drug nanoplex exhibited size and zeta potential of 160-410 nm and -35-50 mV, respectively. The individual drug payloads were readily manipulated by varying the CIP/ITZ mass ratio in the feed, resulting in CIP and ITZ payloads in the range of 60-30% and 15-45%, respectively. The CIP-ITZ nanoplex, however, exhibited diminished CIP supersaturation generation, thus lower CIP solubility enhancement, compared to the single-drug CIP nanoplex. The CIP-ITZ nanoplex, nonetheless, remained capable of generating high ITZ supersaturation level. Dual-drug nanoplex was successfully prepared with a high degree of control over its physical characteristics. Nevertheless, whether dual-drug nanoplex always exhibits diminished solubility enhancement compared to its single-drug counterparts needs to be investigated using different poorly-soluble drugs.


Design, Synthesis and Biological Evaluation of Palladium (II) Complexes with 1-(substituted benzyl) azetidine-3,3-dicarboxylates as Leaving Group.
A series of palladium complexes with 2,2'-bipyridine and 1-(substituted benzyl) azetidine- 3, 3-dicarboxylates as ligands were synthesized and characterized by IR, (1)H-NMR, ESI-MS spectra and elemental analysis. The in vitro cytotoxicity assays were carried out against A549, HCT-116, HepG-2 and SGC7901 cancer cell lines. The result showed that most of the complexes possessed moderate antiproliferative activity against HCT-116, HepG-2 and SGC7901 cell lines. Complex 12 (with 2,2'-bipyridine and 1-(3-methoxylbenzyl)azetidine-3,3-dicarboxylate as ligand) was the most potent antitumor agent among all thirteen complexes, which showed comparable or better cytotoxicity against all four tested cancer cell lines than carboplatin. The interaction between complex 12 and pET22b plasmid DNA was investigated by agarose gel electrophoresis, and the result of the study showed that complex 12 had no obvious interaction with the plasmid DNA.


Comparative Proteome-wide Characterization of Three Different Tissues of High-Protein Mutant and Wild Type Unravels Protein Accumulation Mechanisms in Rice Seeds.
Improving the proteins and amino acid contents of rice seeds is one of the prime objectives of plant breeders. We recently developed an EMS mutant/high-protein mutant (HPM) of rice that exhibits 14.8% of the total protein content as compared to its parent Dharial (wild-type), which shows only 9.3% protein content in their mature seeds. However, the mechanisms underlying the higher protein accumulation in these HPM seeds remain largely elusive. Here, we utilized high-throughput proteomics to examine the differences in the proteome profiles of the embryo, endosperm, and bran tissues of Dharial and HPM seeds. Utilizing a label-free quantitative proteomic and subsequent functional analyses of the identified proteins revealed that nitrogen compound biosynthesis, intracellular transport, protein/amino acid synthesis, and photosynthesis-related proteins were specifically enriched in the endosperm and bran of the high-protein mutant seed. Our data have uncovered proteome-wide changes highlighting various functions of metabolic pathways associated with protein accumulation in rice seeds.


Efficient synthetic access to a new family of highly potent bryostatin analogues via a Prins-driven macrocyclization strategy.
The step-economical synthesis of a new class of bryostatin analogues that contain the complete oxycarbocyclic core ring system of the bryostatin natural products is reported. These agents are convergently assembled via a highly efficient, functional-group-tolerant, and stereoselective Prins-driven macrocyclization. These tetrahydropyranyl B-ring analogues are among our most potent and efficacious analogues to date, exhibiting nanomolar and picomolar activities in protein kinase C affinity assays as well as in cellular antiproliferation assays.


Structure-function studies on beta-glycosidase from Sulfolobus solfataricus. Molecular bases of thermostability.
beta-Glycosidase from the extreme thermophilic archaeon Sulfolobus solfataricus is a thermostable tetrameric protein with a molecular mass of 240 kDa which is stable in the presence of detergents and has a maximal activity above 95 degrees C. An understanding of the structure-function relationship of the enzyme under different chemical-physical conditions is of fundamental importance for both theoretical and application purposes. In this paper we report the effect of basic pH values on the structural stability of this enzyme. The structure of the enzyme was studied at pH 10 and in the temperature range 25-97.5 degrees C using circular dichroism, Fourier-transform infrared and fluorescence spectroscopy. The spectroscopic data indicated that the enzyme stability was strongly affected by pH 10 suggesting that the destabilization of the protein structure is correlated with the perturbation of ionic interactions present in the native protein at neutral pHs. These experiments give support to the observation derived from the 3D-structure, that large ion pair networks on the surface stabilize Sulfolobus solfataricus beta-glycosidase.


Clarifying the beneficial effects of plant growth-promoting rhizobacteria for reducing abundances of antibiotic resistance genes during swine manure composting.
This study investigated the effects on antibiotic resistance genes (ARGs) and the related mechanisms of different plant growth-promoting rhizobacteria (PGPR) inoculation strategies during composting: no inoculation (CK), inoculation in initial phase (T1), inoculation in cooling phase (T2), and inoculation in both initial and cooling phases (T3). After composting, the total relative abundances (RAs) of ARGs decreased by 0.26 and 0.03 logs under T3 and T2, respectively, but increased by 0.05 and 0.22 logs under T1 and CK. The abundances of eight ARGs were lowest under T3, including some high risk ARGs with clinical importance. Bioavailable Cu significantly affected the readily removed ARGs, and PGPR inoculation decreased the bioavailability of Cu. T3 reduced the abundances of potential pathogen hosts, inhibited horizontal gene transfer by reducing the RAs of mobile gene elements (0.48 logs), and downregulated the expression of genes related to ARG propagation, thereby decreasing the ecological risk of ARGs.


Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation.
Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in of 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, P < .001) and inferior overall survival (52% vs 68%, P = .05). The sensitivity and specificity of ASC MRD positivity for progression and death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in multivariable analysis (hazard ratio [HR], 3.7; P < .001). Post-ASCT surveillance MRD testing of plasma, but not PBMC samples, reliably identified patients with an impending relapse. A positive plasma MRD result was associated with inferior PFS (HR, 3.0; P = .016) in a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range, 0-518 days). In conclusion, the detection of MRD in ASC samples is associated with a very high risk of relapse, justifying alternative treatment strategies or trials of novel consolidation options in these patients. Furthermore, post-ASCT MRD monitoring may facilitate the evaluation of the early initiation of treatment at molecular relapse. This trial has been registered at www.clinicaltrials.gov as #NCT02362997.


Structure, orientation and affinity for interfaces and lipids of ideally amphipathic lytic LiKj(i=2j) peptides.
The behavior of lytic ideally amphipathic peptides of generic composition LiKj(i=2j) and named LKn, n=i+j, is investigated in situ by the monolayer technique combined with the recently developed polarization modulation IR spectroscopy (PMIRRAS). A change in the secondary structure occurs versus peptide length. Peptides longer than 12 residues fold into alpha-helices at interfaces as expected from their design, while enough shorter peptides, from 9 down to 5 residues, form intermolecular antiparallel beta-sheets. Analysis of experimental and calculated PMIRRAS spectra in the amide I and II regions show that peptides are flat oriented at the interfaces. Structures and orientation are preserved whatever the nature of the interface, air/water or DMPC monolayer, and the lateral pressure. Peptide partition constants, KaffPi, are estimated from isobar surface increases of DMPC monolayers. They strongly increase when Pi decreases from 30 mN/m to 8 mN/m and they vary with peptide length with an optimum for 12 residues. This non-monotonous dependence fits with data obtained in bilayers and follows the hemolytic activity of the peptides. Lipid perturbations due to peptide insertion essentially detected on the PO4- and CO bands indicate disorder of the lipid head groups. Lysis induced on membranes by such peptides is proposed to first result from their flat asymmetric insertion.


ASCO Outlines Minimum Standards and Exemplary Attributes for Research Sites: Previews Tools to Be Provided.
Encouraging community oncologists to consider how to enhance their research programs and also to give practitioners not already involved in research a clearer understanding of what it involves.


Postnatal differentiation of sexual preference in male pigs.
Attraction to sexually mature males and the immobilization response were evaluated after postpubertal estrogen treatment of ovariectomized females and of males castrated within 48 hr after birth or at 4 or 8 months of age. The time spent in the end of an evaluation pen which housed a mature intact male, the proportion of animals that showed the immobilization response, and the latency to onset and the duration of this response were similar in ovariectomized females and males castrated within 48 hr after birth. These two groups spent more time in the male end of the evaluation pen as opposed to the opposite end which housed an ovariectomized female, showed a shorter latency to the onset of the immobilization response, and expressed this response for a greater number of days than males castrated either at 4 or 8 months of age. Males castrated at 4 or 8 months did not show a strong preference for either a mature male or an ovariectomized female. The immobilization response in estrogen-treated males castrated at 4 or 8 months of age diminished as these animals became older. On the basis of the observations made in this study, attraction to a mature, intact male is a sexually dimorphic behavioral trait in pigs, and defeminization of this trait in male pigs is associated with the pubertal increase in testicular steroid secretion. Presently, pigs are the only mammalian species in which a role has been identified for pubertal, testicular steroid secretion in the defeminization process.


N E. coli, inducible DNA repair is error-prone with regard to lethality.
The umuC gene is a member of the inducible SOS repair network in E. coli. The experiments reported here indicate that the product of the umuC locus can make lethal mistakes during its normal repair function. Such "lethal repair" may be a major factor in establishing a cell's sensitivity to radiation.


Abnormal expression of the RI subunit of cyclic AMP-dependent protein kinase in Y-79 retinoblastoma cells.
The cyclic AMP-dependent protein kinases of Y-79 retinoblastoma cells were analyzed by DEAE Sephacel column chromatography, SDS-polyacrylamide gel electrophoresis, and immunoblotting. Both type I and type II protein kinases (characteristic of fetal and mature retina respectively) were observed. In addition, free RI (type I regulatory subunit) was present in Y-79 cells; three other retinoblastoma cell lines also showed evidence of free RI in immunoblot analysis. Northern blot analysis of poly A+-enriched RNA from Y-79 cells showed a 4.5 kb RI transcript and a 6.0 kb RII transcript. The single 4.5 kb RI message is typical of normal retina, in contrast to other tissues and cell lines in which a 2.0 kb message predominates. Since RI expression appears to be post-transcriptionally inhibited in normal retina, it is suggested that free RI dimers in retinoblastoma is the result of loss of repression of translation of this transcript and that the free RI pool may contribute to the unregulated growth of these cells.


Shear thinning effect on liquid foam distribution in heterogeneously constricted in vitro airway models.
Treating diseased lung regions using inhalation therapy is often limited due to airway constrictions and obstructions that significantly reduce aerosol deposition efficiency. Intratracheal administration of liquid foams is a potential strategy to improve pulmonary drug delivery to these affected airway regions. Here, we use effective viscosity measurements and in vitro small-airway models to examine how shear thinning effects in the foam can be leveraged to achieve a more uniform distribution within heterogeneously constricted or partially obstructed airways. We find that a foamed solution based on the formulation of Tacholiquin® exhibited a 5.75-fold decrease in effective viscosity across a shear rate range spanning 970 to 14'500 s-1. As a result, the foam volume penetrating through the constricted airway models was up to 154% higher compared with air, depending on the cross-sectional area of the constrictions. This proof-of-concept study represents a first step towards understanding the transport mechanics of liquid foams towards future pulmonary delivery applications.


Higher blood pressure in adolescent boys after very preterm birth and fetal growth restriction.
Although preterm birth predisposes for cardiovascular disease, recent studies in children indicate normal blood pressure and arterial stiffness. This prospective cohort study therefore assessed blood pressure and arterial stiffness in adolescents born very preterm due to verified fetal growth restriction (FGR). Adolescents (14 (13-17) years; 52% girls) born very preterm with FGR (preterm FGR; n = 24) and two control groups born with appropriate birth weight (AGA), one in similar gestation (preterm AGA; n = 27) and one at term (term AGA; n = 28) were included. 24-hour ambulatory blood pressure and aortic pulse wave velocity (PWV) and distensibility by magnetic resonance imaging were acquired. There were no group differences in prevalence of hypertension or in arterial stiffness (all p ≥ 0.1). In boys, diastolic and mean arterial blood pressures increased from term AGA to preterm AGA to preterm FGR with higher daytime and 24-hour mean arterial blood pressures in the preterm FGR as compared to the term AGA group. In girls, no group differences were observed (all p ≥ 0.1). Very preterm birth due to FGR is associated with higher, yet normal blood pressure in adolescent boys, suggesting an existing but limited impact of very preterm birth on cardiovascular risk in adolescence, enhanced by male sex and FGR. Very preterm birth due to fetal growth restriction was associated with higher, yet normal blood pressure in adolescent boys. In adolescence, very preterm birth due to fetal growth restriction was not associated with increased thoracic aortic stiffness. In adolescence, very preterm birth in itself showed an existing but limited effect on blood pressure and thoracic aortic stiffness. Male sex and fetal growth restriction enhanced the effect of preterm birth on blood pressure in adolescence. Male sex and fetal growth restriction should be considered as additional risk factors to that of preterm birth in cardiovascular risk stratification.


Do Beliefs about the Pathogenetic Role of Amyloid Affect the Interpretation of Amyloid PET in the Clinic.
Beliefs of dementia experts about the pathogenic role of amyloid in Alzheimer's disease (AD) may affect the use of amyloid positron emission tomography (PET). To assess the role attributed to amyloid in AD pathogenesis by Italian dementia experts, and whether this modulates the impact of amyloid PET results in their diagnostic workup. 22 dementia experts rated their beliefs about the pathogenic role of amyloid. Then, we asked them to rate the probability of change in diagnosis based on the result of amyloid PET for 7 case vignettes, depicting patients who initially received a diagnosis based on a comprehensive workup and later received amyloid PET results consistent or inconsistent with the clinical picture. 55% of the experts assigned a dominant role to amyloid, and 32% attributed a similar role to amyloid and tau in AD pathogenesis. The probability of change in diagnosis ranged from 17% (SD = 21.6) for cases with consistent to 51% (SD = 34) for cases with inconsistent PET versus clinical data. Diagnostic change was not biased by the clinicians' beliefs about AD pathogenesis. This work supports an unbiased interpretation of amyloid PET across different beliefs about the pathogenic role of amyloid, and a belief-independent reluctance to change diagnosis in cases where change is expected and recommended.


Effectiveness of Two Differently Processed Bovine-Derived Xenografts for Alveolar Ridge Preservation with a Minimally Invasive Tooth Extraction Approach: A Feasibility Clinical Trial.
Xenogeneic-derived biomaterials are among the most routinely employed bone substitutes for immediate grafting of extraction sites as a modality of alveolar ridge preservation (ARP). The deproteinized bovine bone material is widely used and documented around the world. The present pilot clinical trial evaluated and compared the clinical and morphologic alterations of extraction sites after ARP using two commercially available yet differently processed bovine bone grafts. A total of 20 adjacent extraction sites in 10 patients were included. All sites received the exact same ARP therapy except for the type of bovine bone graft, which was randomly assigned between two adjacent extraction sockets in 10 patients (Group A received Bio-Oss particles and Group B received Cerabone particles). At all sites, healing was monitored at the time of surgery and at 1, 2, 3, and 4 months postoperative. All of the augmented extraction sites achieved successful implant therapy regardless of the bone graft material used for ARP. Six weeks after implant placement, second-stage/uncovering procedures were performed without complications. Intergroup comparisons of the crestal gingival healing process (CGHP), mean transversal crestal ridge resorption (MTRR), and mean implant primary stability (MIPS) were in favor of Group A sites (treatment with Bio-Oss particles).


Ectopic ascariasis: report of a case with adult worms in the kidney.
Six adult Ascaris lumbricoides were found in the pelvis and calyces of the left kidney of a 25-year-old woman in Mexico. Prior to death three worms had emerged from a subcutaneous abscess which at autopsy was found to communicate with the colon through fistulas to the upper ureter above an occluding calculus, and from the renal capsule to the skin near the left iliac crest.


Evidence of intrathecal immunoglobulin synthesis in stroke: a cohort study.
Immune mechanisms are included in stroke pathophysiologic factors, but the frequency and role of intrathecal antibodies is unclear and diagnostic tests are not routinely performed on cerebrospinal fluid (CSF). To determine the frequency of intrathecal immunoglobulin synthesis in a well-characterized cohort of patients who experienced "noninflammatory"acute stroke. Retrospective cohort study. University hospital neurology department. Patients (n=318) with stroke who were undergoing lumbar puncture during diagnostic workup and 79 control patients. Cerebrospinal fluid–specific immunoglobulin(IgG, IgM, and IgA) synthesis was significantly(P.001) more frequent after stroke (24.8%) compared with the incidence in age- and sex-matched controls(2.5%). Furthermore, 31.3% of stroke patients demonstrated blood-brain barrier dysfunction and 18.1% displayed pleocytosis. The strong association between CSF-specific immunoglobulin synthesis and stroke suggests a role in the development of cerebral ischemia and might constitute an immunologically defined stroke subgroup.


Pacing strategy of a wheelchair athlete in a 5x and 10x Ironman ultra triathlon: a case study.
For disabled athletes such as wheelchair athletes, there is no knowledge about competing and pacing during a long-distance triathlon such as an Ironman triathlon. This study aimed to investigate the pacing strategy of a paraplegic wheelchair athlete competing and finishing a Quintuple Iron ultra-triathlon (i.e., five times 3.8 km swimming, 180 km handbike cycling and 42.195 km wheelchair racing in five days) and a Deca Iron ultra-triathlon (10 times the same distance in 10 days). Data from an ultra-distance triathlon race (Swissultra) covering 5x and 10x Ironman distance were collected. Official performance data were acquired from the race organizer's website and athlete's personal information from the athlete through online interviews. The athlete is a man born in 1962, the races analysed in this study were held in the summer of 2017 (5x) and 2019 (10x). The split times for swimming, cycling and running, the overall race times for each Ironman and the lap times in cycling (handbike) and running (wheelchair) were analysed. The athlete finished the Quintuple Iron ultra-triathlon in an overall race time of 66:28:31 h:min:s and the Deca Iron ultra-triathlon in 137:03:20 h:min:s. He adopted an even pacing in both races in split disciplines and for overall race time. The paraplegic wheelchair athlete was able to finish both a Quintuple and a Deca Iron ultra-triathlon by adopting an even pacing in all split disciplines and for overall race time.IMPLICATIONS FOR REHABILITATIONTriathlon is a growing sport among athletes with spinal cord injury.Ultra-triathlons are ultra-endurance events and pacing is a key aspect to a successful race regardless the athlete's category.An athlete with a spinal cord injury finished a 5x and 10x Ironman ultra-triathlon applying an even pacing strategy.


Interrelation between baroreceptor and macula densa mechanisms in the control of renin secretion.
1. It was the aim of this study to examine the interrelation between 'baroreceptor' function and the macula densa signal in the control of renin secretion from the kidneys. To this end we investigated the effects of frusemide and bumetanide, two different inhibitors of the macula densa Na(+)-K(+)-2Cl- cotransport, on pressure-dependent renin release from isolated perfused rat kidneys. In addition, pressure modulation of renin secretion from hydronephrotic kidneys devoid of macula densa structures was examined. 2. Basal flow rate through isolated kidneys was 13.5 +/- 1.0 ml min-1 g-1 at a renal artery pressure of 100 mmHg and corresponding renin secretory rates were 5.5 +/- 0.5 (ng angiotensin I (Ang I) h-1) min-1 g-1 (mean +/- S.E.M., n = 15). 3. Frusemide (10-100 microM) and bumetanide (5-50 microM) increased urine flow rates and stimulated urinary sodium excretion in a dose-dependent fashion from 13.0 +/- 2.5 mumol min-1 g-1 (n = 10) under control conditions to maximal values of 38.0 +/- 5.0 (n = 5) and 37.0 +/- 2.0 mumol min-1 g-1 (n = 5), respectively. Both drugs also induced concentration-dependent decreases of the renal vascular resistance. The vasorelaxant effects of frusemide and bumetanide were paralleled by an increase of renin secretion to a maximum of 21 +/- 4 (ng Ang I h-1) min-1 g-1 (n = 10). On a molar basis bumetanide was twice as potent as frusemide in stimulating renin secretion. 4. Lowering of the perfusion pressure from 100 to 40 mmHg resulted in a prompt increase of renin release yielding secretion rates of 92 +/- 10 (ng Ang I h-1) min-1 g-1 (n = 15). In the presence of frusemide (100 microM) and bumetanide (50 microM) renin secretion rates at 40 mmHg were 97 +/- 11 and 133 +/- 24 (ng Ang I h-1) min-1 g-1 (n = 6), respectively. Renin release stimulated by bumetanide was significantly reduced to 8.0 +/- 1.5 (ng Ang I h-1) min-1 g-1 (n = 5) by elevating the perfusion pressure from 100 to 140 mmHg. 5. Lowering the renal artery pressure from 100 to 40 mmHg in isolated perfused rat hydronephrotic kidneys devoid of tubular structures increased renin secretion rates from 4.5 +/- 1.0 to 22.5 +/- 2.5 (ng Ang I h-1) min-1 (n = 5).(ABSTRACT TRUNCATED AT 400 WORDS)


Suppression of thioredoxin system contributes to silica-induced oxidative stress and pulmonary fibrogenesis in rats.
Silicosis is one of the most prevalent occupational lung diseases worldwide. This study aimed to investigate the possible mechanism that silica affected thioredoxin (Trx) system during the development of silicosis in vivo. Male Wistar rats were randomly divided into saline group and silica group in which rats were intratracheally instilled with a single dose of silica suspension (50mg in 1ml saline/rat). After 7, 15 or 30 days instillation, rats were sacrificed. Biochemical parameters and histopathology were assessed. Our results demonstrated that silica could significantly cause the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) as well as activate antioxidative protein Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein Trx in the early exposure to silica. The inhibition of Trx activity and the down-regulated expression of thioredoxin reductase (TrxR), suggesting that the function of Trx system may be suppressive induced by silica. Content of lung hydroxyproline and histopathological results showed significant fibrosis development with time. In conclusion, our study demonstrated that silica could suppress the Trx system to perturb the redox balance, elicit oxidative stress, and eventually induce pulmonary fibrosis.


MicroRNA-155 triggers a cellular antiviral immune response against Chandipura virus in human microglial cells.
Chandipura virus (CHPV) belongs to the family Rhabdoviridae and has a single-stranded RNA genome that causes encephalitis among children in India's tropical states. Activation of the antiviral immune response upon viral infection is important for the host's defense. In response to CHPV infection, the brain resident macrophages (microglial cells) control the pathogenic insults. The microRNAs (miRNAs) are 22 nts non-coding RNAs that serve as delicate regulators of their target genes at the post-transcriptional level. In this study, we explored miR-155 mediated antiviral response in CHPV infected human microglial cells. The gene and protein expression patterns were studied through quantitative real-time PCR (qPCR) and immunoblotting, respectively. Additionally, miRNA target validation was done by overexpression and knockdown of miR-155. We observed an increased expression of miR-155 in CHPV infected human microglial cells. The upregulated miR-155 suppresses the Suppressor of Cytokine Signalling 1 (SOCS1). Reduced SOCS1, in turn, led to enhanced phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1) and induction of Interferon-β (IFN-β), which promoted the expression of IFN-stimulated gene 54 (ISG54) and IFN-stimulated gene 56 (ISG56). In this study, miR-155 positively modulated the cellular antiviral response by enhancing type I IFN signalling through inhibition of SOCS1 in CHPV infected microglial cells.


Atypical involvement of central nervous system in classic Hodgkin lymphoma: a case report.
Hodgkin lymphoma is a systemic disease that commonly involves the cervical, supraclavicular, and mediastinal lymph nodes. The involvement of central nervous system in Hodgkin lymphoma is extremely rare, and diagnosis is usually established using distinct morphological and immunohistochemical staining on the tissue biopsied. Extranodal presentation of HL is a rare occurrence. It has been evident that prognosis is encouraging in patients with disease that is limited to just central nervous system initially or as relapse, compared with involvement of multiple sites of relapse. We herein report a case of a 35-year-old South-East Asian male with relapsed Hodgkin lymphoma. The patient developed a parotid gland lesion, cervical lymphadenopathy with significant weight loss, and intermittent night sweats. Along with spread to the central nervous system, there was a high suspicion of tuberculosis. Upon biopsy of his cervical lymph node, the patient was confirmed to have Hodgkin lymphoma. Immediate treatment began with six cycles of chemotherapy consisting of adriamycin, bleomycin, vinblastine, and dacarbazine. The patient received three cycles of chemotherapy consisting of ifosfamide, carboplatin, and etoposide but then was lost to follow-up. Five years later, the patient suffered a road traffic accident. Upon work-up, a right parietal space-occupying lesion with moderate cerebral edema and midline shift was found on computed tomography of the brain. The patient underwent resection of the space-occupying lesion of brain, with features consistent with classical Hodgkin lymphoma on histopathology examination. It is crucial for such lesions to be investigated meticulously to rule out any secondary disease process. Relapsed Hodgkin lymphoma with central nervous system involvement is relatively rare with just over two dozen cases reported to date and is observed infrequently in developing nations. Therefore, space-occupying lesion should always be investigated, and biopsy of such lesions is gold standard to establish diagnosis. With timely appropriate therapy, complete remission can be achieved. However, large-scale studies would be prudent to explore the presentation, survival, and treatment options for patients with Hodgkin lymphoma involving the central nervous system.


[Urinary elimination of urinary tetrahydroaldosterone measured by gas-phase chromatography. Normal values in adults].
The authors describe a method of titration of tetrahydroaldosterone in the urine, requiring an internal non-radioactive standard. This method uses high performance liquid chromatography as a mean of isolating tetrahydroaldosterone (THAldo) and chromatography in gaseous phase as a method of titration in the form of heptafluorobutyrate after oxidation into gamma lactone. It permits to detect 3 ng of gamma lactone of THAldo corresponding to a urinary concentration of 16 nmol/l.


Autoimmune hemolytic anemia and carcinoma: an unusual association.
Four patients with Coombs'-positive hemolytic anemia associated with carcinoma are presented and compared to 12 previously described patients. These patients commonly seek medical attention for symptoms of anemia rather than for complaints due to the tumor mass. The physician should particularly evaluate for an underlying carcinoma when a patient over the age of 60 years presents with autoimmune hemolytic anemia. Autoimmune hemolytic disease has been demonstrated in patients with a wide variety of tumors, including squamous cell carcinomas, adenocarcinomas, hypernephromas, oat cell carcinomas and a seminoma. Corticosteroid treatment is less effective in autoimmune hemolytic disease associated with carcinoma than in idiopathic autoimmune hemolysis. Tumor extirpation in patients with localized neoplastic disease may abolish the autoimmune hemolytic anemia. Control of the carcinoma through irradiation and chemotherapy together with corticosteroid therapy and/or splenectomy lessened the anemia in some patients. The positive Coombs' test may revert to negative with tumor excision or control. Subsequently, the positivity of the Coombs' reaction may provide a clue to recurrent neoplastic activity. The pathogenic mechanism underlying the association between carcinoma and autoimmune hemolytic disease is poorly understood.


Adapting granular materials through artificial evolution.
Over 200 years after Coulomb's studies, a general connection between the mechanical response of a granular material and the constituents' shape remains unknown. The key difficulty in articulating this relationship is that shape is an inexhaustible parameter, making its systematic exploration infeasible. Here we show that the role of particle shape can, however, be explored efficiently when granular design is viewed in the context of artificial evolution. By introducing a mutable representation for particle shapes, we demonstrate with computer simulation how shapes can be evolved. As proof of principle, we predicted motifs that link shape to packing stiffness, discovered a particle that produces aggregates that stiffen-rather than weaken-under compression, and verified the results using three-dimensional printing. More generally, our approach facilitates the exploration of the role of arbitrary particle geometry in jammed systems, and invites the discovery and design of granular matter with optimized properties.


Genomic landscape, immune characteristics and prognostic mutation signature of cervical cancer in China.
This study aimed to analyse the genomic alteration profiles and immune characteristics of a cohort of Chinese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and immunotherapy as well as their prognostic significance. PD-L1 expression and clinicopathological information were obtained from 98 cervical cancer patients. Differences in PD-L1 expression and gene mutations between squamous cell carcinoma (SCC) and adenocarcinoma (AC) were analysed by the chi-square test or Fisher's exact test. Differences in gene mutations between our cohort and The Cancer Genome Atlas (TCGA) cohort were tested by Fisher's exact test. Logistic regression was used to analyse factors influencing TMB-high. Positive PD-L1 expression was significantly higher in cervical SCC than in cervical AC (87% vs. 39%, p < 0.001). Frequently mutated genes in cervical cancer included the PIK3CA, KMT2D, and KMT2C genes, among others. PIK3CA gene mutation rates were significantly higher in SCC than in AC (p = 0.004). The TERT gene mutation rate was significantly higher in our cohort than in the TCGA cohort (12% vs. 1%, p < 0.001). The independent predictors of high TMB were KMT2C and LRP1B gene mutations (p < 0.05). We also found that PTEN mutations were associated with worse survival (median PFS, 12.16 vs. 21.75 months, p = 0.0024). Cervical SCC and AC have different molecular profiles and immune characteristics, suggesting that targeted treatments for SCC and AC patients may improve clinical outcomes. KMT2C and LRP1B gene mutations are independent predictors of TMB-high status in cervical cancer. We also proposed the prognostic value of PTEN mutations.


The utility of self-emulsifying oil formulation to improve the poor solubility of the anti HIV drug CSIC.
CSIC (5-chloro-3-phenylsulfonylindole-2-carboxamide), a non-nucleoside reverse transcriptase inhibitor (NNRTI) has not been advanced as a therapeutic anti-HIV candidate drug due to its low aqueous solubility and poor bioavailability. The objective of this work was to formulate CSIC into self-emulsifying oil formulations for the purpose of improving its aqueous solubility and evaluating in vitro antiretroviral activity. CSIC self-emulsifying oil formulations (SEFs) were formulated and evaluated for droplet size, zeta potential, polydispersity index (PDI), viscosity, emulsification time, stability and bioactivity. Results showed significantly improved solubility of CSIC in the SEFs.The concentration of co-surfactant affected the droplet size, zeta potential and polydispersity index. In vitro bioactivity studies showed that the CSIC SEFs retained full anti-HIV activity. The in vitro data from this first attempt to formulate CSIC SEFs suggest that improvement on the aqueous solubility of CSIC through this delivery system may accentuate its antiretroviral effectiveness in vivo via bioavailability enhancement. The formulation is therefore intended as an oral anti-HIV agent for prophylactic and therapeutic uses.


Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling.
Epicardial adipose tissue (EAT) accumulation is associated with cardiac arrhythmias. The effect of EAT secretome (EATs) on cardiac electrophysiology remains largely unknown. The purpose of this study was to investigate the arrhythmogenicity of EATs and its underlying molecular and electrophysiological mechanisms. We collected atrial EAT and subcutaneous adipose tissue (SAT) from 30 patients with atrial fibrillation (AF), and EAT from 3 donors without AF. The secretome was collected after a 24-hour incubation of the adipose tissue explants. We cultured neonatal rat ventricular myocytes (NRVMs) with EATs, subcutaneous adipose tissue secretome (SATs), and cardiomyocytes conditioned medium (CCM) for 72 hours. We implemented the electrophysiological changes observed after EATs incubation into a model of human left atrium and tested arrhythmia inducibility. Incubation of NRVMs with EATs decreased expression of the potassium channel subunit Kcnj2 by 26% and correspondingly reduced the inward rectifier K+ current IK1 by 35% compared to incubation with CCM, resulting in a depolarized resting membrane of cardiomyocytes. EATs decreased expression of connexin43 (29% mRNA, 46% protein) in comparison to CCM. Cells incubated with SATs showed no significant differences in Kcnj2 or Gja1 expression in comparison to CCM, and their resting potential was not depolarized. Cardiomyocytes incubated with EATs showed reduced conduction velocity and increased conduction heterogeneity compared to SATs and CCM. Computer modeling of human left atrium revealed that the electrophysiological changes induced by EATs promote sustained reentrant arrhythmias if EAT partially covers the myocardium. EAT slows conduction, depolarizes the resting potential, alters electrical cell-cell coupling, and facilitates reentrant arrhythmias.


Pressure ulcers in critically ill patients - Preventable by non-sedation? A substudy of the NONSEDA-trial.
Pressure ulcers still pose a significant clinical challenge to critically ill patients. This study is a substudy of the multicenter NONSEDA-trial, where critically ill patients were randomised to sedation or non-sedation during mechanical ventilation. The objective of this substudy was to assess if non-sedation affected the occurrence of pressure ulcers. Retrospective assessment of data from a single NONSEDA-trial site. Mixed intensive care unit. The occurrence of pressure ulcers, described by grade and location. 205 patients were included. Patients with pressure ulcers in the two groups were comparable with regards to baseline data. There were 44 ulcers in 32 patients in the sedated group and 31 ulcers in 25 patients in the non-sedated group (p=0.08). 64% of the ulcers in sedated patients were located on sacrum and heels, whereas 68% of the ulcers in non-sedated patients were related to equipment (p=0.03). Non-sedation did not significantly reduce the number of pressure ulcers. Non-sedation significantly affected the location of ulcers: non-sedated patients mainly had ulcers related to equipment, whereas sedated patients mainly had ulcers on the sacrum and heels.


Retinohypothalamic pathway in the dove demonstrated by anterograde HRP.
The hypothalamic suprachiasmatic nucleus (SCN) of the ring dove was demonstrated by the presence of labeled retinal processes. Horseradish peroxidase or tritiated proline were injected into the vitreous of the eye and were transported in an anterograde manner to label the SCN. After identifying the retinorecipient area of the hypothalamus by anterograde tracing procedures, a diffusely organized nucleus corresponding to this region was noted in Nissl material.


[Craniofacial dysmorphosis: orthodontic and surgical-orthodontic treatment of borderline cases].
The authors, described the typical cranio-facial anomalies in the border-line cases, consider the possibilities of the orthodontic therapy or else of the alternative orthodontic-surgical therapy. The advantages and disadvantages are commented.


Limitations of using pregnancy-associated alpha-2 glycoprotein as a tumour marker.
The development of a new enzyme-linked immunoassay for pregnancy-associated alpha-2 glycoprotein (alpha 2-PAG) has provided an opportunity to reassess the value of this protein as a tumour marker. Serum samples from 800 healthy individuals and patients with various benign and malignant diseases were assayed. There was a very wide range of alpha 2-PAG levels in normal females (1- greater than 100 mg/l), and although the levels found in normal males were lower and better defined, this intrinsic variation between individuals makes a single determination in a tumour-bearing patient meaningless. Also, the levels of alpha 1-PAG in patients with advanced cancer were not significantly different from levels in localized cancer, benign disease or even healthy controls, and furthermore, levels before and after successful cancer treatment did not show a significant change. Our results therefore indicate that alpha 2-PAG is unsuitable for use as a tumour marker as there was no apparent relationship between the levels of alpha 2-PAG and either tumour burden or response to treatment.


A rat subchronic study transcriptional point of departure estimates a carcinogenicity study apical point of departure.
Considerations of human relevance and animal use are driving research to identify new approaches to inform risk assessment of chemicals and replace guideline-based rodent carcinogenicity tests. Here, the hypothesis was tested across four agrochemicals that 1) a rat 90-day transcriptome-based BEPOD is protective of a rat carcinogenicity study and 2) a subchronic liver or kidney BEPOD would approximate a cancer bioassay apical POD derived from other organs and a rat subchronic BEPOD would approximate a mouse cancer bioassay apical POD. Using RNA sequencing and BMDExpress software, liver and/or kidney BEPOD values were generated in male rats exposed for 90 days to either Triclopyr Acid, Pronamide, Sulfoxaflor, or Fenpicoxamid. BEPOD values were compared to benchmark dose-derived apical POD values generated from rat 90-day and rodent carcinogenicity studies. Across all four agrochemicals, findings showed that a rat 90-day study BEPOD approximated the most sensitive apical POD (within 10-fold) generated from the 90-day rat study and long-term rodent carcinogenicity studies. This study supports the conclusion that a subchronic transcriptome-based BEPOD could be utilized to estimate an apical POD within a risk-based approach of chronic toxicity and carcinogenicity agrochemical assessment, abrogating the need for time- and resource-intensive rodent carcinogenicity studies and minimizing animal testing.


Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survival.
HLA matching and mismatching, while inversely related, are not exact opposites. Here we determined the independent effects of HLA matching and mismatching on outcomes in deceased donor kidney transplant recipients. The United Network for Organ Sharing database (1995-2012) was utilized and analyzed for delayed graft function, one-year acute rejection, and death-censored graft survival using combined multivariable models including HLA matching and mismatching. Sensitivity analyses were performed using the subgroup of deceased donor kidney transplant patients after 2003 with more uniform HLA nomenclature and resampling analyses using bootstrapping on complete data available from 96,236 recipients. Individually, both HLA matching and mismatching showed significant associations with graft survival. Adjusting the model to take into account both matching and mismatching simultaneously, the degree of HLA mismatching lost significance while matching continued to have a significant prediction for delayed graft function, the one-year acute rejection rate, and graft survival. Sensitivity analyses and bootstrapping showed similar results for all studied outcomes. Thus, analysis of this large cohort demonstrates the apparent greater association of HLA matching over HLA mismatching on both early allograft events as well as graft survival. Future analyses should preferentially utilize HLA matching as a covariate over mismatching for accurately reflecting impact on graft outcomes.


A framework for screening sites at risk from contaminants of emerging concern.
Trace levels of a variety of currently unregulated organic chemicals have been detected in treated wastewater effluents and surface waters that receive treated effluents. Many of these chemicals of emerging concern (CECs) originate from pharmaceuticals and personal care products that are used widely and that frequently are transported "down the drain" to a wastewater treatment plant (WWTP). Actual effects of CECs on aquatic life have been difficult to document, although biological effects consistent with effects of some CECs have been noted. There is a critical need to find appropriate ways to screen wastewater sites that have the greatest potential of CEC risk to biota. Building on the work of several researchers, the authors present a screening framework, as well as examples based on the framework, designed to identify high-risk versus lower-risk sites that are influenced by WWTP effluent. It is hoped that this framework can help researchers, utilities, and the larger water resource community focus efforts toward improving CEC risk determinations and management of these risks.


Behavioural differentiation of rats confronted to a complex diving-for-food situation.
Previous studies have shown that a behavioural differentiation appeared in groups of rats subjected to an experimental design in which access to the feeder was made difficult. Some rats brought back food pellets to the cage (divers) while the others (non-divers) stayed in the sole home cage and obtained food only by stealing it from divers. In this study, we elaborated a more complex diving-for-food device which allowed divers to consume the food in a second cage away from non-divers. As a result, the expected lack of suppliers should not allow the emergence of the non-diver status. Unexpectedly, our results showed the apparition of non-divers and the persistence of divers (divers c1) bringing food back to the initial cage. Two new categories of rats appear: individuals which consume the food in the second cage where they stay once they have reached it (divers c2), or occasionally go back to the initial cage throughout the experiment (divers c1c2). Our results show the influence of spatial environment on social organization of rats and suggest that social pressure strongly determines the emergence of specialized roles in a group.


Distinguishing Myth from Fact: Photocarcinogenesis and Phototherapy.
Ultraviolet (UV) radiation contributes to the development of skin cancer through direct and indirect DNA damage, production of reactive oxygen species, and local immunomodulation. The association between UV radiation and skin cancer has raised concern for the risk of carcinogenesis following phototherapy. The photocarcinogenic impact of psoralen and UVA radiation (PUVA) has been extensively studied, whereas limited safety studies exist for other phototherapy modalities, such as broadband and narrowband UVB and UVA1. Because of the as of yet unclear risk, patients who have undergone any type of phototherapy should be followed for age-appropriate skin cancer screening.


Effects of ruthenium red on accumulation and cytotoxicity of m-AMSA, vinblastine and daunorubicin in leukemia cells.
Effects of ruthenium red on accumulation and cytotoxicity of m-AMSA, vinblastine and daunorubicin were examined in the P388 murine leukemia cell line and in an adriamycin-resistant subline, P388/ADR, which is cross-resistant to all three agents. Ruthenium red increased m-AMSA accumulation by both P388 and P388/ADR cells; the extent of this effect was a function of the concentration of both agents. Uptake enhancement occurred within 5 min of exposure of cells to ruthenium red and was readily reversed when cells were suspended in fresh medium. A 24-hr exposure to ruthenium red was needed to affect vinblastine or daunorubicin accumulation, and the effect was substantially less than that observed with m-AMSA. Ruthenium red protected P388 cells from m-AMSA toxicity. These data, together with reports indicating a protective effect of ruthenium red against vinblastine and anthracycline toxicity, suggest that the dye promotes tight binding of m-AMSA and other agents to cellular loci on which toxic effects are not exerted.


Deletion of corticotropin-releasing factor binding protein selectively impairs maternal, but not intermale aggression.
Corticotropin-releasing factor (CRF) binding protein (CRF-BP) is a secreted protein that acts to bind and limit the activity of the neuropeptides, CRF and urocortin (Ucn) 1. We previously selected for high maternal defense (protection of offspring) in mice and found CRF-BP to be elevated in the CNS of selected mice. We also previously determined that both CRF and Ucn 1 are potent inhibitors of offspring protection when administered centrally. Thus, elevated CRF-BP could promote defense by limiting endogenous actions of CRF or Ucn 1. To test this hypothesis, we crossed the deletion for CRF-BP into the mice selected for high maternal defense and evaluated offspring protection and other maternal behaviors. CRF-BP knockout (KO) mice exhibited significant deficits in maternal aggression relative to wild-type (WT) mice in three different measures. Other maternal features were almost identical between groups, including dam and pup weight, litter size, nursing time, and pup retrieval. Both groups performed similarly in a forced swim stress test and aggression in both groups was reduced following the swim test. Virgin KO female mice exhibited higher levels of anxiety-like behavior in terms of decreased time in the light portion of the light/dark box test. For males, no differences in light/dark box or swim test were found. However, increased anxiety-like behavior in male KO mice was identified in terms of contact and approach to a novel object both with and without previous exposure to the swim test. No differences in isolation induced resident intruder male aggression were found between groups. Together, these results indicate that loss of CRF-BP selectively impairs maternal, but not intermale aggression and that loss of the gene induces anxiety-like behavior in males and females, but there are sex differences in terms of how that anxiety is revealed.


Determination of common genetic variants in cytidine deaminase (CDA) gene in Indian ethnic population.
Cytidine deaminase (CDA) is the major enzyme involved in metabolism of gemcitabine, a pyrimidine analog widely used for chemotherapy of solid tumors. While only low amounts of administered gemcitabine undergo intracellular phosphorylation into active forms and involve in antineoplastic activities, majority of it is rapidly inactivated by CDA and excreted to avoid drug toxicity. Knowledge of the genetic polymorphisms mildly effecting cellular activity of the enzyme CDA is therefore crucial to understanding drug-induced toxicities associated with gemcitabine. Functional significance and allele frequencies for common SNPs including 79A>C (*2) and 208G>A (*3) have been reported in various ethnic populations including Caucasian, African, Korean and Japanese. However, such studies have not been reported in any Indian sub-population. In the present study, conventional polymerase chain reaction (PCR) based amplification using gene specific primers and Sanger sequencing were performed to identify CDA variants in 50 healthy individuals from Indian sub-population. Established common variant 79A>C known to reduce CDA activity was observed at a frequency of 0.14 in the study cohort. In addition to other known variants, one novel variant, c.325-209T>C was detected at a frequency of 0.06. Genetic variants in CDA gene and their frequencies established in our study hold value in pharmacogenetics.


Cellular localization of keratin in proliferative epithelial processes and neoplasms of the human ovary.
Cytokeratins are one of the intermediate cytoplasmic filaments which contribute to the cytoskeleton. Keratins have recently been demonstrated in normal and neoplastic tissues as well as in human cell lines. It has been suggested that the cellular location of keratin may reflect tissue-specific or epithelial type differentiation. Twenty-three examples of human ovaries containing the full spectrum of epithelial proliferations from inflammatory reactive processes to malignant neoplasia were studied for the cellular distribution of cytokeratin using antisera to human keratin. Nineteen cases contained immunoreactive keratin which was limited to the epithelial cells: 2/2 inflammatory, 8/10 benign tumors, 5/7 borderline tumors, 4/4 carcinomas. There was marked regional heterogeneity in keratin expression such that adjacent morphologically-identical cells could be functionally distinguished by the immunoreactive staining. The predominant cellular localization of keratin varied between histological tumor types in the benign neoplasms: serous = apical, subciliary; endometrioid = apical; mucinous = basal. This pattern was lost in the cytological progression to borderline and malignant tumors. In borderline tumors, the most intense reactivity was noted in areas of cellular atypia and proliferation. In borderline and malignant tumors, keratin was usually present in basal cytoplasmic regions contiguous with stroma.


Resilience in children with chronic illness: Tests of the shift-and-persist and skin-deep resilience theories.
This study investigated, and discusses the integration of, the shift-and-persist (SAP) and skin-deep resilience (SDR) theories. The SAP theory states that the combination of shifting (adjusting oneself to stressful situations through strategies like emotion regulation) and persisting (enduring adversity with strength by finding meaning and maintaining optimism) will be beneficial to physical health in children experiencing adversity. The SDR theory states that high striving/self-control will be beneficial to mental health but detrimental to physical health among those confronting adversity. This study investigated 308 children ages 8-17 experiencing the adversity of a chronic illness (asthma). SAP and SDR (striving/self-control) were assessed via questionnaires, and physical health (asthma symptoms, inflammatory profiles), mental health (anxiety/depression, emotional functioning), and behavioral (medication adherence, activity limitations, collaborative relationships with providers) outcomes were measured cross-sectionally. SAP was associated with better physical health, whereas SDR was associated with worse physical health. Both were associated with better mental health. Only SDR was associated with better behavioral outcomes. Implications of findings and discussion of how to integrate these theories are provided. We suggest that future interventions might seek to cultivate both SAP and SDR to promote overall better health and well-being across multiple domains in children experiencing adversity.


Evaluation of tissue adhesives in closure of scleral tunnel incisions.
Using a biomechanical wound strength model, we compared the efficacy of cyanoacrylate and fibrin glues used to close scleral tunnel incisions. Scleral tunnel incisions were made in four groups of rabbits: (1) traditional self-sealing incision, (2) modified non-self-sealing incision, (3) method 2, closed with cyanoacrylate glue, or (4) method 2, closed with fibrin glue. Overall, Groups 1 and 4 showed the least clinical reaction, the slightest decrease in intraocular pressure (which recovered to baseline by day 7), and the most significant recovery of postoperative astigmatism. Initially, the bursting pressure in Groups 1 and 3 was statistically the highest (P < .005). By day 3, wound strengths in Groups 1 and 4 were comparable. Bursting pressure decreased in Groups 2 and 3 by day 7. Our results indicate that clinical responses, intraocular pressure, induced astigmatism, and ultimately wound strength were comparable in fibrin-glue-closed scleral pocket and sutureless self-sealing cataract incisions. Although cyanoacrylate glue cures immediately and initially demonstrates a strong adhesive quality, it causes a severe inflammatory response that inhibits subsequent collagen remodeling. Fibrin tissue adhesives may have an application as adjunctive means of closing scleral tunnel incisions.


Distribution of the FYBES and RHCE*ce(733C>G) alleles in an Argentinean population: implications for transfusion medicine.
The understanding of the molecular bases of blood groups makes possible the identification of red cell antigens and antibodies using molecular approaches, especially when haemagglutination is of limited value. The practical application of DNA typing requires the analysis of the polymorphism and allele distribution of the blood group genes under study since genetic variability was observed among different ethnic groups. Urban populations of Argentina are assumed to have a white Caucasian European genetic component. However, historical and biological data account for the influence of other ethnic groups. In this work we analyse FY and RH blood group alleles attributed to Africans and that could have clinical implications in the immune destruction of erythrocytes. We studied 103 white trios (father, mother and child, 309 samples) from the city of Rosario by allele specific PCRs and serological methods. The data obtained were analysed with the appropriate statistical test considering only fathers and mothers (n = 206). We found the presence of the FY*BES and RHCE*ce(733C>G) alleles and an elevated frequency (0.0583) for the Dce haplotype. The number of individuals with a concomitant occurrence of both alleles was significantly higher than that expected by chance. We found that 4.68% of the present gene pool is composed by alleles primarily associated with African ancestry and about 10% of the individuals carried at least one RH or FY allele that is predominantly observed among African populations. Thirteen percent of Fy(b-) subjects were FY*A/FY*BES. Taken together, the results suggest that admixture events between African slaves and European immigrants at the beginning of the 20th century made the physical characteristics of black Africans to be invisible nowadays. Considering that it was a recent historical event, the FY*BES and RHCE*ce(733C>G) alleles did not have time to become widespread but remain concentrated within families. These findings have considerable impact for typing and transfusion strategy in our population, increasing the pool of compatible units for Fy(b-) individuals requiring chronic transfusion. Possible difficulties in transfusion therapy and in genotyping could be anticipated and appropriately improved strategies devised, allowing a better management of the alloimmunization in the blood bank.


John Auer and Auer rods; controversies revisited.
John Auer first described needle or rod-shaped intracytoplasmic inclusion bodies in leukemia cells in 1906. Auer rods can be seen in myeloid neoplasms ranging from acute myeloid leukemias (AML) to myelodysplasia, but not in normal or non-neoplastic reactive states. This article briefly describes John Auer's experience and discusses debates on Auer rods, and criticizes their place in the definition of refractory anemia with excess of blasts-2 (RAEB-2) in the WHO classification of the myelodysplastic syndromes (MDS).


Interleukin-17 receptor polymorphism predisposes to primary graft dysfunction after lung transplantation.
Primary graft dysfunction (PGD), with an incidence of 11% to 57%, is a major cause of morbidity and mortality within the first 30 days after lung transplantation (LTx). In this study, we postulate that recipient genetic variants in interleukin-17 and -23 receptor genes (IL-17R and IL-23R, respectively) may predispose LTx recipients to an increased risk for developing PGD. Seven genetic variants of IL-17R and IL-23R were successfully genotyped in 431 lung transplant recipients. Our primary end-point was PGD and secondary end-points were time to extubation, intensive care unit (ICU) stay, bronchoalveolar lavage neutrophilia and serum C-reactive protein. The AA genotype of the rs882643 genetic variant of IL-17R was associated with higher PGD grades at 0 hour (adjusted p = 0.042), 12 hours (adjusted p = 0.013) and 48 hours (adjusted p = 0.0092) after LTx. The GG genotype of the rs2241049 genetic variant of IL-17R was associated with higher PGD grades at 48 hours (adjusted p = 0.0067) after LTx. For both genetic variants, no association was found with extubation time, ICU stay, post-operative BAL neutrophilia, serum CRP, chronic lung allograft dysfunction (CLAD) or graft loss. Both genetic variants of IL-17R (rs882643 and rs2241049) were associated with PGD. This confirms a genetic predisposition toward PGD and suggests a role of IL-17 in driving neutrophilia in PGD.


NK cell education via nonclassical MHC and non-MHC ligands.
Natural killer (NK) cell education, a process for achieving functional maturation and self-tolerance, has been previously defined by the interaction between self-major histocompatibility complex class I (MHC-I) molecules and their specific inhibitory receptors. Over the past several years, growing evidence has highlighted the important roles of nonclassical MHC-I and non-MHC-I molecules in NK cell education. Herein, we review the current knowledge of NK cell education, with a particular focus on nonclassical MHC-I- and non-MHC-I-dependent education, and compare them with the classical MHC-I-dependent education theory. In addition, we update and extend this theory by presenting the 'Confining Model', discussing cis and trans characteristics, reassessing quantity and quality control, and elucidating the redundancy of NK cell education in tumor and virus infection.


Thymol provokes burst of action potentials in neurons of snail Caucasotachea atrolabiata.
Thymol, a phenolic monoterpene, is well known for its antimicrobial, antifungal and antioxidant properties. In spite of wide use in oral care products, pharmaceutical and cosmetic preparation and in food industry, the effects of thymol on the neuronal activity and intrinsic properties have not been well studied. We studied the effects of thymol on the spontaneous activity and action potential properties of central neurons of snail Caucasotachea atrolabiata. Thymol (1 mM) altered action potentials characteristics and provoked epileptiform burst firing in snail neurons, which were partially reversible after washout. Before burst firing, action potentials had lower amplitude and maximum rising slope, while the threshold voltage was raised. These results suggest the inhibition of ion channels underlying action potential initiation and upstroke. The maximum falling slope and afterhyperpolarization were also considerably reduced, suggesting the inhibition of potassium channels. Thymol (0.5 mM) that was not able to induce burst firing in snail neurons, synergistically acted with potassium channel blocker, tetraethyl ammonium, to induce burst firing, which also supports the importance of potassium channel inhibition, especially delayed rectifier potassium channels, to the thymol-induced alteration of firing pattern. The thymol-induced burst firing seems to be dependent on both sodium and calcium currents. Our findings provide evidences for the ability of thymol in altering the firing mode of central neurons of snail, which apparently involves the inhibition of calcium and potassium currents. These results further support the interaction of thymol with ion channels and emphasize on the vulnerability of nervous system to this compound.


The Environmental Health Impact of Hurricane Katrina on New Orleans.
Hurricane Katrina caused unprecedented flood damage to New Orleans, Louisiana, and has been the costliest hurricane in US history. We analyzed the environmental and public health outcomes of Hurricane Katrina by using Internet searches to identify epidemiological, sociodemographic, and toxicological measurements provided by regulatory agencies.Atmospheric scientists have now warned that global warming will increase the proportion of stronger hurricanes (categories 4-5) by 25% to 30% compared with weaker hurricanes (categories 1-2).With the new $14.6 billion Hurricane Storm Damage Risk Reduction System providing a 100-year storm surge-defensive wall across the Southeast Louisiana coast, New Orleans will be ready for stronger storms in the future.


Single cell analysis of lipid rafts.
Lipid rafts are plasma membrane microdomains that serve as platforms for the assembly of proteins involved in signal transduction pathways. Given that lipid rafts are relatively resistant to cold extraction with nonionic detergents, lipid raft associated and nonassociated proteins have been identified using biochemical methods such as sucrose-gradient density centrifugation. For identification of raft-associated proteins in individual cells, imaging methods, such as fluorescence microscopy, can be used. Detergent solubilization of non-raft regions of the plasma membrane and extraction of non-raft associated proteins are done on cells affixed to microscope slides and prior to immunostaining. This methodology has the advantages of requiring smaller cell numbers than traditional biochemical methods and also permits the study of migration of signaling proteins into and out of rafts during cell activation. An additional adaptation of the method allows identification of lipid raft-associated proteins during cognate interactions between cells. Here, as an example, we describe the methodology used in our laboratory to study lipid raft-associated molecules during T lymphocyte interactions with antigen-presenting cells.


Characterization of Key Aroma-Active Compounds in Rough and Moderate Fire Rougui Wuyi Rock Tea (Camellia sinensis) by Sensory-Directed Flavor Analysis and Elucidation of the Influences of Roasting on Aroma.
Rougui Wuyi rock tea (WRT) with the premium aroma is a subcategory of oolong tea. Roasting is a unique process that provides a comprehensive aroma to WRT. The key aroma-active compounds of rough Rougui WRT (RR) and Rougui WRT with moderate fire (RM) were characterized by sensory-directed flavor analysis. A total of 80 aroma-active compounds were identified by gas chromatography-olfactometry-time-of-flight-mass spectrometry (GC-O-TOF-MS) and two-dimensional comprehensive gas chromatography-olfactometry-mass spectrometry (GC × GC-O-MS), and 42 of them revealing high flavor dilution (FD) factors (16-4096) during aroma extract dilution analysis were quantitated. Finally, the aroma recombination and omission experiments confirmed 26 odorants as key aroma-active compounds in Rougui WRT. Roasting enhanced the aroma of roasted, woody, burnt/smoky, and cinnamon-like odor impressions in RM evoked by 2- and 3-methylbutanal, furaneol, 3-methylbutanoic acid, propanoic acid, methional, β-myrcene, 2-pentylfuran, 5- and 6-methyl-2-ethylpyrazine, and furfural. In contrast, hexanal, linalool, (Z)-3-hexen-1-ol, (Z)-4-heptenal, (E)-2-heptenal, geraniol, pentanal, and β-nerolidol were responsible for the more intense floral, fruity, and grassy/fresh leaf-like aroma attributes in RR.


Efficacy, acceptability, and tolerability of antidepressants for sleep quality disturbances in post-traumatic stress disorder: A systematic review and network meta-analysis.
Sleep quality disturbances are a common occurrence in post-traumatic stress disorder (PTSD) and may remain after evidence-based treatment for PTSD has been implemented. If left untreated, sleep disturbance can perpetuate or aggravate the disorder. A systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) was conducted comparing efficacy, acceptability, and tolerability among antidepressants for sleep quality improvement in PTSD, using Cochane's RoB2.0 and GRADE approach for NMA. The Cochrane Library, LILACS, PsycINFO, PTSDpubs, and PubMed Central databases were searched from inception to November 29, 2020, leading to the retrieval of 3733 reports. After the selection process, seven RCTs were included in the review (N = 600). We found low certainty of evidence (LCE) that sertraline may improve sleep quality (measured by PSQI) in adult patients with PTSD (MD -0.48, 95% CrI -0.63 to -0.32). Sertraline was as well accepted (RR 1.12, 95% CrI -0.83 to 1.52, very low certainty [VLCE]) and as well tolerated as placebo (RR 0.58, 95% CrI 0.28 to 1.14, LCE). Mirtazapine (MD -3.35, 95% CrI -9.06 to 2.39, LCE), paroxetine (MD -3.13, 95% CrI -7.47 to 1.26, VLCE), nefazodone (MD -0.25, 95% CrI -5.95 to 5.38, VLCE), and bupropion (MD -2.28, 95% CrI -4.75 to 0.21, VLCE) were similar to placebo for improving sleep quality. These antidepressants resulted in little or no benefit for sleep in PTSD. Although the NMA suggested that sertraline may improve sleep in PTSD compared to placebo, due to the low certainty, these estimates are not robust enough to guide clinical decisions.


The prognosis factor of adjuvant radiation therapy after surgery in uterine sarcomas.
This retrospective study evaluated the role of adjuvant radiotherapy (AR) after surgery in patients with uterine sarcoma and analyzed the prognostic factors of local-regional failure-free survival (LRFFS) and overall survival (OS). A study of a total of 182 patients with uterine sarcoma was conducted between June 1994 and October 2014. Adjuvant radiotherapy was defined as postoperative external beam radiation to the pelvis (30-50 Gray/10-25 fractions at five fractions/week). The primary end point was LRFFS, and the secondary end point was OS. Kaplan-Meier curves were compared using the log-rank test. Cox regression analyses were used to determine prognosticators for LRFFS and OS. The median follow-up time of all patients was 75 months, with a 5-year LRFFS of 62.1%. The 2-year and 5-year LRFFS rates were longer for those who received AR than for those who did not receive AR (83.4% vs 70.3%; 78% vs 55.3%; P=0.013). The 5-year OS of all patients was 56.2%, and no significant differences were observed in the 2-year and 5-year OS rates between these two groups (82.7% vs 71.4%; 64.1% vs 51.7%; P=0.067). Importantly, in patients with leiomyosarcoma, the 2-year and 5-year LRFFS and OS rates were longer for those who received AR than for those who did not receive AR (P=0.04 and P=0.02 for the 2-year and 5-year LRFFS, respectively). Patients with uterine sarcoma who were treated with AR after surgery demonstrated an improved LRFFS compared with those who were treated with surgery alone, especially those patients with leiomyosarcoma. Therefore, the role of personalized adjuvant radiation for patients with uterine sarcoma still requires further discussion.


Association of overexpression of hexokinase II with chemoresistance in epithelial ovarian cancer.
This aim of this study was to evaluate the relationship between hexokinase II expression and chemoresistance in epithelial ovarian cancer. One hundred and eleven paraffin-embedded specimens from patients with epithelial ovarian cancer were immunohistochemically stained for hexokinase II. Subsequently, the association between hexokinase II overexpression and clinicopathologic characteristics including chemoresistance was assessed. Survival analyses were also performed for evaluating the prognostic value of hexokinase II overexpression. Tumor recurrence within 6 months after termination of first-line chemotherapy was considered to indicate chemoresistance. Hexokinase II overexpression was associated with chemoresistance (p = 0.029) and was an independent risk factor for chemoresistance [odds ratio (OR) 3.37; 95 % confidence interval (CI) 1.07-10.62; p = 0.038] along with non-optimal debulking surgery (OR 4.93; 95 % CI 1.43-16.98; p = 0.011). Hexokinase II overexpression was significantly associated with decreased progression-free survival (p = 0.002) and showed a similar trend for overall survival (p = 0.101). Cox regression analysis revealed that hexokinase II overexpression was an independent prognostic factor for early recurrence (hazard ratio 2.63; 95 % CI 1.40-4.92; p = 0.002). Our findings suggest that hexokinase II overexpression is associated with short progression-free survival, which could be associated with chemoresistance in epithelial ovarian cancer.


Computer-aided diagnosis as a second reader: spectrum of findings in CT studies of the chest interpreted as normal.
To assess the performance of an automated computer-aided detection (CAD) system as a second reader on chest CT studies interpreted as normal at routine clinical interpretation. Chest CT studies were processed using a prototype CAD system for automated detection of lung lesions. Three experienced radiologists analyzed each CAD finding and confirmed or dismissed the marked image features as lung lesions. Noncalcified, focal lung lesions were classified according to size as being of high (> or = 10 mm), intermediate (5 to 9 mm), or low (< or = 4 mm) significance. Two sub-specialized academic tertiary referral centers in the United States and Germany. Chest CT studies were performed in 100 patients, with results initially reported as normal at clinical double reading. Indications for chest CT were suspected pulmonary embolism (PE) [n = 33], lung cancer screening in a high-risk population (n = 28), or follow-up for a cancer history (n = 39). Reevaluation of all chest CT studies for focal lung lesions with the CAD system as a second reader. Prevalence and spectrum of lung lesions missed at routine clinical interpretation but found by the CAD system. In 33% (33 of 100 patients), CAD detected significant lung lesions that were not previously reported. Fifty-three significant lesions were detected (mean, 1.6 lesions per case), of which 5 lesions (9.4%) were of high significance, 21 lesions (39.6%) were of intermediate significance, and 27 lesions (50.9%) were of low significance. In the PE group, the lung cancer screening group, and the group with a cancer history, four patients (12.1%), six patients (21.4%), and nine patients (23.1%), respectively, had focal lung lesions of high and/or intermediate significance. The false-positive rate of the CAD system was an average of 1.25 per case (range, 0 to 11). Significant lung lesions are frequently missed at routine clinical interpretation of chest CT studies but may be detected if CAD is used as an additional reader.


[Preiser's disease. A case study].
The idiopathic avascular necrosis of the scaphoid or Preiser's disease is condition about which few cases have been described. In the majority of cases, it is debatable whether it is actually a spontaneous osteonecrosis, or a pathological process secondary to a systematic disease, or a result of chemotherapy treatment, or associated with taking steroids. We present the case of a 20-year old woman, with no previous trauma, with pain in her right wrist, which progressed over a period of four years. It was wrongly diagnosed as a tendinitis, and was treated conservatively without any improvement. A simple X-ray was requested that showed an abnormality of the proximal pole of the scaphoid that was beginning to fragment; a fact which was confirmed later by performing a CT scan. This was followed by nuclear magnetic resonance spectroscopy (NMR), which showed signs of ischaemia, mainly in the proximal pole. There were signs of viability in the distal fragment in the NMR using paramagnetic contrast. After the imaging tests, idiopathic avascular necrosis of the scaphoid was diagnosed. The surgical treatment consisted of the removal of necrotic fragments of the proximal pole and removal of the posterior interosseous-nerve. Two years after the intervention, the patient is asymptomatic and with a complete range of movement in the operated wrist.


Increased vaccine tolerability and protection via NF-κB modulation.
Improving adjuvant responses is a promising pathway to develop vaccines against some pathogens (e.g., HIV or dengue). One challenge in adjuvant development is modulating the inflammatory response, which can cause excess side effects, while maintaining immune activation and protection. No approved adjuvants yet have the capability to independently modulate inflammation and protection. Here, we demonstrate a method to limit inflammation while retaining and often increasing the protective responses. To accomplish this goal, we combined a partial selective nuclear factor kappa B (NF-kB) inhibitor with several current adjuvants. The resulting vaccines reduce systemic inflammation and boost protective responses. In an influenza challenge model, we demonstrate that this approach enhances protection. This method was tested across a broad range of adjuvants and antigens. We anticipate these studies will lead to an alternative approach to vaccine formulation design that may prove broadly applicable to a wide range of adjuvants and vaccines.


Antilymphoid activity of leptospiral exoproducts.
Intraperitoneal application of supernatant fluid of L. patoc caused a pronounced and transient fall in peripheral lymphocyte count of Syrian hamsters. Pathogenic and possible cancerologic aspects of this findings are discussed.