Comparison of amplitude-modulated (direct) and frequency-modulated ambulatory techniques for recording ischemic electrocardiographic changes.
Continuous ambulatory electrocardiographic monitoring of ST-segment configuration has become a useful technique for evaluation of myocardial ischemia. Concern that direct or amplitude-modulated (AM) recording and playback systems have inherent limitations that cause inaccurate ST-segment recordings has led to preference for frequency-modulated (FM) devices. To determine the accuracy of AM and FM ambulatory electrocardiographic systems, the signal was compared from the same set of 2 bipolar leads simultaneously recorded by standard electrocardiography and AM and FM recorders in 14 patients during treadmill exercise. Also, simultaneous AM and FM recorders were compared in 9 ambulatory patients in 16 monitoring sessions. The AM recording system accurately reproduced ST segments recorded during treadmill exercise (range 4.0 mm of ST-segment depression to 2.0 mm of ST elevation) when measured at the J point (r = 0.91, p less than 0.0001), and 0.08 second after the J point (r = 0.95, p less than 0.0001). FM recording was equally accurate (r = 0.89 and 0.95, respectively, p less than 0.0001). Similarly, during ambulatory recording, the AM technique accurately recorded maximal ST depression in each episode as recorded by the FM device (28 episodes, range 0 to 3 mm of ST depression, r = 0.85, p less than 0.0001). Both AM and FM ambulatory electrocardiographic systems can accurately reproduce ST-segment deviation associated with ischemia and can be used to monitor transient ST-segment changes in patients with coronary artery disease.


Clinical and functional determinants of coronary flow reserve in non-ischemic dilated cardiomyopathy: an echocardiographic study.
Coronary flow reserve (CFR) is impaired in non-ischemic dilated cardiomyopathy (DCM). Mechanisms by which such impairment occurs are still unknown, but cofactors such as diastolic compressive force, left ventricular hypertrophy, and microvascular disease have been implied. In order to characterize the determinants of CFR in non-ischemic DCM, we evaluated 110 non-ischemic DCM patients (58 men; age=61+/-12 years) and 21 age- and gender-matched control patients (14 men; age=59+/-13 years) by transthoracic (n=88) or transesophageal (n=22) dipyridamole (0.84 mg/ kg in 10') stress echocardiography. All patients showed angiographically normal coronary arteries. Non-ischemic DCM patients had an ejection fraction <45% while control patients had normal left ventricular systolic function. CFR was assessed on LAD by pulsed Doppler as the ratio of maximal vasodilation (dipyridamole) to rest peak diastolic coronary flow velocity. Mean CFR value was 2.0+/-0.6 for DCM patients and 3.2+/-0.5 for controls (p<0.01). At individual non-ischemic DCM patient analysis, 46 patients had normal CFR> or =2 (Group 1) and 64 patients had abnormal CFR<2 (Group 2). On univariate analysis, CFR reduction correlated with NYHA functional class (r=-0.33, p=0.001), left ventricular ejection fraction ( r=0.23, p=0.02), end-systolic volume (r=-0.23, p=0.02), systolic pulmonary artery pressure (r=-0.42, p=0.0001), deceleration time (r=0.24, p=0.02). Logistic multiregression analysis showed that only NYHA functional class significantly and negatively correlated with CFR (odds ratio=0.9; 95% confidence intervals: 0.03-.35, p=0.0001). In patients with non-ischemic DCM, CFR is reduced but with substantial individual variability, only partially accounted for by level of systolic and diastolic dysfunction. The clinical functional class is the strongest predictor of CFR reduction in these patients, with lowest flow reserve found in more advanced NYHA class.


Lipoamino acid-based micelles as promising delivery vehicles for monomeric amphotericin B.
Lipoamino acid-based micelles have been developed as delivery vehicles for the hydrophobic drug amphotericin B (AmB). The micellar solubilisation of AmB by a gemini lipoamino acid (LAA) derived from cysteine and its equimolar mixtures with the bile salts sodium cholate (NaC) and sodium deoxycholate (NaDC), as well as the aggregation sate of the drug in the micellar systems, was studied under biomimetic conditions (phosphate buffered-saline, pH 7.4) using UV-vis spectroscopy. Pure surfactant systems and equimolar mixtures were characterized by tensiometry and important parameters were determined, such as critical micelle concentration (CMC), surface tension at the CMC (γCMC), maximum surface excess concentration (Γmax), and minimum area occupied per molecule at the water/air interface (Amin). Rheological behaviour from viscosity measurements at different shear rates was also addressed. Solubilisation capacity was quantified in terms of molar solubilisation ratio (χ), micelle-water partition coefficient (KM) and Gibbs energy of solubilisation (ΔGs°). Formulations of AmB in micellar media were compared in terms of drug loading, encapsulation efficiency, aggregation state of AmB and in vitro antifungal activity against Candida albicans. The LAA-containing micellar systems solubilise AmB in its monomeric and less toxic form and exhibit in vitro antifungal activity comparable to that of the commercial formulation Fungizone.


Overlap in drug-disease associations between clinical practice guidelines and drug structured product label indications.
Clinical practice guidelines (CPGs) recommend pharmacologic treatments for clinical conditions, and drug structured product labels (SPLs) summarize approved treatment indications. Both resources are intended to promote evidence-based medical practices and guide clinicians' prescribing decisions. However, it is unclear how well CPG recommendations about pharmacologic therapies match SPL indications for recommended drugs. In this study, we perform text mining of CPG summaries to examine drug-disease associations in CPG recommendations and in SPL treatment indications for 15 common chronic conditions. We constructed an initial text corpus of guideline summaries from the National Guideline Clearinghouse (NGC) from a set of manually selected ICD-9 codes for each of the 15 conditions. We obtained 377 relevant guideline summaries and their Major Recommendations section, which excludes guidelines for pediatric patients, pregnant or breastfeeding women, or for medical diagnoses not meeting inclusion criteria. A vocabulary of drug terms was derived from five medical taxonomies. We used named entity recognition, in combination with dictionary-based and ontology-based methods, to identify drug term occurrences in the text corpus and construct drug-disease associations. The ATC (Anatomical Therapeutic Chemical Classification) was utilized to perform drug name and drug class matching to construct the drug-disease associations from CPGs. We then obtained drug-disease associations from SPLs using conditions mentioned in their Indications section in SIDER. The primary outcomes were the frequency of drug-disease associations in CPGs and SPLs, and the frequency of overlap between the two sets of drug-disease associations, with and without using taxonomic information from ATC. Without taxonomic information, we identified 1444 drug-disease associations across CPGs and SPLs for 15 common chronic conditions. Of these, 195 drug-disease associations overlapped between CPGs and SPLs, 917 associations occurred in CPGs only and 332 associations occurred in SPLs only. With taxonomic information, 859 unique drug-disease associations were identified, of which 152 of these drug-disease associations overlapped between CPGs and SPLs, 541 associations occurred in CPGs only, and 166 associations occurred in SPLs only. Our results suggest that CPG-recommended pharmacologic therapies and SPL indications do not overlap frequently when identifying drug-disease associations using named entity recognition, although incorporating taxonomic relationships between drug names and drug classes into the approach improves the overlap. This has important implications in practice because conflicting or inconsistent evidence may complicate clinical decision making and implementation or measurement of best practices.


Malignancy of intracerebral lesions evaluated with 11C-methionine-PET.
Positron emission tomography (PET) allows examination of a variety of physiological parameter, including blood flow, glucose, amino acid and oxygen metabolism. However, correlation of PET scan findings and the degree of malignancy of intracerebral tumors continues to be controversial. Nine patients with primarily diagnosed intraparenchymal brain tumors were included in this study. We performed 11C-methionine-PET (met-PET) prior to surgical treatment and the differential absorption ratio (DAR) was calculated. All patients underwent open or stereotactic surgery and specimens for pathological diagnosis were obtained. The biological activity of each tumor was determined by calculation of the proliferation index from MIB-1 immunohistochemistry. The DAR of met-PET for individual tumors correlated with the histological diagnosis and degree of malignancy and this was further confirmed by good correlation with the MIB-1 proliferation index. We conclude that met-PET may be a reliable and effective preoperative evaluation to determine the type and malignancy of intraparenchymal brain lesions.


Chromatin assembly in Xenopus oocytes: in vivo studies.
We have followed the time course of chromatin assembly, DNA supercoiling, and transcription on a Xenopus 5S RNA gene clone injected into germinal vesicles of Xenopus oocytes. During the first 2 hr after DNA injection, there is a gradual enhancement in transcription that correlates with the increase in superhelical density of the DNA template; on the other hand, nucleosome assembly is already completed by 10-30 min after DNA injection. To probe further the DNA structure in the assembled minichromosomes, we injected enzymes and chemicals into the germinal vesicle. DNAase I and topoisomerase I injections reveal that the circular DNA has been assembled into two discrete and equally abundant types of chromatin: one type, which we call "dynamic" chromatin, is torsionally strained and is thus fully relaxed by those two enzymes. The other type, which we call "static" chromatin, still yields supercoiled DNA molecules after deproteinization. The dynamic chromatin is also relaxed by injection of novobiocin, and simultaneously, 5S RNA transcription is turned off. The results of our in vivo experiments suggest that the dynamic chromatin is the one that is transcriptionally active. We discuss the biological relevance of these findings.


Moderate-vigorous physical activity and all-cause mortality in COPD: could bouts matter?
For people with COPD, performance of physical activity in bouts confers a greater survival benefit than total physical activity alone, suggesting that the manner in which physical activity is undertaken may be important for people with COPD https://bit.ly/3Gy2Gjl.


Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2.
The Tec-family kinase Btk contains a lipid-binding Pleckstrin homology and Tec homology (PH-TH) module connected by a proline-rich linker to a 'Src module', an SH3-SH2-kinase unit also found in Src-family kinases and Abl. We showed previously that Btk is activated by PH-TH dimerization, which is triggered on membranes by the phosphatidyl inositol phosphate PIP3, or in solution by inositol hexakisphosphate (IP6) (Wang et al., 2015, https://doi.org/10.7554/eLife.06074). We now report that the ubiquitous adaptor protein growth-factor-receptor-bound protein 2 (Grb2) binds to and substantially increases the activity of PIP3-bound Btk on membranes. Using reconstitution on supported-lipid bilayers, we find that Grb2 can be recruited to membrane-bound Btk through interaction with the proline-rich linker in Btk. This interaction requires intact Grb2, containing both SH3 domains and the SH2 domain, but does not require that the SH2 domain be able to bind phosphorylated tyrosine residues - thus Grb2 bound to Btk is free to interact with scaffold proteins via the SH2 domain. We show that the Grb2-Btk interaction recruits Btk to scaffold-mediated signaling clusters in reconstituted membranes. Our findings indicate that PIP3-mediated dimerization of Btk does not fully activate Btk, and that Btk adopts an autoinhibited state at the membrane that is released by Grb2.


Vulnerabilities in clinician-parent exchanges and the cascade of communication traps: a review.
This review considers parent-clinician interactions that are associated with vulnerabilities in communication and what we refer to as 'communication traps'. Communication traps are defined by high-stress situations with affect-laden subject matter that can lead to progressively dysfunctional communications/exchanges that are avoidable. While this framework was developed in neonatology, it can be applied to other clinical practices.Communication competencies in paediatrics require the rapid development of a therapeutic alliance between parents and clinicians to ensure the provision of best care to their infants. In order to facilitate parent-clinician communication, our framework focuses clinicians' attention on the affective, behavioural and cognitive (ABC) cues that are indicative of real, apparent or potential communication traps. Strategies are provided to slow down clinicians' responses to more effectively consider ABC cues that suggest if patients/parents have failed to engage or disengage from a situation. This framework is illustrated by presenting a narrative synthesised from a number of experiences that clinicians have encountered. This review identifies key decision points in the communication process that, if left unaddressed, can cascade into communication traps which may be difficult to escape.Using results from communication studies and psychological research, our framework was developed to identify key decision points for ABC cues that can be used to prevent falling into communication traps.


Hand and foot abnormalities associated with genetic diseases.
The small bones and soft tissues of the hands and feet can be affected by systemic disorders, and frequently, the findings are quite unique and virtually diagnostic for some genetic or metabolic disorders. Photographs and imaging studies for the hands and feet are available in a digitized system, which has been approved by our hospital institutional review board. Examination of these and their description can establish a relationship with some degree of certainty to a series of highly variable and uncommon clinical disorders. Description of the clinical, physiologic and genetic characteristics, and illustrations of hand and foot abnormalities are provided for an array of diseases, including Ellis-van Creveld syndrome, fibrodysplasia ossificans progressiva, achondroplasia, Kniest dysplasia, pseudo- and pseudo-pseudohypoparathyroidism, acromegaly, nail-patella syndrome, Marfan's disease, cartilage-hair hypoplasia, and several forms of mucopolysaccharidosis. The findings support the concept that many genetic disorders can often be diagnosed by clinical and imaging examination of the patient's hands and feet.


The effect of organic modifiers on electrospray ionization charge-state distribution and desorption efficiency for oligonucleotides.
The chemical composition of the solution has a critical impact on the electrospray desorption efficiency of oligonucleotides. Several physiochemical properties of various organic modifiers were investigated with respect to their role in the desorption process of oligonucleotides. The Henry's Law Constant, which reflects the volatility of alkylamines, was found to have a prominent effect on both the electrospray charge state distribution and desorption efficiency of oligonucleotides. Alkylamines with higher k(H,cc)(aq/gas) values such as hexylamine, piperidine, and imidazole reduced the charge state distribution by forming complexes with the oligonucleotide and dissociating from it in the gas phase, while alkylamines with extremely low k(H,cc)(aq/gas) values reduced the electrospray charge state distribution by facilitating ion emission at an earlier stage of the electrospray desorption process. Ion-pairing agents with moderate k(H,cc)(aq/gas) values do not alter the electrospray charge state distribution of oligonucleotides and their ability to enhance oligonucleotide ionization followed the order of decreasing k(H,cc)(aq/gas) values. The Henry's Law Constant also correlated to the impact of the acidic modifiers on oligonucleotide ionization efficiency. Ionization enhancement effects were observed with hexafluoroisopropanol, and this effect was attributed to its low k(H,cc)(aq/gas) and moderate acidity. The comprehensive effects of both alkylamine and hexafluoroisoproapnol on the electrospray ionization desorption of oligonucleotides were also evaluated, and acid-base equilibrium was found to play a critical role in determining these effects.


Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue.
Idiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment. AEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments. AEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs. These results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.


Evaluation of nitrogen removal, functional gene abundance and microbial community structure in a stormwater detention basin.
Stormwater control measures such as detention basins are used to mitigate the negative effects of urban stormwater resulting from watershed development. In this study, the performance of a detention basin in mitigating nitrogen pollution was examined and the abundance of N-cycling genes (amoA, nirK, nosZ, hzsB and Ntsp-amoA) present in the soil media of the basin was measured using quantitative PCR. Results showed a net export of nitrogen from the basin, however, differences between in- and outflow concentrations were not significant. Furthermore, the quantitative PCR showed that nirK (denitrification gene) was more abundant in the winter season, whereas amoA (nitrification gene) was more abundant in the summer season. The abundance of nirK, Ntsp-amoA and hzsB genes also varied with the sampling depth of soil and based on 16S rRNA gene sequencing of soil samples, Actinobacteria and Proteobacteria were the most dominant phyla. Species diversity appeared higher in summer, while the top and bottom layer of soil clustered separately based on the bacterial community structure. These results underline the importance of understanding nitrogen dynamics and microbial processes within stormwater control measures to enhance their design and performance.


Angiotensin II modulates VEGF-driven angiogenesis by opposing effects of type 1 and type 2 receptor stimulation in the microvascular endothelium.
Vascular endothelial growth factor (VEGF) is a main stimulator of pathological vessel formation. Nevertheless, increasing evidence suggests that Angiotensin II (Ang II) can play an augmentory role in this process. We thus analyzed the contribution of the two Ang II receptor types, AT(1)R and AT(2)R, in a mouse model of VEGF-driven angiogenesis, i.e. oxygen-induced proliferative retinopathy. Application of the AT(1)R antagonist telmisartan but not the AT(2)R antagonist PD123,319 largely attenuated the pathological response. A direct effect of Ang II on endothelial cells (EC) was analyzed by assessing angiogenic responses in primary bovine retinal and immortalized rat microvascular EC. Selective stimulation of the AT(1)R by Ang II in the presence of PD123,319 revealed a pro-angiogenic activity which further increased VEGF-driven EC sprouting and migration. In contrast, selective stimulation of the AT(2)R by either CGP42112A or Ang II in the presence of telmisartan inhibited the VEGF-driven angiogenic response. Using specific inhibitors (pertussis toxin, RGS proteins, kinase inhibitors) we identified G(12/13) and G(i) dependent signaling pathways as the mediators of the AT(1)R-induced angiogenesis and the AT(2)R-induced inhibition, respectively. As AT(1)R and AT(2)R stimulation displays opposing effects on the activity of the monomeric GTPase RhoA and pro-angiogenic responses to Ang II and VEGF requires activation of Rho-dependent kinase (ROCK), we conclude that the opposing effects of the Ang II receptors on VEGF-driven angiogenesis converge on the regulation of activity of RhoA-ROCK-dependent EC migration.


Bleomycin-induced epithelial-mesenchymal transition in sclerotic skin of mice: possible role of oxidative stress in the pathogenesis.
Epithelial-mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100mg/kg body weight/day) injected daily for 3weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice.


Racial and ethnic disparities in mortality from gastric and esophageal adenocarcinoma.
Racial/ethnic differences in mortality have not been well studied for either non-cardia gastric cancer (NCGC) or cardia gastric cancer (CGC). The aim of this study was to examine the US mortality rates for these cancer subtypes, as well as esophageal adenocarcinoma (EAC) as a comparator. We identified 14 164 individuals who died from NCGC, 5235 from CGC, and 13 982 from EAC in the Surveillance, Epidemiology, and End Results database between 2004 and 2016. Age-adjusted incidence-based mortality rates and corresponding annual percent changes (APCs) were calculated. Analyses were stratified by race/ethnicity, age, and stage of disease at diagnosis. The mortality rate in NCGC was two- to threefold higher in blacks, Hispanics, and Asians/Pacific Islanders (PI) than non-Hispanic whites, and was significant across all age groups and stages of disease (P < .01). Mortality in CGC was higher in non-Hispanic whites than blacks and Asians/PI, particularly in individuals in the 50-64 year age group and those with stage IV disease. Mortality in EAC was two- to sixfold higher in non-Hispanic whites than all other groups across all age groups and stages of disease. From 2004 to 2016, mortality rates were stable across all racial/ethnic groups in NCGC and CGC, and in minority groups with EAC, but have been rising in non-Hispanic whites with EAC (APC 3.03, 95% CI 0.17-5.96). This is the largest study of incidence-based mortality in CGC and NCGC and demonstrates racial/ethnic differences in mortality between these subtypes. Mortality rates for NCGC are highest in minority groups, and have been stable in recent years despite declining incidence. Mortality rates for CGC are marginally higher in middle-aged non-Hispanic whites with advanced disease, though have remained stable. In contrast, mortality in EAC has been rising for non-Hispanic whites, in parallel to incidence. Further studies are needed to refine prevention strategies for high-risk individuals dying from these specific cancer subtypes.


Measuring step count: why it is important not to assume measures are reliable.
The validity and reliability of pedometer software Apps versus the previously investigated spring lever and piezoelectric pedometers is unknown. To evaluate the validity and reliability (in adults aged 18-65) of two pedometer software Apps, the Walk Star and the Accupedo, with spring lever (Digi-Walker CW 700) and piezoelectric (Omron HJ-720ITC and Tanita PD-724) pedometers in the measurement of step count. The criterion for comparison was researcher tallied direct observation of step count using an electronic E3-EHT hand held tally counter. Eighteen participants walked for 5minutes on a treadmill at slow (2miles per hour) moderate (3miles per hour) and fast walking (4miles per hour) speeds and on urban streets and upon grass at a perceived "comfortable" walking speed. Bland and Altman plots show wide limits of agreement observed for the Yamax CW 700, Accupedo App and Walk Star App, suggesting these pedometers are unsuitable for measuring step counts in individuals due to high random error (indicating low reliability). Narrow limits of agreement were observed for the Omron HJ-720ITC and the Tanita PD-724 pedometers compared against Tally count and were considered suitable for use. The validity and reliability of pedometers cannot be assumed but must be tested and ensured before use in measuring step count.


PET imaging with 11C-acetate in prostate cancer: a biochemical, radiochemical and clinical perspective.
In the present study, the potential clinical role of 11C-acetate PET mainly in the differential diagnosis, in the staging and in the follow-up of prostate cancer patients is reported. Each of the above points has been accurately investigated by studying the specific biochemical and radiobiochemical behaviour of this positron emitter compound. The imaging quality of 11C-acetate PET and its unique mechanisms of cellular uptake, make such radiotracer a powerful tool in evaluating all the steps of the prostatic cancer.


Repeat subculture of known positive blood cultures: costly and ineffective in detecting polymicrobial bacteremias.
Reincubation and subsequent subculture at 72 h of previously positive blood cultures failed to demonstrate an increase in detection of polymicrobial bacteremia as has been previously reported. These procedures increased the cost of blood cultures between 140-192% without yielding new organisms. No new information was gained in 94.7% of cultures and, in 11.1% of the cultures, less information was obtained either because the cultures were sterile or because the original organisms could not be reisolated.


Effect of various protein diets on growth, renal function, and survival of uremic rats.
The effects on growth, renal function, and survival of three isocaloric diets of various protein content (14, 27, and 37 g/100 g in diets I, II, and III, respectively) were compared in uremic rats and in controls. Diet I provided the minimal requirements in all amino acids for gorwing rats. In controls fed ad lib, weight and length gain were better with high protein diets, whereas they were inversely related to the diet protein content in uremic rats. The higher the protein intake, the higher the progressive elevation of BUN and serum creatinine and the mortality rate. Because proteins were supplied by fish flour, their increase was associated with increased mineral content, and the conclusions are restricted to the use of natural proteins: a moderately restricted protein diet securing only the minimal requirements had a beneficial effect on growth and survival of rats with reduced kidney mass. Avoiding any excess in proteins from the early stage of renal disease is suggested.


Multihospital system enhances employee relations, programs.
Key elements of a successful personnel management program created within a new multihospital system are presented, along with the difficulties and opportunities accompanying the changeover.


The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.
Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I-IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730.


Robust, versatile DNA FISH probes for chromosome-specific repeats in Caenorhabditis elegans and Pristionchus pacificus.
Repetitive DNA sequences are useful targets for chromosomal fluorescence in situ hybridization. We analyzed recent genome assemblies of Caenorhabditis elegans and Pristionchus pacificus to identify tandem repeats with a unique genomic localization. Based on these findings, we designed and validated sets of oligonucleotide probes for each species targeting at least 1 locus per chromosome. These probes yielded reliable fluorescent signals in different tissues and can easily be combined with the immunolocalization of cellular proteins. Synthesis and labeling of these probes are highly cost-effective and require no hands-on labor. The methods presented here can be easily applied in other model and nonmodel organisms with a sequenced genome.


Anterior Cruciate Ligament Reconstruction With Bone-Patellar Tendon-Bone Graft Through a Rectangular Bone Tunnel Made With a Rectangular Retro-dilator: An Operative Technique.
Good clinical results have been reported with anatomic anterior cruciate ligament (ACL) reconstructions in which rectangular bone-patellar tendon-bone (BTB) grafts were fixed into rectangular bone tunnels made at anatomic ACL insertion sites of the femur and tibia (anatomic rectangular tunnel BTB ACL reconstruction). Notwithstanding these good results, some problems have remained unsolved, including procedural complexity and risk of damage to the femoral posterior tunnel wall, damage to nerves and blood vessels, and damage to cartilage. The purpose of this report is to present our technique of ACL reconstruction with BTB graft through a rectangular bone tunnel made with a rectangular retro-dilator. Our procedure may become a safe option for anatomic rectangular tunnel BTB ACL reconstruction because of the following advantages: (1) bone tunnels can be created more safely and accurately than in methods using transtibial and far medial portals, (2) the bone tunnel preparation procedure is less invasive than the standard outside-in method, (3) technical failure-related risks are lower because the guidewire is inserted only once, and (4) the operation time is shorter because the method is a single-bundle procedure.


Rates of recurrent preterm birth by obstetrical history and cervical length.
This study was undertaken to determine rates of recurrent preterm birth according to number of prior preterm births, 1 versus 2 or more and cervical length by endovaginal ultrasound at 22(0) to 24(6) weeks, less than 25 mm versus more than 25 mm. We retrospectively analyzed data from charts of women with prior spontaneous preterm birth seen in a Prematurity Prevention Clinic from 1998 through 2004. Women with a history of 1 or more spontaneous preterm births (18(0)-36(6) weeks) were included. Women with multiple gestations, uterine anomalies, and prior cervical surgery were excluded. Transvaginal sonography was used to evaluate each woman's cervical length at 22(0) to 24(6) weeks. Cerclage, bed rest, tocolysis, and steroids were used when clinically appropriate. Primary outcome was gestational age at delivery less than 32 and less than 35 weeks. Data were analyzed according to number of prior preterm births (1 vs > or = 2) and sonographic cervical length at 22(0) to 24(6) weeks (<25 mm vs > or = 25 mm). A total of 188 eligible women were evaluated. Median gestational age of earliest preterm birth was 26.3 weeks. Of the total 188, 118 (62.8%) women had 1 prior and 70 (37.2%) had 2 or more preterm births. Thirty-eight (20.2%) of the women had a cervical length less than 25 mm and 150 (79.8%) had a cervical length 25 mm or greater. A higher percentage of women with a cervical length less than 25 mm and 2 or more preterm births delivered less than 32 weeks compared with women with 1 prior preterm birth, although this did not reach statistical significance (21.5% vs 12.5%, P = .47). Rates of delivery less than 35 weeks in women with a cervical length less than 25 mm were similar in those with a history of 1 and 2 or more preterm births. Women who had 2 or more prior preterm births were analyzed separately to identify if a cervical length greater than 30 mm or greater than 35 mm could be reassuring for decreasing the risk of recurrent preterm birth. Rates of preterm birth less than 32 and less than 35 weeks were similar in women whose cervical length was less than 25 mm at 22(0) to 24(6) weeks, regardless of number of prior preterm births. Women with 2 prior preterm births and a cervix greater than 35 mm were at low risk for subsequent preterm birth less than 35 weeks.


Taurine inhibits hydrogen peroxide-induced oxidative stress, inflammatory response and apoptosis in liver of Monopterus albus.
Fish are extremely vulnerable to environmental stimulation and produce oxidative stress. Among them, hydrogen peroxide is an oxidative stress source that cannot be ignored in fish, which can cause physical disorders, inflammation and even death. Taurine was revealed to reduce oxidative damage and inflammation caused by toxic substances, but whether it can reduce toxicity of rice field eel caused by H2O2 has not been determined. Thus, the intervention effects of taurine on H2O2-induced oxidative stress, inflammation, apoptosis, and autophagy in rice field eel. The results showed that oxidative injury in the liver was determined after H2O2 injection, as indicated by enhanced serum AST and ALT activities, inhibited the antioxidant function (increased MDA and ROS contents, decreased antioxidant enzymes, inhibited nrf2 transcription level), and induced inflammatory response (upregulated il-1β, il-6, il-8, and il-12β gene expression, downregulated tgf-β1 gene expression, activated the transcription level of nf-κb, tlr-3, and tlr-7). In addition, bax, caspase3, beclin1, and Lc3B gene expression were significantly upregulated after H2O2 injection, while bcl2 and p62 gene expression were downregulated, leading to the occurrence of apoptosis and autophagy. In contrast, adding 0.2 and 0.5% taurine to feed significantly alleviated this damage, as indicated by the recovery of the aforementioned bioindicators, and the effect of 0.5% taurine addition is better than 0.2%. Overall, these results suggested that taurine can relieve the liver toxicity induced by H2O2, which enriched the toxic mechanism of H2O2 on fish and provided evidence for the protective effect of taurine on liver.


Antiasthmatic effects of onions: inhibition of 5-lipoxygenase and cyclooxygenase in vitro by thiosulfinates and "Cepaenes".
Nine thiosulfinates (TS) and four "Cepaenes" (CS) isolated from onions and/or synthetized by us showed dose dependent (0.25 to 100 microM) marked inhibitory effects on both cyclooxygenase (CA, tested on sheep seminal vesicle microsomes) and 5-lipoxygenase activity (LO, tested on porcine leukocytes). The following rank order of activity was observed: saturated aliphatic TS less than aromatic TS approximately alpha, beta-unsaturated TS less than CS. CS inhibited both CA and LO by more than 75% at 10 and 1 microM concentrations respectively. Most likely, these in vitro effects are responsible for antiinflammatory and antiasthmatic properties of onion extracts observed in vivo, at least in part.


Heat transfer coefficient: Medivance Arctic Sun Temperature Management System vs. water immersion.
To improve heat transfer, the Medivance Arctic Sun Temperature Management System (Medivance, Inc., Louisville, CO, USA) features an adhesive, water-conditioned, highly conductive hydrogel pad for intimate skin contact. This study measured and compared the heat transfer coefficient (h), i.e. heat transfer efficiency, of this pad (hPAD), in a heated model and in nine volunteers' thighs; and of 10 degrees C water (hWATER) in 33 head-out immersions by 11 volunteers. Volunteer studies had ethical approval and written informed consent. Calibrated heat flux transducers measured heat flux (W m-2). Temperature gradient (DeltaT) was measured between skin and pad or water temperatures. Temperature gradient was changed through the pad's water temperature controller or by skin cooling on immersion. The heat transfer coefficient is the slope of W m-2/DeltaT: its unit is W m-2 degrees C-1. Average with (95% CI) was: model, hPAD = 110.4 (107.8-113.1), R2 = 0.99, n = 45; volunteers, hPAD = 109.8 (95.5-124.1), R2 = 0.83, n = 51; and water immersion, hWATER = 107.1 (98.1-116), R2 = 0.86, n = 94. The heat transfer coefficient for the pad was the same in the model and volunteers, and equivalent to hWATER. Therefore, for the same DeltaT and heat transfer area, the Arctic Sun's heat transfer rate would equal water immersion. This has important implications for body cooling/rewarming rates.


Role of the unfolded protein response in topography-induced osteogenic differentiation in rat bone marrow mesenchymal stem cells.
The topography of biomaterials can significantly influence the osteogenic differentiation of cells. Understanding topographical signal transduction is critical for developing biofunctional surfaces, but the current knowledge is insufficient. Recently, numerous reports have suggested that the unfolded protein response (UPR) and osteogenic differentiation are inter-linked. Therefore, we hypothesize that the UPR pathway may be involved in the topography-induced osteogenesis. In the present study, different surface topographies were fabricated on pure titanium foils and the endoplasmic reticulum (ER) stress and UPR pathway were systematically investigated. We found that ER stress and the PERK-eIF2α-ATF4 pathway were activated in a time- and topography-dependent manner. Additionally, the activation of the PERK-eIF2α-ATF4 pathway by different topographies was in line with their osteogenic induction capability. More specifically, the osteogenic differentiation could be enhanced or weakened when the PERK-eIF2α-ATF4 pathway was promoted or inhibited, respectively. Furthermore, tuning of the degree of ER stress with different concentrations of thapsigargin revealed that mild ER stress promotes osteogenic differentiation, whereas excessive ER stress inhibits osteogenic differentiation and causes apoptosis. Taken together, our findings suggest that the UPR may play a critical role in topography-induced osteogenic differentiation, which may help to provide new insights into topographical signal transduction. Suitable implant surface topography can effectively improve bioactivity and eventual bone affinity. However, the mechanism of topographical signaling transduction is unclear and criteria for designation of an appropriate implant surface topography is lacking. This study shows that the ER stress and PERK-eIF2α-ATF4 pathway were activated by micro- and micro/nano-topographies, which is corresponding to the osteogenic induction abilities of these topographies. Furthermore, we have found that mild ER stress improves osteogenic differentiation, whereas excessive ER stress inhibits osteogenic differentiation and causes apoptosis. Our findings demonstrate that the UPR plays a critical role in the topography induced osteogenic differentiation, which may help to provide new insights into the topographical signaling transduction.


Postasphyxial encephalopathy in preterm neonates.
Perinatal asphyxia is an important determinant of infant neurological outcome. There are very few studies looking exclusively at postasphyxial encephalopathy in preterm neonates. We studied the neurologic and sonographic abnormalities in 40 preterm babies with severe birth asphyxia during their hospital stay and till 3 months corrected age. 87.5 % of the asphyxiated preterm babies had neonatal neurologic abnormality, compared to only 17% of the control babies (p<0.0001). Generalised hypotonia and reduced activity were the commonest abnormalities (observed in 85% of asphyxiated babies) while depressed sensorium (60%) and seizures (35%) were seen in more severe cases. White matter disease (WMD-including periventricular flare, cerebral edema and periventricular leucomalacia) was significantly more frequent in the study cases (34.5% in study cases vs 7.5% in controls, p<0.0001) as was grade 3/4 intraventricular hemorrhage(IVH) (25% in study cases vs 2.5% in controls, p<0.0001). There was 11 fold higher mortality among the asphyxiated babies (23 deaths in study cases vs 2 in controls, p<0.0001). The survivors had a significantly higher incidence of both mild and severe neurological abnormalities at corrected age of 3 months among the asphyxiated babies. There was a good correlation between the severity of the neonatal encephalopathy as well as the sonographic findings and the outcome.


LEDs Make It Resilient: Effects on Plant Growth and Defense.
Light spectral composition influences plant growth and metabolism, and has important consequences for interactions with plant-feeding arthropods and their natural enemies. In greenhouse horticulture, light spectral composition can be precisely manipulated by light-emitting diodes (LEDs), and LEDs are already used to optimize crop production and quality. However, because light quality also modulates plant secondary metabolism and defense, it is important to understand the underlying mechanisms in the context of the growth-defense trade-off. We review the effects of the spectral composition of supplemental light currently used, or potentially used, in greenhouse horticulture on the mechanisms underlying plant growth and defense. This information is important for exploring opportunities to optimize crop performance and pest management, and thus for developing resilient crop-production systems.


Mediated effects of insomnia in the association between problematic social media use and subjective well-being among university students during COVID-19 pandemic.
Recently, the use of social media has penetrated many aspects of our daily lives. Therefore, it has stimulated much debate and polarisation regarding its impact on mental well-being. The present study investigated the association between problematic use of social media, subjective well-being, and insomnia's potential mediator. A proportionate random sample was collected from a Univerity in Algeria between March and April 2020.The participants (n=288; mean [SD] age = 20.83 [2.13]) involved 101 (35.1%) males. Nearly three-fourths of the participants (n=214; 74.3%) used up more-than three hours daily surfing on social media. Their mean (SD) score was 15.64 (4.80) on the Bergan Social Media Addiction Scale, 16.19 (9.15) on the Arabic Scale of Insomnia, and 28.13 (7.90) on the overall subjective well-being. Structural equation modeling (SEM) revealed an indirect correlation between problematic use of social media and the overall subjective well-being of users. Similarly, the indirect but not direct effects were found for the overall subjective well-being subdomains. Moreover, all SEM models have a satisfactory fit with the data. Based on the results, it can be concluded that insomnia appears to play an important role in mediating the association between subjective well-being and problematic social media use. This suggests the importance of tackling the issues of insomnia and problematic use of social media for university students. It also has important implications in dealing with the misuse of social media, especially during the covid-19 pandemic.


[Impairments in metabolism of amino acids - precursors of gasotransmitters - in the premature birth].
The content of amino acids - sources of gasotransmitters and the activity of enzymes of their metabolism have been studied in the placenta and amniotic fluid in full-term and complicated by preterm birth (PB). Determination of amino acids was carried out using an automatic analyzer; specific spectrophotometric methods were used to assess the activity of enzymes. The development of PB is accompanied by changes in the amino acid level already in the second trimester of pregnancy. Correlation of differently directions was found between the level of amino acids and the activity of the corresponding enzymes. The imbalance of amino acids in the fetoplacental system in PB is accompanied by a change in the production of their low molecular weight derivatives gas transmitters (NO, CO, H2S), which play an important role in the regulation of numerous metabolic processes.


Adaptive filtering enhances information transmission in visual cortex.
Sensory neuroscience seeks to understand how the brain encodes natural environments. However, neural coding has largely been studied using simplified stimuli. In order to assess whether the brain's coding strategy depends on the stimulus ensemble, we apply a new information-theoretic method that allows unbiased calculation of neural filters (receptive fields) from responses to natural scenes or other complex signals with strong multipoint correlations. In the cat primary visual cortex we compare responses to natural inputs with those to noise inputs matched for luminance and contrast. We find that neural filters adaptively change with the input ensemble so as to increase the information carried by the neural response about the filtered stimulus. Adaptation affects the spatial frequency composition of the filter, enhancing sensitivity to under-represented frequencies in agreement with optimal encoding arguments. Adaptation occurs over 40 s to many minutes, longer than most previously reported forms of adaptation.


Combined treatment with ruxolitinib and MK-2206 inhibits the JAK2/STAT5 and PI3K/AKT pathways via apoptosis in MDA-MB-231 breast cancer cell line.
Due to deficiencies in the expression of hormone receptors, such as PR, ER and HER2, it is challenging to treat triple-negative breast cancer, which does not respond to single targeted therapy. Ruxolitinib is a Janus kinase (JAK)1/JAK2 inhibitor. MK-2206 is an allosteric AKT inhibitor. Due to the limited activities of ruxolitinib and MK-2206 for monotherapy, the need for cotreatment with other drugs has emerged. This study is the first to examine the effects of ruxolitinib and MK-2206 cotreatment on apoptosis and JAK2/STAT5 and PI3K/AKT signaling in MDA-MB-231 breast cancer cells. Additionally, this work aimed to decrease the side effects of ruxolitinib and increase its anticancer effects with MK-2206 cotreatment. Cell viability was reduced in a dose- and time-dependent manner after exposure to ruxolitinib, MK-2206 or both for 48 h, as shown by MTT assay. Ruxolitinib had a synergistic antiproliferative effect, as demonstrated by colony formation and wound healing assays. The effects of ruxolitinib, MK-2206 and their combination on apoptosis, as well as PI3K/AKT and JAK/STAT signaling, were examined by western blot analyses. Cotreatment with ruxolitinib and MK-2206 reduced proliferation with the dual inhibition of JAK2/STAT5 and PI3K/AKT signaling by decreasing PI3K, AKT, JAK2, STAT5, Caspase-9, Caspase-7, PARP, c-Myc, and Bcl-2 and increasing P53 and PTEN protein expression. Our results revealed the roles of P53 and PTEN in the regulation of apoptosis and the PI3K/AKT and JAK2/STAT5 signaling pathways. The dual inhibition of JAK2/STAT5 and PI3K/AKT may reduce metastasis by decreasing tumor cell survival.


Effects of lixisenatide treatment on mild cachexia and related metabolic abnormalities in Walker-256 tumour-bearing rats.
Lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the treatment of type 2 diabetes mellitus (T2DM). It increases insulin (INS) secretion and can decrease INS resistance, improving metabolic disorders in this disease. However, its effects on metabolic disturbances in cancer-bearing, which also exhibit decreased INS secretion and INS resistance, changes that may contribute to weight loss (cachexia), have not yet been evaluated. The purpose of this study was to investigate the lixisenatide treatment effects on mild cachexia and related metabolic abnormalities in Walker-256 tumour-bearing rats. Lixisenatide (50 μg kg-1 , SC) was administered once daily, for 6 days, after inoculation of Walker-256 tumour cells. Acute lixisenatide treatment did not improve hypoinsulinemia, INS secretion and INS resistance of tumour-bearing rats. It also did not prevent the reduced glucose and increased triacylglycerol and lactate in the blood and nor the loss of retroperitoneal and epididymal fat of these animals. However, acute lixisenatide treatment accentuated the body mass loss of tumour-bearing rats. Therefore, lixisenatide, unlike T2DM, does not improve hypoinsulinemia and INS resistance associated with cancer, evidencing that it does not have the same beneficial effects in these two diseases. In addition, lixisenatide aggravated weight loss of tumour-bearing rats, suggesting that its use for treatment of T2DM patients with cancer should be avoided. SIGNIFICANCE OF THE STUDY: Lixisenatide increases insulin secretion and appears to reduce insulin resistance in T2DM. However, lixisenatide treatment does not improve hypoinsulinemia and insulin resistance associated with cancer, as it does in T2DM, and aggravated weight loss, suggesting that its use for treatment of T2DM patients with cancer should be avoided.


Hepatic effects of lung-protective pressure-controlled ventilation and a combination of high-frequency oscillatory ventilation and extracorporeal lung assist in experimental lung injury.
Ventilation with high positive end-expiratory pressure (PEEP) can lead to hepatic dysfunction. The aim of this study was to investigate the hepatic effects of strategies using high airway pressures either in pressure-controlled ventilation (PCV) or in high-frequency oscillatory ventilation (HFOV) combined with an arteriovenous extracorporeal lung assist (ECLA). Pietrain pigs underwent induction of lung injury by saline lavage. Ventilation was continued for 24 hours either as PCV with tidal volumes of 6 ml/kg and PEEP 3 cmH2O above the lower inflection point of the pressure-volume curve or as HFOV (≥ 12 Hz) with a mean tracheal airway pressure 3 cmH2O above the lower inflection point combined with arteriovenous ECLA (HFOV+ECLA). Fluids and norepinephrine stabilized the circulation. The indocyanine green plasma disappearance rate, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, glutamate dehydrogenase, lactate dehydrogenase and creatine kinase were determined repeatedly. Finally, liver neutrophils were counted and liver cell apoptosis was assessed by terminal deoxynucleotidyl transferase nick end labeling (TUNEL). Aspartate aminotransferase increased in the PCV group about three-fold and in the HFOV+ECLA group five-fold (p<0.001). Correspondingly, creatine kinase increased about two-fold and four-fold, respectively (p<0.001). Lactate dehydrogenase was increased in the HFOV+ECLA group (p<0.028). The number of neutrophils infiltrating the liver tissue and the apoptotic index were low. High airway pressure PCV and HFOV with ECLA in the treatment of lavage-induced lung injury in pigs did not cause liver dysfunction or damage. The detected elevation of enzymes might be of extrahepatic origin.


A stochastic model of chromatin modification: cell population coding of winter memory in plants.
Biological memory, a sustained cellular response to a transient stimulus, has been found in many natural systems. The best example in plants is the winter memory by which plants can flower in favorable conditions in spring. For this winter memory, epigenetic regulation of FLOWERING LOCUS C (FLC), which acts as a floral repressor, plays a key role. Exposure to prolonged periods of cold results in the gradual suppression of FLC, which allows plants to measure the length of cold and to flower only after a sufficiently long winter. Although many genes involved in histone modifications have been isolated, molecular mechanisms of winter memory are not well understood. Here, we develop a model for chromatin modification, in which the dynamics of a single nucleosome are aggregated to on/off behavior of FLC expression at the cellular level and further integrated to a change of FLC expression at the whole-plant level. We propose cell-population coding of winter memory: each cell is described as a bistable system that shows heterogeneous timing of the transition from on to off in FLC expression under cold and measures the length of cold as the proportion of cells in the off state. This mechanism well explains robust FLC regulation and stable inheritance of winter memory after cell division in response to noisy signals. Winter memory lasts longer if deposition of the repressive histone mark occurs faster. A difference in deposition speed would discriminate between stable maintenance of FLC repression in annuals and transient expression in perennials.


Cross-scanner reproducibility and harmonization of a diffusion MRI structural brain network: A traveling subject study of multi-b acquisition.
Characterization of brain networks by diffusion MRI (dMRI) has rapidly evolved, and there are ongoing movements toward data sharing and multi-center studies. To extract meaningful information from multi-center data, methods to correct for the bias caused by scanner differences, that is, harmonization, are urgently needed. In this work, we report the cross-scanner differences in structural network analyses using data from nine traveling subjects (four males and five females, 21-49 years-old) who underwent scanning using four 3T scanners (public database available from the Brain/MINDS Beyond Human Brain MRI project (http://mriportal.umin.jp/)). The reliability and reproducibility were compared to those of data from another set of four subjects (all males, 29-42 years-old) who underwent scan-rescan (interval, 105-147 days) with the same scanner as well as scan-rescan data from the Human Connectome Project database. The results demonstrated that the reliability of the edge weights and graph theory metrics was lower for data including different scanners, compared to the scan-rescan with the same scanner. Besides, systematic differences between scanners were observed, indicating the risk of bias in comparing networks obtained from different scanners directly. We further demonstrate that it is feasible to reduce inter-scanner variabilities while preserving the inter-subject differences among healthy individuals by modeling the scanner effects at the level of network matrices, when traveling-subject data are available for calibration between scanners. The present data and results are expected to serve as a basis for developing and evaluating novel harmonization methods.


Calcium-channel blockers in prophylaxis and treatment of asthma.
Calcium-channel blocking drugs do not induce bronchoconstriction in susceptible persons with cardiac disease and concomitant hyperreactive airways (such as asthma or chronic bronchitis). The ways in which calcium blockers might in fact play a beneficial role in preventing bronchoconstriction or inducing bronchodilation in asthma are explored. Nifedipine and verapamil have been shown to inhibit the bronchoconstriction provoked by exercise, histamine, methacholine and antigen. The potential mechanisms by which this protective effect is mediated--whether by direct action on tracheobronchial smooth muscle, inhibition of release of mediators from activated mast cells or both--are examined by reviewing in vitro studies of both cell systems. Calcium blockers also exhibit some bronchodilating activity in vitro. Early clinical trials of these drugs in ambulatory asthmatic patients have shown little, if any, therapeutic benefit, but results must be considered preliminary in view of the nature of the short-term, small-scale trials performed to date. Regardless of their therapeutic potential in obstructive lung diseases, the calcium-channel blockers offer a powerful probe into the role of calcium in the physiologic make-up of airways and, in particular, the pathophysiologic features of airway hyperreactivity.


Replication of DNA containing cisplatin lesions and its mutagenic consequences.
Cisplatin [cis-diamminedichloroplatinum II] is widely used in the treatment of a broad range of tumors. A number of biological and biochemical results indicate that the reaction of cisplatin with DNA is responsible for the cytotoxic action of the drug. However, cisplatin can induce mutagenesis and may be carcinogenic in humans. Error prone replication of damaged DNA must be considered as a possible mechanism of mutagenesis. In this short review, we present data indicating that DNA containing cisplatin lesions can be replicated by prokaryotes and eukaryotes in a mutagenic fashion.


[Pain therapy in in-patients with cancer. Effects of a manual-based approach as guideline for pain-consulting service at a university hospital].
Appropriate medication is an important and substantial part in the therapy of tumor-induced pain. The objective of this study was to investigate the efficiency of anaesthesiology-based consultant service characterizing the quality of this type of treatment in daily clinical practice of a university hospital, i. e., in the patient profile of a tertiary center (study design: systematic clinical, unicenter observational study reflecting clinical practice and study-based control of therapeutic care quality). In the course of consulting function with regard to pain care on the single wards a considerable portion of cancer patients are recieving drugs. For most patients such care comprises several consultations and subsequently initiated treatment modifications. The consulting function ends if the patients feel free of pain or report a substantial improvement. From 1/1/2010 to 12/31/2012 detailed information on the drug therapy applied prior to, during and after the consultation was prospectively documented.This data was retrospectively evaluated as "pre-vs.-post" comparison (Chi-squared test, Fisher's exact test and McNemar's test), in particular, focussing on the quality of pain medication using the WHO index as well as pain intensity obtained by means of the visual analogue scale (VAS). In total, 375 in-patients were treated. The modified pain medication by the anesthesiological consultant service led to a significant increase (p < 0.001; Wilcoxon's test) in the mean WHO index from 6.37 (SD, 1.83) to 8.43 (SD, 1.47). Furthermore, a reduction of VAS from 5.00 (SD, 2.39) to 2.64 (SD, 1.64) was noted (p < 0.001; Wilcoxon's test). The consequent application of established guidelines (according to WHO scheme) and the WHO index leads to a qualitative and measurable improvement of drug therapy for cancer-related pain.


Modelling the relationships between EEG signals, movement kinematics and outcome in soccer kicking.
The contribution of cortical activity (e.g. EEG recordings) in various brain regions to motor control during goal-directed manipulative tasks using lower limbs remains unexplored. Therefore, the aim of the current study was to determine the magnitude of associations between EEG-derived brain activity and soccer kicking parameters. Twenty-four under-17 players performed an instep kicking task (18 m from the goal) aiming to hit 1 × 1 m targets allocated in the goalpost upper corners in the presence of a goalkeeper. Using a portable 64-channel EEG system, brain oscillations in delta, theta, alpha, beta and gamma frequency bands were determined at the frontal, motor, parietal and occipital regions separately for three phases of the kicks: preparatory, approach and immediately prior to ball contact. Movement kinematic measures included segmental linear and relative velocities, angular joint displacement and velocities. Mean radial error and ball velocity were assumed as outcome indicators. A significant influence of frontal theta power immediately prior to ball contact was observed in the variance of ball velocity (R 2 = 35%, P = 0.01) while the expression of occipital alpha component recorded during the preparatory phase contributed to the mean radial error (R 2 = 20%, P = 0.049). Ankle eversion angle at impact moment likely mediated the association between frontal theta power and subsequent ball velocity (β = 0.151, P = 0.06). The present analysis showed that the brain signalling at cortical level may be determinant in movement control, ball velocity and accuracy when performing kick attempts from the edge of penalty area. Trial registration number #RBR-8prx2m-Brazilian Registry of Clinical Trials ReBec. The online version contains supplementary material available at 10.1007/s11571-022-09786-2.


Human teratocarcinomas.
Teratocarcinomas are one of the commonest forms of cancer in young adult men. Cell lines derived from these tumors, and particularly the cell lines composed of their embryonal carcinoma (EC) stem cells, may provide useful information concerning the development and subsequent pathology of teratocarcinomas in humans. In addition, it is likely that human EC cells resemble early embryonic cells and can be used as an in vitro counterpart of such cells from the human embryo. Several common properties of human EC cells have been identified, and a human EC cell line, TERA-2, that is capable of extensive somatic differentiation has been cloned. In nude mice, TERA-2 EC cells form tumors containing neural elements and glandular structures that resemble primitive gut. In culture, these EC cells can be induced to differentiate by exposure to retinoic acid and hexamethylenebisacetamide (HMBA). Differentiation is marked by the disappearance of several cell surface antigens characteristic of human EC cells, and the appearance of other antigens on the various subsets of differentiated derivatives. In retinoic acid-induced cultures, these differentiated derivatives include neurons and cells permissive for the replication of cytomegalovirus, a virus that can cause birth defects in humans. On the other hand, HMBA appears to activate an alternative pathway of differentiation for TERA-2 EC cells, although the identity of the resulting cells remains to be elucidated. In addition to providing a tool for analyzing the evolution of teratocarcinomas in human patients, the TERA-2 EC cells may provide us with insights into the mechanisms of cellular differentiation in the human embryo and a model in which to investigate how teratogenic agents such as HCMV can disrupt these processes.


Role of circular RNA in myocardial ischemia and ageing-related diseases.
Circular RNA (circRNA) is a new endogenous transcription product, which has attracted significant attention in RNA biology research.CircRNA comprise exons or introns involved in regulation of various mechanisms.These molecules are stable and species-specific, as well as cell and tissue-specific.Cardiovascular diseases particularly myocardial ischemia and ageing-related diseases, pose a major health care burden and novel treatments and biomarkers should be explored.Recent findings indicate that circRNAs are implicated in biological processes, such as glucose metabolism, fatty acid oxidation, mitochondrial biosynthesis, implying that they are potential targets for myocardial ischemia treatment.In the present review, the functions of circRNAs in the heart are described, with emphasis given on in the relationship with myocardial ischemia and cardiac aging-related diseases.Directions for future research are also summarized.


The effects of three bioreductive drugs (mitomycin C, RSU-1069 and SR4233) on cell lines selected for their sensitivity to mitomycin C or ionising radiation.
We have investigated the cross-sensitivity of a number of cell lines to three different classes of bioreductive drugs under both aerobic and hypoxic conditions. The cell lines used were selected for their sensitivity to DNA-damaging agents and fall into two groups. One group, MMC cells derived from CHO-K1 cells (Robson et al., 1985), show a range of sensitivities to mitomycin C in air. The second group, irs cells were cloned from V79 Chinese hamster fibroblasts (Jones et al., 1987) and exhibit sensitivity to ionising radiation. The sensitivity of both groups of cells to mitomycin C (MMC), RSU-1069 and SR4233 was assessed under aerobic and hypoxic conditions. No difference in aerobic or hypoxic toxicity of MMC was observed for CHO-K1 or MMC sensitive cell lines (MMC-2 and MMC-3). However, the MMC-resistant cell line (MMCr) was 10 times more sensitive under hypoxic than aerobic conditions. This suggests that MMCr cells lack or are deficient in the enzymes responsible for activating MMC under aerobic conditions compared to other MMC cells. In contrast, differential toxicities of between 3 and 30 have been observed for all CHO cells treated with RSU-1069 and SR4233. Treatment of V79 and irs cells with RSU-1069 and SR4233 also resulted in selective toxicity towards hypoxic cells. Differential toxicities between 50 and 100 were observed for V79 cells. For both RSU-1069 and SR4233, the hypoxic toxicities were similar in V79 and irs cells but in air, the radiation sensitive cells were up to 10 times more sensitive than wild type cells.


Different versions of the Alcohol Use Disorders Identification Test (AUDIT) as screening instruments for underage binge drinking.
The changes experienced in recent years in the conceptualization of binge drinking (BD) make it necessary to revise the usefulness of the existing instruments for its detection among minors. The AUDIT and its abbreviated versions have shown their utility in different populations and consumption ranges, but there has been little research into their use in the detection of BD among adolescents. This study tests the capacity of the AUDIT, AUDIT-C and AUDIT-3 to identify BD adolescents, indicating the optimal cut-off points for each sex. High school students self-administered the AUDIT and completed a weekly self-report of their alcohol intake. BD is classified into different groups according to parameters like the quantity consumed and its frequency in the past six months, adjusting the cut-off points for each case. The results obtained with a sample of 634 adolescents (15-17 years old/52.2% female) indicate that cut-off points of 4 on the AUDIT and 3 on the AUDIT-C show the best fit. Dividing the sample by sexes, the AUDIT and the AUDIT-C would detect BD males with scores of 5 and 4, respectively (with the AUDIT-C being more sensitive), and BD females with a score of 3 on both (the more sensitive being the AUDIT). All three versions are adequate to classify BD adolescents but none of them made it possible to safely differentiate binge drinkers with different consumption intensities.


Effect of cold air therapy in relieving spasticity: applied to spinalized rabbits.
Before-After trial measured prior to cold air therapy, immediately following, after 30 and 60 min. To determine the effect of cold air therapy in relieving spasticity, the optimal intramuscular temperature, and the duration of spasticity relief attained by cold air therapy. Clinical research laboratory, Seoul, Korea. Forty-six spastic paraplegic rabbits with spinal cord injury. Spastic paraplegia was induced by transection of spinal cord in 46 rabbits. Cold air was applied to triceps surae muscles for 30 min at three different intramuscular temperatures (25, 30 and 32.5 degrees C). Clinical parameters of spasticity (muscle tone, Babinski's sign, muscle stretch reflex and ankle clonus) and electrophysiologic parameters (F/M ratio and H/M ratio) were measured immediately following, after 30 and 60 min. In the 32.5 degrees C group, relief in spasticity lasted less than 30 min. In the 30 and 25 degrees C groups, the decrease in spasticity lasted for at least 30 min clinically. The spasticity relief was observed only immediately following treatment when measured electrophysiologically. However, six out of 16 cases (37.5%) in the 25 degrees C group showed complete motor conduction block. To relieve spasticity with cold air therapy, the intramuscular temperature should be maintained at 30 degrees C. The duration of spasticity relief lasted from between 30-60 min after cold air therapy. We certify that all applicable institutional and governmental regulations concerning the ethical use of animals were followed during the course of this research.


Tissue distribution and biochemical properties of an interspecific tumour-associated gamma foetal antigen.
A late-gestation neonatal antigen (gamma foetal antigen; gamma-FA) immunologically and biochemically unrelated to murine alpha-foetoprotein, was identified in several spontaneous and carcinogen-induced sarcomas and hepatic carcinomas of the mouse and rat. An approximate mol. wt of 35,000 for gamma-FA from both foetus and tumour was obtained by molecular-sieve chromatography and sucrose-gradient centrifugation. Radial immunodiffusion analyses of organ extracts indicated that gamma-FA could be found in several neonatal tissues, the highest concentration occurring in the spleen. In the 2-month-old mouse, only splenic tissue contained gamma-FA and at much lower levels than in the organ of the newborn mouse.


Ki-67 labeling index may be a promising indicator to identify "very high-risk" gastrointestinal stromal tumor: a multicenter retrospective study of 1022 patients.
We sought to determine whether Ki-67 labeling index (LI) was an independent prognostic factor for gastrointestinal stromal tumor (GIST). A multicenter cohort of 1022 patients undergoing surgical resection of primary GIST between August 2004 and October 2015 was retrospectively analyzed. Immunohistochemical analysis was performed to evaluate expression of Ki-67 in their paraffin-embedded tissue samples. The optimal cutoff value of Ki-67 LI was determined as 6% by receiver operating characteristics curve analysis. Multivariate analysis showed that Ki-67 LI was a significant predictor of overall survival (OS) (hazard ratio: 1.793; 95% confidence interval, 1.240-2.593; P=.002). When stratified by modified National Institutes of Health classification, it was still independently associated with OS in high-risk and non-high-risk patients (P=.001 and P=.055, respectively). Of note, the prognostic significance of Ki-67 LI was also maintained when stratified by tumor size, mitotic index, tumor site, and histological subtype (all Ps<.05). In addition, high-risk patients with Ki-67 LI >6% exhibited a significantly poorer OS rate than those with Ki-67 LI ≤6% (53.6% versus 88.7%, respectively; P=.001). The area under the receiver operating characteristics curve for Ki-67 LI was higher than that of modified National Institutes of Health classification component in high-risk patients (P=.029). Therefore, Ki-67 LI is a promising predictor of outcome in GIST, especially in high-risk patients, and it may have important clinical utility in identifying "very high-risk" patients for rational targeted therapy.


Influence of a 6-8 kHz audiometric notch on transient evoked otoacoustic emissions.
Thirty-eight patients with known unilateral cochlear hearing loss at 6 and/or 8 kHz were examined for transient evoked otoacoustic emissions (TEOAEs). These findings were compared with those of the contralateral "normal hearing" ear. Statistically significant lower values of echo reproducibility and amplitude were recorded in hearing-impaired ears, together with a more narrow TEOAE spectrum. In addition to these findings, a globally reduced amplitude of the cochlear response was found that was unrelated to the frequency impaired in pure-tone audiometry (6, 8, or 6-8 kHz). Since patients' audiometric thresholds at such frequencies could influence test results, findings could possibly be due to an altered echo travelling wave across the most basal part of the cochlea or to coexisting damage in the rest of Corti's organ that were undetectable with standard audiometry. A significant overlap was found between the results from hearing-impaired ears and those from normally hearing ones. Although TEOAEs were not helpful in the present study in identifying patients with a unilateral hearing loss at 6 and/or 8 kHz when compared to normal contralateral ears, they are still considered to play an important role in the follow-up of subjects at risk for hearing damage.


Electron spin resonance studies on properties of ceruloplasmin and transferrin in blood from normal human subjects and cancer patients.
The methodology of blood sample preparation and analysis has been examined to further evaluate the technique of electron spin resonance (ESR) for possible use in detecting cancer and in monitoring the progress of cancer therapy. Frozen whole blood and serum samples from 278 normal donors and 97 cancer patients were studied by ESR for signal intensity from Cu+2 bound to ceruloplasmin (g factor = 2.05). The signal from this species (Cu+2-CP) in serum rose sharply during the first two hours of storage at room temperature after being drawn from the subject, and then reached a plateau. The average Cu+2-CP ESR signal intensity was significantly different for control groups of males, females not taking estrogen medication, and females taking estrogens. The mean ESR signal intensities of Cu+2-CP from cancer patients separated into the same groups as the control data were approximately twice as great as the mean control levels. Total serum copper levels were correlated with ESR intensities of Cu+2-CP and indicated that the ratio of Cu+2/Cu+1 in CP is higher in serum from cancer patients than from controls.


Pulmonary perfusion during lipopolysaccharide (LPS) induced fetal endotoxemia in the preterm fetal sheep.
To study endotoxin induced changes in pulmonary blood flow during normoxia and hypoxia and analyzed the role of nitric oxide (NO) and endothelin (ET) in this process. Twenty-seven fetal sheep were chronically instrumented at 107+/-1 days (term is 147 days). Experiments were performed 3 days after surgery. Fetuses were randomized into four groups. Group 1: control group (n=5); Group 2: LPS group (n=6) with lipopolysaccharide (LPS) injection at t -60min; Group 3: L-NAME (n=6) with nitro-l-arginine methyl ester (l-NAME) treatment at t -75min; Group 4: l-NAME+LPS group (n=6) with nitro-l-arginine methyl ester (l-NAME) pre-treatment at t -75min and LPS administration at t -60min as described above; Group 5: BQ123+LPS group (n=4) with BQ123 pre-treatment at t -75min and LPS injection at t -60min as described above. Unlike in control fetuses, there was a marked elevation in pulmonary perfusion in response to LPS induced endotoxemia during normoxia (+112%; p<0.01), which was even further increased during hypoxia (+434%; p<0.001). This increase was partially blocked by BQ123 (p<0.05) and completely abolished by pre-treatment with l-NAME (p<0.001). During fetal endotoxemia, pulmonary perfusion is increased by LPS induced production of nitric oxide. This may have a significant impact in the fetal inflammatory response syndrome, particularly in the inflammation of the fetal lungs observed in response to intrauterine infection.


In vivo drug delivery of gemcitabine with PEGylated single-walled carbon nanotubes.
Gemcitabine (GEM) is an anticancer agent widely used in non-small cell lung and pancreatic cancers. The clinical use of GEM has been limited by its rapid metabolism and short plasma half-life. These restrictions lead to frequent administration of high drug doses which can cause severe side effects. Therefore, new delivery strategies are needed aiming toward improved therapeutic effects. Single-walled carbon nanotubes (SWCNTs) are emerging as promising carriers for drug delivery due to their unique properties including high drug loading capacities, notable cell membrane penetrability and prolonged circulation times. In this work, pristine SWCNTs were functionalized through carboxylation, acylation, amination, PEGylation and finally GEM conjugation. The prepared SWCNT-GEM and SWCNT-PEG-GEM conjugates were characterized by FTIR, NMR, DSC and TEM to confirm the successful functionalization. The amount of GEM bound to the conjugates was 43.14% (w/w) for the SWCNT-GEM and 37.32% for the SWCNT-PEG-GEM, indicating high loading capacity. MTT assay on the human lung carcinoma cell line (A549) and the human pancreatic carcinoma cell line (MIA PaCa-2) demonstrated that the SWCNT-GEM was more cytotoxic than SWCNT-PEG-GEM and GEM. The SWCNT-PEG-GEM conjugates afford higher efficacy in suppressing tumor growth than SWCNT-GEM and GEM in B6 nude mice. The results demonstrate that the new formulation of GEM is useful strategy for improving the antitumor efficacy of GEM.


Oxidative stress and increased formation of vasoconstricting F2-isoprostanes in patients with reversible cerebral vasoconstriction syndrome.
The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) is unknown. Oxidative stress is detrimental to endothelial function and vascular reactivity. We hypothesized that the oxidative stress marker 8-iso-prostaglandin F2α, which is also a potent vasoconstrictor, might contribute to the pathogenesis of RCVS. Recruited participants included 103RCVS patients, 53 patients with primary headache with acute severe attacks, and 54 healthy controls. Subjects recruited prior to 2009 were discovery cohort, whereas those after 2009, replication cohort. Urine samples were obtained from all patients at registration and from 79 patients with RCVS again at remission stage. Urine 8-iso-prostaglandin F2α was analyzed by liquid chromatography-tandem mass spectrometry. Patients with RCVS received magnetic resonance angiography and transcranial color-coded sonography. In RCVS patients, the urine 8-iso-prostaglandin F2α level was higher than that in the other groups in discovery, replication, and combined cohorts (RCVS, 0.29±0.18; primary headache with acute severe attacks, 0.21±0.19; control, 0.18±0.09ng/mg creatinine; P<0.001), and it was positively correlated with the flow velocities of major intracranial arteries, especially within the first week of disease onset (middle cerebral artery, Spearman's correlation coefficient [rs]=0.580, P=0.002; anterior cerebral artery, rs=0.472, P=0.042; posterior cerebral artery, rs=0.457, P=0.022; basilar artery, rs= 0.530, P=0.002). The 8-iso-prostaglandin F2α level decreased from the ictalto remission stage in RCVS patients (0.31±0.21 vs 0.16±0.10ng/mg creatinine, P<0.001). 8-Iso-prostaglandin F2α was higher in patients with RCVS and correlated with the severity of vasoconstrictions. Further studies are required to explore its potential pathogenic role.


Behçet's syndrome.
Behçet's syndrome (BS) shows a peculiar distribution, with a much higher prevalence in countries along the ancient Silk Road compared with rest of the world. BS also seems to follow a more severe course in ethnic groups with higher prevalence. Diagnosis depends on clinical findings. Criteria sets may not help in patients with less frequent types of involvement. Management strategies should be modified according to the age and sex of the patient and the organs involved. Being a serious health problem in endemic areas, BS also attracts global attention as a model to study inflammatory diseases of unknown cause.


Effects of Latency on Estimates of the COVID-19 Replication Number.
There is continued uncertainty in how long it takes a person infected by the COVID-19 virus to become infectious. In this paper, we quantify how this uncertainty affects estimates of the basic replication number [Formula: see text], and thus estimates of the fraction of the population that would become infected in the absence of effective interventions. The analysis is general, and applies to all SEIR-based models, not only those associated with COVID-19. We find that when modeling a rapidly spreading epidemic, seemingly minor differences in how latency is treated can lead to vastly different estimates of [Formula: see text]. We also derive a simple formula relating the replication number to the fraction of the population that is eventually infected. This formula is robust and applies to all compartmental models whose parameters do not depend on time.


[Revision of acetabular loosening using an acetabular shell with screws].
The different techniques for the revision of the acetabular loosening are reviewed. In our department, we use the acetabular flanged shell fixed with screws. Three cases illustrate this promising process.


Well-Being and Safety Among Inpatient Psychiatric Staff: The Impact of Conflict, Assault, and Stress Reactivity.
Psychiatric staff are faced with multiple forms of hostility, aggression, and assault at work, collectively referred to as workplace violence, which typically is activated by patients but can also come from coworkers and supervisors. Whether workplace violence adversely affects staff well-being may be related not only to its presence, but also to an individual's stress reactivity. At a large public psychiatric hospital, an online survey was completed by 323 clinical care staff, of whom 69.5 % had experienced physical assault in the previous 12 months. Staff well-being (depression, anger, and physical health) and staff safety concerns were adversely affected by conflicts with other staff members and by individual reactivity to social conflict and to assault. To improve staff well-being, in addition to safety protocols, interventions should target staff relationships, personal health maintenance practices, and individual coping skills for dealing with adverse workplace experiences.


Negative-strand RNA viruses: the plant-infecting counterparts.
While a large number of negative-strand (-)RNA viruses infect animals and humans, a relative small number have plants as their primary host. Some of these have been classified within families together with animal/human infecting viruses due to similarities in particle morphology and genome organization, while others have just recently been/or are still classified in floating genera. In most cases, at least two striking differences can still be discerned between the animal/human-infecting viruses and their plant-infecting counterparts which for the latter relate to their adaptation to plants as hosts. The first one is the capacity to modify plasmodesmata to facilitate systemic spread of infectious viral entities throughout the plant host. The second one is the capacity to counteract RNA interference (RNAi, also referred to as RNA silencing), the innate antiviral defence system of plants and insects. In this review an overview will be presented on the negative-strand RNA plant viruses classified within the families Bunyaviridae, Rhabdoviridae, Ophioviridae and floating genera Tenuivirus and Varicosavirus. Genetic differences with the animal-infecting counterparts and their evolutionary descendants will be described in light of the above processes.


Acrolein induces inflammatory response underlying endothelial dysfunction: a risk factor for atherosclerosis.
Endothelial dysfunction by proinflammatory stimuli represents an important link between risk factors and the pathologic mechanisms underlying atherosclerosis. Thus, control of the inflammatory status of endothelial cells is crucial to limiting the disease. Tobacco smoking induces inflammatory reactions and promotes atherosclerosis; however, the mechanism that links cigarette smoking to an increased incidence of atherosclerosis is poorly understood. Our study demonstrates that acrolein, a known toxin in tobacco smoke, elevates oxidative stress via inactivation of thioredoxin reductase and stimulates expression of cyclooxygenase-2 through activation of the protein kinase C, p38 mitogen-activated protein kinase, and cAMP response element-binding protein pathway in endothelial cells. Our finding suggests that acrolein may play a role in the progression of atherosclerosis.


Is the association between balanitis xerotica obliterans and penile carcinoma underestimated?
To determine the incidence of balanitis xerotica obliterans (BXO) in a consecutive series of penile carcinomas in one centre, as BXO is a common penile disease that usually involves the prepuce and glans, and there have been sporadic case reports of the association between BXO and penile carcinoma, although it is uncertain if there is a specific causal relationship. The reported incidence of penile carcinoma in patients with BXO is 2.6-5.8%, leading some to advocate circumcision in all cases, with close follow-up in those with persistent glanular disease. We prospectively analysed all cases of penile cancer referred to the unit over a 54-month period, to determine the prevalence of BXO. In all, 155 patients with penile malignancy were reviewed, 44 of whom had BXO (28%). This group included 34 men with squamous cell carcinoma and 10 with carcinoma in situ; in 39, BXO and malignancy presented synchronously. In three other cases, cancer occurred in the background of chronic persistent BXO; in two cases penile cancer was truly metachronous. The tumours with associated BXO tended to be of lower stage and grade, and the patients presented when younger, but this was not statistically significant. A significant proportion of patients with penile malignancy have a histological diagnosis of BXO. We think that patients presenting with long-standing BXO and those in whom BXO has not resolved after circumcision warrant biopsies and a careful follow-up.


Endoscopic full thickness resection vs. transanal endoscopic microsurgery for local treatment of rectal neuroendocrine tumors - a retrospective analysis.
Local treatment of small well-differentiated rectal neuroendocrine tumors (NETs) is recommended by current guidelines. However, although several endoscopic methods have been established, the highest R0 rate is achieved by transanal endoscopic microsurgery (TEM). Since a recently published study about endoscopic full thickness resection (eFTR) showed a R0 resection rate of 100%, the aim of this study was to evaluate both methods (eFTR vs. TEM). We retrospectively analyzed all patients with rectal NET treated either by TEM (1999-2018) or eFTR (2016-2019) in two tertiary centers (University Hospital Wuerzburg and Ulm). We analyzed clinical, procedural, and histopathological outcomes in both groups. Twenty-eight patients with rectal NET received local treatment (TEM: 13; eFTR: 15). Most tumors were at stage T1a and grade G1 or G2 (in the TEM group two G3 NETs were staged T2 after neoadjuvant chemotherapy). In both groups, similar outcomes for en bloc resection rate, R0 resection rate, tumor size, or specimen size were found. No procedural adverse events were noted. Mean procedure time in the TEM group was 48.9 min and 19.2 min in the eFTR group. eFTR is a convincing method for local treatment of small rectal NETs combining high safety and efficacy with short interventional time.


Practitioners' experiences of adolescent suicidal behaviour in peer groups.
WHAT IS KNOWN ON THE SUBJECT?: Group suicidal behaviour can be devastating for all concerned. There is an absence of research on adolescent suicidal group behaviour. The perspectives of practitioners' experiences of these groups are largely lacking from research literature. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Practitioners work regularly with suicidal behaviour in adolescent peer groups. Practitioners identify peer relationships in groups as complex, including elements that are both suicide encouraging and preventing. Practitioners identify a range of ways in which young people become involved in suicidal behaviour in groups, including indirectly through risk taking and care-seeking as well as directly suicidal or self-harming. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Assessments of young people should routinely include a focus on the qualities of peer relations, including those in the online/digital realm. Assessments and interventions need to consider the complexity of group relationships and roles, and the multiplicity of factors that can contribute to suicidal behaviour in groups. Interventions that sustain therapeutic connectedness are helpful for taking dynamic/fluctuating risks into account. Introduction Group suicidal behaviour by young people can have harmful effects; it may be increasing, influenced by online media and reported increasing self-harm rates; new knowledge and understanding to inform interventions is required. Aim To explore how practitioners experience group suicidal behaviour amongst adolescents, how they assess risks/needs, and how these insights inform understanding about these groups. Method Ten practitioners, including Mental Health Nurses, were interviewed in one multidisciplinary CAMHS, in England. Data analysis was by Thematic Analysis (Braun & Clarke 2006). Results Participants described frequently working with suicidal groups. Roles in groups include suicide encouraging and preventing. Practitioners identify risky and protective connections between young people, online and offline. Clinical tensions include living with suicidal risks, emotional and positional challenges, and getting to grips with digital media. Discussion Peer groups appear to have a larger role in adolescent suicide than recognized to date. Practitioners need to assess young people's roles in groups, their diverse motivations and to understand constantly changing digital media. Implications for practice Assessments of suicide risk for young people should routinely include focus on peer relations including the online/digital realm. Maintaining relationships with vulnerable young people facilitates managing fluctuating risks and understanding different group dynamics.


GLUT1 and p63 expression in endometrial intraepithelial and uterine serous papillary carcinoma.
To analyse the expression patterns of GLUT1, p63 and p53 and the possible correlation between these markers in uterine serous papillary carcinoma (USPC) and endometrial intraepithelial carcinoma (EIC). Fourteen cases of USPC, 12 of which also showed EIC, were examined for GLUT1, p63 and p53 immunoreactivity. Four-micrometre sections from formalin-fixed paraffin-embedded tissue were immunostained using commercially available primary antibodies and Dako Envision Plus reagents for visualization. Membranous GLUT1 immunoreactivity was observed in all cases, including all 14 invasive tumours (100%) and 11 of 12 associated EICs (92%), and was confined to neoplastic cells. In USPC, staining tended to be strongest in superficial antistromal regions. p63 positivity was found in 8/14 (57%) USPCs and 9/12 (75%) associated EICs. In 11 cases p53 was overexpressed in both invasive USPC (11/14; 79%) and EIC (11/12; 92%). p53+ USPCs tended to be positive for p63, whereas p53- USPCs were also negative for p63. GLUT1 is expressed in the vast majority of USPC and EIC, suggesting a biological role during the early steps of carcinogenesis in endometrial serous neoplasms. GLUT1 expression may be induced by hypoxia-related as well as other mechanisms.


Mechanisms of the effect of 1,1-dimethyl-3-hydroxybutyl phosphonic acid derivatives on synaptic transmission in neuromuscular junction.
We studied the effect of homologues derivatives of 1,1-dimethyl-3-hydroxybutyl phosphonic acid on synaptic transmission in frog neuromuscular junction. Here we reviewed general mechanisms of inhibition of the postsynaptic current.


Utilizing a Single Silica Nanospring as an Insulating Support to Characterize the Electrical Transport and Morphology of Nanocrystalline Graphite.
A graphitic carbon, referred to as graphite from the University of Idaho thermolyzed asphalt reaction (GUITAR), was coated in silica nanosprings and silicon substrates via the pyrolysis of commercial roofing tar at 800 °C in an inert atmosphere. Scanning electron microscopy and transmission electron microscopy images indicate that GUITAR is an agglomeration of carbon nanospheres formed by the accretion of graphitic flakes into a ~100 nm layer. Raman spectroscopic analyses, in conjunction with scanning electron microscopy and transmission electron microscopy, indicate that GUITAR has a nanocrystalline structure consisting of ~1-5 nm graphitic flakes interconnected by amorphous sp3 bonded carbon. The electrical resistivities of 11 single GUITAR-coated nanospring devices were measured over a temperature range of 10-80 °C. The average resistivity of all 11 devices at 20 °C was 4.3 ± 1.3 × 10-3 Ω m. The GUITAR coated nanospring devices exhibited an average negative temperature coefficient of resistivity at 20 °C of -0.0017 ± 0.00044 °C-1, which is consistent with the properties of nanocrystalline graphite.


Supplement consumption in people who makes exercise in Northern Mexico gyms.
Physical activity and sports have acquired great importance in contemporary society, given that they have created trends to improve performance, strength and muscle mass through the consumption of nutritional supplements. To determine the profile of the consumer and the type of nutritional supplements in people attending the gyms of the northern border of Tamaulipas. It was carried out a cross-sectional and descriptive study in a sample of 800 people attending gyms in 4 cities in the border area between the United States and Mexico, in the state of Tamaulipas (Reynosa, Rio Bravo, Nuevo Laredo and Matamoros). A survey was applied to determine the profile of the consumer and the type of supplements they consumed. 81% of people who went to a gym consumed nutritional supplements, and both genders used them, regardless of their body mass index. The most used supplements were proteins, essential amino acids and nitric oxide. Improving sports performance, beauty or aesthetics, health care and finally compensating losses were the reasons selected to justify the consumption of nutritional supplements.


Risk of coronary stenosis after adjuvant radiotherapy for breast cancer.
Adjuvant radiotherapy (RT) for breast cancer is associated with an increased risk of ischemic heart disease. We examined the risk of coronary artery stenosis in a large cohort of women with breast cancer receiving adjuvant RT. A cohort of women diagnosed with breast cancer between 1992 and 2012 in three Swedish health care regions (n = 57,066) were linked to the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) to identify women receiving RT who subsequently underwent a percutaneous coronary intervention (PCI) due to coronary stenosis. Cox regression analyses were performed to examine risk of a coronary intervention and competing risk analyses were performed to calculate cumulative incidence. A total of 649 women with left-sided breast cancer and 494 women with right-sided breast cancer underwent a PCI. Women who received left-sided RT had a significantly higher risk of a PCI in the left anterior descending artery (LAD) compared to women who received right-sided RT, hazard ratio (HR) 1.44 (95% confidence interval [CI] 1.21-1.77, p < 0.001). For the proximal, mid, and distal LAD, the HRs were 1.60 (95% CI 1.22-2.10), 1.38 (95% CI 1.07-1.78), and 2.43 (95% CI 1.33-4.41), respectively. The cumulative incidence of coronary events at 25 years from breast cancer diagnosis were 7.0% in women receiving left-sided RT and 4.4% in women receiving right-sided RT. Implementing and further developing techniques that lower cardiac doses is important in order to reduce the risk of long-term side effects of adjuvant RT for breast cancer.


[Mucormycosis. Clinical cases and update].
Mucormycosis is an emerging mycotic infection with high mortality. We described the clinical presentation, evolution and treatment of 5 patients with diagnosis of mucormycosis.