[Early clinical trials in paediatric oncology in Spain: a nationwide perspective].
Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.


Fibrinolytic therapy in peripheral arterial grafts utilizing the "crossed two catheter" technique.
Direct puncture of a thrombosed lower extremity bypass graft may be the only angiographic access to the graft when it cannot be opacified or cannulated by conventional angiographic techniques. In 1 patient, fibrinolytic therapy was performed from this approach using the "crossed two catheter" technique previously described for thrombosed dialysis grafts.


A high-throughput robotic sample preparation system and HPLC-MS/MS for measuring urinary anatabine, anabasine, nicotine and major nicotine metabolites.
Most sample preparation methods characteristically involve intensive and repetitive labor, which is inefficient when preparing large numbers of samples from population-scale studies. This study presents a robotic system designed to meet the sampling requirements for large population-scale studies. Using this robotic system, we developed and validated a method to simultaneously measure urinary anatabine, anabasine, nicotine and seven major nicotine metabolites: 4-Hydroxy-4-(3-pyridyl)butanoic acid, cotinine-N-oxide, nicotine-N-oxide, trans-3'-hydroxycotinine, norcotinine, cotinine and nornicotine. We analyzed robotically prepared samples using high-performance liquid chromatography (HPLC) coupled with triple quadrupole mass spectrometry in positive electrospray ionization mode using scheduled multiple reaction monitoring (sMRM) with a total runtime of 8.5 min. The optimized procedure was able to deliver linear analyte responses over a broad range of concentrations. Responses of urine-based calibrators delivered coefficients of determination (R(2)) of >0.995. Sample preparation recovery was generally higher than 80%. The robotic system was able to prepare four 96-well plate (384 urine samples) per day, and the overall method afforded an accuracy range of 92-115%, and an imprecision of <15.0% on average. The validation results demonstrate that the method is accurate, precise, sensitive, robust, and most significantly labor-saving for sample preparation, making it efficient and practical for routine measurements in large population-scale studies such as the National Health and Nutrition Examination Survey (NHANES) and the Population Assessment of Tobacco and Health (PATH) study.


Volvulus of the sigmoid colon: a ten-year study.
A ten-year study of volvulus of the sigmoid colon is presented. Although the results of treatment of volvulus of the sigmoid colon are generally improving, the challenge for further improvement remains.


A vulnerability analysis in the Fei-tsui reservoir watershed in Taiwan.
The vulnerability analysis method has been widely used in many environmental fields. In recent years, the tool has succeeded in comprehensive assessment of environmental problems. This study applied the vulnerability and resilience analysis method on watershed conservation and grasped the environmental change capacity that watershed could bear. The Fei-tsui reservoir watershed in Northern Taiwan provided the setting for the case study reported herein. This study considered both internal and external effect factors, including watershed vulnerability, rainfall energy and the distances between the outlet and subbasins, and developed a new index, WP, for the priority restraints strategies on the land-use activities. The land-use restraint index can be a significant criterion for watershed protection and management strategies.


Original aortic valve plasty with autologous pericardium for quadricuspid valve.
Quadricuspid aortic valves represent a very rare pathology. Most cases have been discovered incidentally during heart operations or at autopsy. Patients may become symptomatic with aortic regurgitation. We encountered a symptomatic patient with aortic regurgitation and a quadricuspid aortic valve. Successful aortic valve plasty was done with our original technique of tricuspid replacement by glutaraldehyde-treated autologous pericardium.


Prognostic value of low skeletal muscle mass in patient treated by exclusive curative radiochemotherapy for a NSCLC.
Low skeletal muscle mass is a well-known prognostic factor for patients treated for a non-small-cell lung cancer by surgery or chemotherapy. However, its impact in patients treated by exclusive radiochemotherapy has never been explored. Our study tries to evaluate the prognostic value of low skeletal muscle mass and other antropometric parameters on this population. Clinical, nutritional and anthropometric date were collected for 93 patients treated by radiochemotherapy for a NSCLC. Anthropometric parameters were measured on the PET/CT by two methods. The first method was a manual segmentation at level L3, used to define Muscle Body Area (MBAL3), Visceral Fat Area (VFAL3) and Subcutaneous Fat Area (SCFAL3). The second method was an software (Anthropometer3D), allowing an automatic multislice measurement of Lean Body Mass (LBMAnthro3D), Fat Body Mass (FBMAnthro3D), Muscle Body Mass (MBMAnthro3D), Visceral Fat Mass (VFMAnthro3D), and Sub-Cutaneous Fat Mass (SCFMAnthro3D) on the PET/CT. All anthropometrics parameters were normalised by the patient's height. The primary end point was overall survival time. Univariate and then stepwise multivariate cox analysis were performed for significant parameters. Finally, Spearman's correlation between MBAL3 and MBMAnthro3D was assessed. Forty-one (44%) patients had low skeletal muscle mass. The median overall survival was 18 months for low skeletal muscle mass patients versus 36 months for non-low skeletal muscle mass patients (p = 0.019). Low skeletal muscle mass (HR = 1.806, IC95% [1.09-2.98]), serums albumin level < 35 g/l (HR = 2.203 [1.19-4.09]), Buzby Index < 97.5 (HR = 2.31 [1.23-4.33]), WHO score = 0 (HR = 0.59 [0.31-0.86] and MBMAnthro3D < 8.56 kg/m2 (HR = 2.36 [1.41-3.90]) were the only significant features in univariates analysis. In the stepwise multivariate Cox analysis, only MBMAnthro3D < 8.56 kg/m2 (HR = 2.16, p = 0.003) and WHO score = 0 (HR = 0.59, p = 0.04) were significant. Finally, muscle quantified by MBAL3 and MBMAnthro3D were found to be highly correlated (Spearman = 0.9). Low skeletal muscle mass, assessed on the pre-treatment PET/CT is a powerful prognostic factor in patient treated by radiochemotherapy for a NSCLC. The automatic software Anthropometer3D can easily identify patients a risk that could benefit an adapted therapy.


Volume-activated chloride channels contribute to lipopolysaccharide plus nigericin-induced pyroptosis in bone marrow-derived macrophages.
The representative morphological features of pyroptosis are excessive cell swelling and subsequent membrane rupture. However, the mechanism underlying the cell's inherent inability to regulate volume during the progression of pyroptosis is poorly understood. In the current study, we found that both volume-activated chloride currents (Icl, vol) and the regulatory volume decrease (RVD) were markedly decreased in bone marrow-derived macrophages (BMDMs) undergoing pyroptosis induced by lipopolysaccharides (LPS) and nigericin. The inhibition of ICl, vol and RVD by the chloride channel blockers, tamoxifen or DCPIB, led to the emergence of pyroptosis-like phenotypes such as activated-caspase-1, pyroptotic-body-like bubbles, and a fried-egg-like appearance. Moreover, the expression of the volume-activated chloride channel (VRAC) constituent protein Leucine-Rich Repeat-Containing 8A (LRRC8A) was significantly down-regulated in pyroptotic BMDMs treated with LPS and nigericin. The silencing of LRRC8A expression by small interfering RNA (si)-LRRC8A transfection not only reduced ICl, vol and RVD, but also caused BMDMs to show pyroptosis-like manifestations such as activated-caspase-1, membrane bubbles, and have a fried-egg-like appearance. These results reveal a new mechanism for the loss of volume regulation in the process of pyroptotic cell swelling and strongly suggest that a functional deficiency of VRAC/LRRC8A plays a key role in this disorder.


Crystallization in suspensions of hard spheres: a Monte Carlo and molecular dynamics simulation study.
The crystallization of a metastable melt is one of the most important non-equilibrium phenomena in condensed matter physics, and hard sphere colloidal model systems have been used for several decades to investigate this process by experimental observation and computer simulation. Nevertheless, there is still an unexplained discrepancy between the simulation data and experimental nucleation rate densities. In this paper we examine the nucleation process in hard spheres using molecular dynamics and Monte Carlo simulation. We show that the crystallization process is mediated by precursors of low orientational bond-order and that our simulation data fairly match the experimental data sets.


The Australian Traumatic Brain Injury Initiative: systematic review and consensus process to determine the predictive value of demographic, injury event and social characteristics on outcomes for people with moderate-severe traumatic brain injury.
The objective of the Australian Traumatic Brain Injury (AUS-TBI) Initiative is to develop a data dictionary to inform data collection and facilitate prediction of outcomes of people who experience moderate-severe TBI in Australia. The aim of this systematic review was to summarise the evidence of the association between demographic, injury event and social characteristics with outcomes, in people with moderate-severe TBI, to identify potentially predictive indicators. Standardised searches were implemented across bibliographic databases to 31st March 2022. English-language reports, excluding case-series, which evaluated the association between injury event, demographic and social characteristics, and any clinical outcome in at least ten patients with moderate-severe TBI were included. Abstracts, and full text records, were independently screened by at least 2 reviewers in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association. The review findings were discussed with an expert panel to determine the feasibility of incorporation of routine measurement into standard care. The search strategy retrieved 16,685 records; 867 full-length records were screened, and 111 studies included. Twenty-two predictors of 32 different outcomes were identified; 7 were classified as high-level (age, sex, ethnicity, employment, insurance, education and living situation at the time of injury). After discussion with an expert consensus group, 15 were recommended for inclusion in the data dictionary. This review identified numerous predictors capable of enabling early identification of those at risk of poor outcomes and improved personalisation of care through inclusion in routine data collection.


Adenosine and blood platelets.
Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. Adenosine released from different cells or generated through the activity of cell-surface ectoenzymes exerts its effects through the binding of four different G-protein-coupled adenosine receptors. In platelets, binding of A(2) subtypes (A(2A) or A(2B)) leads to consequent elevation of intracellular cyclic adenosine monophosphate, an inhibitor of platelet activation. The significance of this ligand and its receptors for platelet activation is addressed in this review, including how adenosine metabolism and its A(2) subtype receptors impact the expression and activity of adenosine diphosphate receptors. The expression of A(2) adenosine receptors is induced by conditions such as oxidative stress, a hallmark of aging. The effect of adenosine receptors on platelet activation during aging is also discussed, as well as potential therapeutic applications.


A Graph Clustering Approach to Localization for Adaptive Covariance Tuning in Data Assimilation Based on State-Observation Mapping.
An original graph clustering approach for the efficient localization of error covariances is proposed within an ensemble-variational data assimilation framework. Here, the localization term is very generic and refers to the idea of breaking up a global assimilation into subproblems. This unsupervised localization technique based on a linearized state-observation measure is general and does not rely on any prior information such as relevant spatial scales, empirical cutoff radii or homogeneity assumptions. Localization is performed via graph theory, a branch of mathematics emerging as a powerful approach to capturing complex and highly interconnected Earth and environmental systems in computational geosciences. The novel approach automatically segregates the state and observation variables in an optimal number of clusters, and it is more amenable to scalable data assimilation. The application of this method does not require underlying block-diagonal structures of prior covariance matrices. To address intercluster connectivity, two alternative data adaptations are proposed. Once the localization is completed, a covariance diagnosis and tuning are performed within each cluster, whose contribution is sequentially integrated into the entire covariance matrix. Numerical twin experiment tests show the reduced cost and added flexibility of this approach compared to global covariance tuning, and more accurate results yielded for both observation- and background-error parameter tuning.


Nanopore-related cellular death through cytoskeleton depolymerization by drug-induced ROS.
Prostate cancer (PCa) is a malignant tumor with a very high incidence which ranks second after lung cancer. Although there are many drugs available for the treatment of PCa, their effectiveness and anti-cancer mechanisms still need to be explored. Atomic force microscopy (AFM) could characterize minor morphological changes on cell surfaces, which provides an effective method to explore the interaction between drugs and cells at the nanometer level and further investigate the mechanisms for treating PCa. In our research, AFM visualized pore-like structures in the PC3M cell membrane after treatment with the eminent anticancer agent paclitaxel (PTX). The diameter, depth and number of these pores were in a concentration and time-dependent manner. Reactive oxygen species (ROS) was shown to depolymerize the actin cytoskeleton and make the membrane more sensitive to oxidative damage, thus inducing pore information. After pretreatment with a ROS scavenger, pore formation was prevented. AFM imaging technology provides a new evaluation method for drug-targeted therapy for cancer.


Comparison of 17 isolates of the human parvovirus B 19 by restriction enzyme analysis. Brief report.
The genomes of 17 isolates of the human parvovirus B 19 were compared by restriction with eight endonucleases. All but four isolates proved indistinguishable. A 3.2 kb B 19 DNA fragment was cloned and used as a molecular probe.


Ranking the risks of eighty pharmaceuticals in surface water of a megacity: A multilevel optimization strategy.
Pharmaceuticals in freshwater posed ecological risks to aquatic ecosystem, however, most risk assessments of pharmaceuticals were conducted at screening level, which were limited by the availability of the toxicity data. In this study, risks of 80 pharmaceuticals including 35 antibiotics, 13 antiviral drugs, 13 illicit drugs, and 19 antidepressants in surface water of Beijing were assessed with a proposed multilevel environmental risk optimization strategy. Target pharmaceuticals were detected in surface water samples with the detection frequency from 1.7 % to 100 % and the total concentrations from 31.1 ng/L to 2708 ng/L. Antiviral drugs were the dominant pharmaceuticals. Preliminary screening-level risk assessment indicated that 20 pharmaceuticals posed low to high risks with risk quotient from 0.14 (chloroquine diphosphate) to 27.8 (clarithromycin). Thirteen pharmaceuticals were recognized with low to high risks by an optimized risk assessment method. Of them, the refined probabilistic risk assessment of joint probability curves coupling with a quantitative structure activity relationship-interspecies correlation estimation (QSAR-ICE) model was applied. Clarithromycin, erythromycin and ofloxacin were identified to pose low risks with maximum risk products (RP) of 1.23 %, 0.41 % and 0.35 %, respectively, while 10 pharmaceuticals posed de minimis risks. Structural equation modeling disclosed that human land use and climate conditions influenced the risks of pharmaceuticals by indirectly influencing the concentrations of pharmaceuticals. The results indicated that the multilevel strategy coupling with QSAR-ICE model was appropriate and effective for screening priority pollutants, and the strategy can be used to prioritize pharmaceuticals and other emerging contaminants in the aquatic environment.


Exercise and fluoxetine treatment during adolescence protect against early life stress-induced behavioral abnormalities in adult rats.
Depression is a psychiatric disorder with several comorbidities that has a complicated pathophysiology. Multiple mechanisms such as abnormal hypothalamic-pituitary adrenal (HPA) axis activity, neurotransmission (namely serotonin), and immune-inflammatory responses are involved in the pathophysiology of disease. In this study, we hypothesized that applying exercise (running wheel (RW) and treadmill (TM)) or fluoxetine (FLX) during adolescence could protect adult rats against the negative impact of early-life stress. To do this, we applied maternal separation stress (MS) to neonatal rats from postnatal day (PND) 2 to 14 and at PND 28, rats were divided into 8 experimental groups and were subjected to TM or RW or FLX treatment. After four weeks of physical activity or FLX treatment, at PND 64, behaviors were assessed by applying forced swimming test, sucrose preference test, open-field test, and elevated plus maze test. Serum cortiscosterone (CORT) levels and expression of genes associated with inflammatory factors (Il1β, Hmgb1, and Il6) and serotonergic systems (5-ht2c and 5-ht3a) were studies in the hippocampus (HIPP) and prefrontal cortex (PFC). Our results revealed that RW and FLX treatment during adolescence are capable of attenuating MS-induced depressive- and anxiety-like disorders in adult male rats. These effects were accompanied by the normalization of both serum CORT and the expression of genes in the HIPP and PFC. TM exercise in adolescence showed anxiolytic effects but failed to produce antidepressant-like effects. Results of this study suggest that voluntary physical activity during adolescence can reduce the negative effects of early-life stress through different mechanisms.


Biosensor for direct determination of glucose and lactate in undiluted biological fluids.
This paper describes the implementation of a bienzyme sensor for the direct determination of glucose and lactate in undiluted biological samples. The biosensor exploits the competitive action versus the substrate itself by two different enzymes immobilized into a sandwich of two different membranes. In this way the quantity of substrate reaching the indicating electrode is reduced and this determines an extension of the linearity range.


Interdependence of the two borders in a sodium transporting epithelium. Possible regulation by the transport pool.
Specific binding of 14C-amiloride to the mucosal surface of frog skin epithelium (Rana temporaria) has been used as a measure of the number of sodium entry sites. All binding measurements were made with the mucosal surface bathed in a solution containing 1.1 mM sodium. When manipulations were used which increased the intracellular concentration of sodium the amount of amiloride bound was reduced. The manipulations included flushing the mucosal surface with solutions containing 111 mM sodium after serosal efflux was inhibited with ouabain or potassium removal. Similar results were obtained when cells were loaded with lithium. These effects on amiloride binding did not appear to depend on changes in membrane potential or upon changes in affinity of amiloride for its binding site. It appears that inhibition of serosal sodium efflux from the epithelium causes a reduction of mucosal sodium influx by making entry sites unavailable. This latter may be a result, directly or indirectly, of the sodium concentration in the sodium transport pool.


Management of refractory sustained ventricular tachycardia with amiodarone: a reappraisal.
We examined the value of clinical variables, chronic 24-hour ambulatory ECG monitoring, and chronic electrophysiologic (EP) testing in 49 patients with recurrent and refractory sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) treated with chronic oral amiodarone in order to develop a prospective approach to the management of these patients. All patients underwent control EP studies followed by continuous telemetric cardiac monitoring during oral amiodarone administration (mean duration 29 +/- 6 days, mean dose 739 +/- 230 mg). Follow-up 24-hour ambulatory ECG monitoring and EP studies were performed. Thirty VT recurrences occurred in the first 4 weeks of amiodarone therapy (total incidence, 61%), with the majority (55%) in the first 3 weeks of treatment. During long-term follow-up (1 to 42, mean 15 +/- 12 months), there were 12 symptomatic VT/VF recurrences (incidence 24%). There was a higher incidence of VT recurrences if patients had inducible sustained or nonsustained VT at chronic EP study (p less than 0.01), or complex ventricular arrhythmias on ambulatory ECG monitoring (p less than 0.05). The sensitivity, specificity, and predictive accuracy of chronic EP testing and 24-hour ambulatory ECG monitoring were 100%, 35%, and 51%, and 58%, 84%, and 78%, respectively. Chronic EP testing correctly identified all patients who had their arrhythmia suppressed by amiodarone on long-term follow-up, while 42% of all VT recurrences occurred in patients without complex ventricular arrhythmias on 24-hour ambulatory ECG monitor.(ABSTRACT TRUNCATED AT 250 WORDS)


Individual differences in novelty-seeking predict differential responses to chronic antidepressant treatment through sex- and phenotype-dependent neurochemical signatures.
Women experience major depression at roughly twice the rate of men. Inconclusive clinical evidences assist the notion that responsiveness to antidepressant pharmacotherapy is sexually dimorphic with the two sexes presenting differential responses when treated with tricyclic antidepressants (TCAs). Notably, responsiveness to antidepressive agents presents marked inter-individual variability, the biological basis of which remains elusive. Herein, we sought to investigate putative sex differences to chronic antidepressant treatment with the TCA clomipramine in rats selected on the basis of their reactions to novelty. Our data revealed that high novelty-seeker (HR) male rats were more responsive to clomipramine treatment as far as the alleviation of anxiety and nociception are concerned, compared to low novelty-seeker (LR) males and HR/LR female rats. Surprisingly, chronic clomipramine treatment attenuated depressive-like symptomatology in the forced swim test (FST) of behavioral despair in both sexes albeit in the opposite novelty-seeking phenotypes (i.e. in male HR and female LR). Interestingly in male HR rats, clomipramine treatment diminished serotonergic neurochemical responses post-FST exposure in all limbic brain regions examined, while these were boosted in their LR counterparts. Dopaminergic and glutamatergic neurochemistry also presented phenotype-related alterations. On the contrary, in females the neurochemical substrate was only modestly affected. Notably, corticosteroid responses were augmented in female but attenuated in male drug-treated rats. Overall, the current dataset lends further support that the male sex may benefit to a greater extent when treated with TCAs and reveals that individual differences are associated with qualitative and quantitative sex-related behavioral and neurochemical manifestations in response to chronic antidepressant treatment.


Blockade of the antinociception induced by diclofenac, but not of indomethacin, by sulfonylureas and biguanides.
There is evidence that administration of sulfonylureas, such as glibenclamide and tolbutamide, blocks diclofenac-induced antinociception, suggesting that diclofenac activates ATP-sensitive K(+) channels. However, there is no evidence for the interaction between diclofenac and other hypoglycemic drugs, such as the biguanides metformin or phenformin. Therefore, this work was undertaken to determine whether two sulfonylureas, glibenclamide and glipizide, as well as two biguanides, metformin and phenformin, have any effect on the systemic antinociception that is induced by diclofenac and indomethacin using the rat formalin test as an animal model. Systemic injections of diclofenac (10 to 30mg/kg) and indomethacin (10 to 30mg/kg) produced dose-dependent antinociception during the second phase of the test. Systemic pretreatment with glibenclamide (3 and 10mg/kg), glipizide (3 and 10mg/kg), metformin (100 and 180mg/kg) or phenformin (100 and 180mg/kg) blocked diclofenac-induced systemic antinociception in the second phase of the test (P<0.05). In contrast, pretreatment with glibenclamide, glipizide, metformin or phenformin did not block indomethacin-induced systemic antinociception (P>0.05). These data suggest that diclofenac, but not indomethacin, activated K(+) channels and metformin and phenformin-dependent mechanisms, which resulted in systemic antinociceptive effects in the rat formalin test.


Detection of telomerase activity in patients with pancreatic cancer.
Telomerase, which ensures the unlimited proliferation by adding TTAGGG repeat at the end of the chromosome, is strongly activated at a very high incidence in a variety of malignant neoplasms including pancreatic cancer. In addition to the acquisition of the immortality, telomerase plays an important role in the aggressive behavior of pancreatic cancer. Invasiveness of human pancreatic cancer cells correlates well with telomerase activity. Exposure of pancreatic cancer to anticancer drugs up-regulates telomerase activity, and the increase in telomerase activity correlates with resistance to the drug-induced apoptosis. More important, diagnositic values of telomerase activity are highly focused because of the lack of other specific genetic markers for pancreatic cancer. Samples of pancreatic juice are obtained at endoscopic retrograde pancreatography using a balloon catheter after intraveneous injection of secretin. Because the pancreatic juice has strong protease and RNase activity, addition of protease inhibitors and RNase inhibitors in the telomerase extraction buffer is necessary for the detection of telomerase activity in the pancreatic juice. A telomeric ladder was detected in 80% patients with carcinoma, whereas only 4.3% patients with adenoma and none with chronic pancreatitis showed positive telomerase activity.


Concomitant Infection of Helicobacter pylori and Intestinal Parasites in Adults Attending a Referral Centre for Parasitic Infections in North Eastern Italy.
Helicobacter pylori and intestinal parasites are estimated to infect with high burden worldwide. However, their concomitant infections are poorly determined in industrialized countries, such as Italy. In this study we aim at describing the presence of H. pylori as well as the proportion of coinfections with intestinal parasites among subjects who attended a referral center for tropical diseases in Northern Italy. This was a case-control study. Screening for H. pylori and parasites was performed on stool samples of 93 adults from different geographical origin (Africa, Asia, South-America, East-Europe and Italy). H. pylori infection was examined by CLIA and its cagA positivity was determined by rtPCR. Intestinal parasites (i.e., protozoa and helminths) were examined by microscopy and rtPCR. Sixty-one out of 93 patients (66%) were positive to H. pylori and 31 (33%) were cagA+. Among H. pylori positives, 45 (74%) had a concomitant infection. The coinfection H. pylori-Blastocystis was the most frequent one, followed by H. pylori-E. coli. Multivariable logistic regression showed that positivity to H. pylori was associated with having a coinfection. Our data suggested that H. pylori and intestinal parasitic infections are fairly common in subjects who attended a referral center for tropical diseases in Northern Italy. The high rate of H. pylori infection, and especially the positivity to the virulent cagA+, should be taken into consideration in subjects undergoing screening for parasitic infections.


Psychiatric nursing outcome research: the state of the science.
A review of the nursing literature from 1989 to 1994 indicates that few psychiatric nursing studies are published in the major nursing research journals. The psychiatric specialization literature includes a large number of studies that are classified as either outcome studies or could serve as building blocks for future outcome studies. Few studies build on prior research, resulting in a weak scientific basis for evaluating the outcomes of psychiatric nursing care. Strategies for increasing the quantity and quality of psychiatric nursing outcome research are presented.


Differentiated distribution of norfloxacin in the medullary-cortical part of the kidney in man.
Norfloxacin administered orally in a single dose of 400 mg, rapidly reaches high levels in the renal tissues, and provides an effective therapeutic action against sensitive pathogen germs. Twelve hours after administration, the drug is still detectable in the renal tissue; particularly, it was evidenced a positive tropism in the medullary part of renal parenchyma, where they were found norfloxacin levels far higher than those of cortical parts.


Expression of Escherichia coli tryptophan operon in Rhizobium leguminosarum.
RP4-trp hybrid plasmid containing Escherichia coli whole tryptophan operon was conjugatively transferred from E. coli to Rhizobium leguminosarum strains carrying mutations in different trp genes, converting their Trp- phenotype to Trp+. That the phenotype change of the R. leguminosarum cells was due to the presence of the E. coli tryptophan operon was verified by the isolation of RP4-trp hybrid plasmid from the R. leguminosarum conjugant cells, and by re-transfer of RP4-trp plasmid by conjugation back to E. coli trp and Pseudomonas putida trp strains. Enzymatic activities of anthranilate synthetase and beta subunit of tryptophan synthetase in crude extracts of R. leguminosarum cells containing RP4-trp plasmid were much higher than that of the wild-type cells and were not repressed by the presence of tryptophan in the culture medium.


The effect of 2,2'-substitution on the metabolism and toxicity of dapsone in vitro and in vivo.
The effect of 2,2'-substitution with fluorine, methyl or trifluoromethyl groups on the toxicity, metabolism and pharmacological activity of dapsone has been investigated in vitro and in vivo. There was marked inter-species variation in the bioactivation (N-hydroxylation) of the compounds, as determined by methemoglobin formation. However, the inclusion of fluorine significantly (P<0.01) reduced methemoglobin formation compared with dapsone in all species studied. All three analogs resulted in significantly (P<0.001) less methemoglobinemia than dapsone when given either intraperitoneally or intravenously to the male Wistar rat. Rapid plasma clearance of the analogs through increased lipophilicity and enhanced N-glucuronidation may account for the low toxicity compared with dapsone. Although trifluoromethyl substitution resulted in a loss of activity against respiratory burst in human neutrophils in an in vitro model, all three analogs retained pharmacological activity against Plasmodium berghei malaria in an in vivo mouse model.


Iatrogenic chorioamniotic separation and septostomy following fetoscopic laser photocoagulation for twin-twin transfusion syndrome.
To compare the perinatal outcomes of pregnancies complicated by chorioamniotic separation (CAS) vs septostomy following fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). This was a retrospective cohort analysis of monochorionic diamniotic twin pregnancies with TTTS that underwent FLP at one of two university-affiliated tertiary medical centers between January 2012 and December 2020. CAS and septostomy were diagnosed either during the procedure or by ultrasonography within 24-48 h after FLP. Data on procedure and postprocedure parameters, pregnancy outcomes and survival were collected from the patients' electronic medical records. Pregnancies were stratified according to the presence of CAS, septostomy or neither. Patients diagnosed with both CAS and septostomy were analyzed separately. Of the 522 women included in the cohort, 38 (7.3%) were diagnosed with CAS, 68 (13.0%) with septostomy and 23 (4.4%) with both CAS and septostomy. The remaining 393 (75.3%) women comprised the control group. Groups did not differ in demographic characteristics. The septostomy group had a lower rate of selective fetal growth restriction than did the CAS and control groups (24.2% vs 36.8% vs 42.7%, respectively; P = 0.017). Moreover, intertwin size discordance was lower in the septostomy group (15.1% vs 23.4% in the CAS group and 25.5% in the control group; P = 0.001). Median gestational age at FLP was significantly lower in the CAS group (19.3 weeks vs 20.4 weeks in controls and 20.9 weeks in the septostomy group; P = 0.049). The rate of delivery prior to 34 weeks was significantly higher in the CAS group (89.2%), followed by the septostomy group (80.9%), compared with the control group (69.0%) (P = 0.006). A secondary analysis demonstrated that patients with both CAS and septostomy presented the highest rates of delivery prior to 34 weeks (100%) and 32 weeks (68.2%). CAS and septostomy following laser surgery for TTTS are independently associated with higher rates of preterm delivery. The presence of these two findings in the same patient enhances the risk of prematurity. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.


Effects of combining alcohol and cannabis on driving, breath alcohol level, blood THC, cognition, and subjective effects: A narrative review.
Alcohol and cannabis are the two most commonly found intoxicating substances in fatally injured drivers. Epidemiological studies have demonstrated that the use of alcohol or cannabis can lead to an increase in the risk of a motor vehicle collision. Reducing the risks associated with driving under the influence of alcohol or cannabis is achieved partly through roadside detection of breath alcohol concentrations (BrAC) or blood delta-9-tetrahydrocannabinol (THC) levels. The purpose of the present review is to compile the laboratory studies on the combined effects of alcohol and cannabis on simulated driving as well as those evaluating combinations of these drugs on BrAC or blood THC. Given that driving can be affected by a number of cognitive processes, the literature on the cognitive effects of combinations of alcohol and cannabis is also reviewed, along with a discussion of a potential additive effect on the subjective qualities of these drugs. In sum, it is concluded that alcohol and cannabis have additive effects on driving skills, cognition and subjective effects. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Changes in Biomarkers of Cigarette Smoke Exposure After 6 Days of Switching Exclusively or Partially to Use of the JUUL System with Two Nicotine Concentrations: A Randomized Controlled Confinement Study in Adult Smokers.
Evidence suggests that cigarette smokers who switch to electronic nicotine delivery systems (ENDS) reduce their exposure to harmful toxicants and carcinogens. It is unclear if dual-use is associated with decreases in exposure to toxicants. This parallel-group confinement study assessed changes in biomarkers of exposure (BOEs) over six days among healthy adult smokers who were randomized into 1 of 11 study groups: eight JUUL-brand System (JUUL) groups (4 JUUL flavors [Virginia Tobacco, Menthol, Mint, Mango] × 2 nicotine concentrations [5.0% or 3.0% by weight]); Dual-Use group used preferred JUUL flavor (5.0% nicotine) and ≤50% usual brand (UB) cigarettes/day; UB Cigarette group and one group abstained from all tobacco/nicotine product use (Abstinence group). Urine and blood analysis assessed changes in primary BOE endpoints (NNAL, 3-HPMA, MHBMA, S-PMA COHb) and secondary BOE endpoints (NNN, HMPMA, CEMA, 1-OHP, O-toluidine, 2-NA, 4-ABP) among 279 adult smokers. In JUUL groups, median percent reductions in primary BOEs (Day 6-Baseline) were 90%-≥100% of Abstinence; there were no significant differences between JUUL groups and Abstinence. All reductions in JUUL groups were substantially and statistically significantly greater than reductions in the UB Cigarette group (ps < 0.025). Median reductions in primary BOEs in the Dual-Use group were 43%-55% of Abstinence. Similar results were observed for secondary BOEs. This study suggests that the use of JUUL as a complete or partial substitute (i.e., dual-use with ≥50% reduction in cigarette consumption) for combustible cigarettes can substantially reduce exposure to multiple toxins associated with cigarette smoking. This study adds to the growing body of evidence supporting the utility of ENDS products as potentially reduced-harm alternatives to cigarettes for adult smokers. Adult smokers who switched completely from cigarette smoking to use of the JUUL System ("JUUL") in two nicotine concentrations (5.0% and 3.0%) and four flavors significantly reduced their exposure to multiple classes of cigarette-related toxicants. Additionally, smokers who used JUUL and continued smoking but reduced their daily cigarette consumption by ≥50% (dual users) also significantly reduced their toxicant exposure compared to cigarette smoking.


Interventional sialoendoscopy for treatment of obstructive sialadenitis.
This follow-up study documents the overall success rate of interventional sialoendoscopy; it is a novel, less invasive treatment for obstructive sialadenitis. This was a retrospective follow-up study of 189 patients who underwent a sialoendoscopic procedure at Massachusetts General Hospital from 2004 through 2013. Included were patients who underwent sialoendoscopic treatment for symptoms and clinical findings consistent with obstructive sialadenitis. Four different interventional sialoendoscopic techniques were used: dilation of stricture and irrigation, stone retrieval by basket, stone fragmentation with lithotripsy or laser, and stone removal by endoscopic-assisted "cutdown" operation using the "modified McGurk" technique. The outcome assessed was whether the patient was asymptomatic at 6 months postoperatively. Interventional endoscopic navigation was accomplished in 164 of 189 patients (87%). In 17 cases, the duct orifice was inaccessible owing to scarring, so the duct could not be navigated. Symptomatic relief was achieved in 148 of 164 patients (90%). Dilatation and lavage for sialadenitis without a stone was accomplished in 52 of 189 patients (28%). Sialoliths were retrieved or fragmented in 137 of 164 cases (84%). The results of this study show a high success rate in the treatment of obstructive sialadenitis using interventional sialoendoscopy.


Low incidence of invasive aspergillosis in allogeneic stem cell transplant recipients receiving amphotericin B inhalation prophylaxis.
In this retrospective study we evaluated the impact of amphotericin B (AmB) deoxycholate inhalation prophylaxis on invasive aspergillosis (IA) in 611 allogeneic stem cell transplant (alloSCT) recipients and their tolerance of the inhalations. The inhalations were not used in 1996-2000 (Period I). In 2001-2005 (Period II) all patients with acute graft-versus-host disease treated with high-dose methylprednisolone used the inhalation prophylaxis with a dose of 25 mg daily. No systemic antifungal prophylaxis was routinely used during the study period. IA was detected in 17 (13 proven, 4 probable) out of 257 (6.6%) patients transplanted in Period I and in 9 (6 proven, 3 probable) out of 354 (2.5%) patients transplanted in Period II (P=0.007). The median time to the diagnosis of IA was 95 days and 155 days post transplant in the 2 periods (P=0.225). The mortality of the patients with IA was 94.1% and 66.6% in Period I and Period II. The median duration of AmB inhalation prophylaxis was 84 days. Breakthrough IA was detected in 1 of the 111 (1%) patients during the prophylaxis. No discontinuation of prophylaxis due to side effects was recorded. Overall, with a median follow-up of 3.5 and 4.6 years, 42.4% and 59% of the patients were alive in Period I and Period II, respectively (P=0.001). In conclusion, the incidence of IA fell during the AmB inhalation prophylaxis, and the inhalations were well tolerated. Mortality of patients with IA was high. The overall survival of patients was significantly higher in Period II, indicating the advances made in SCT therapy over the 10-year period.


Neutral alignment resulting from tibial vara and opposite femoral valgus is the main morphologic pattern in healthy middle-aged patients: an exploration of a 3D-CT database.
Given the goal of achieving optimal correction and alignment after knee arthroplasty or high tibial osteotomy, literature focusing on the inter-individual variability of the native knee, tibia and femur with regards to the coronal or sagittal alignment is lacking. The aim of this study was to analyse normal angular values in the healthy middle-aged population and determine differences of angular values according to inter-individual features. The first hypothesis was that common morphological patterns may be identified in the healthy middle-aged non-osteoarthritic population. The second hypothesis was that high inter-individual variability exists with regards to gender, ethnicity and alignment phenotype. A CT scan-based modelling and analysis system was used to examine the lower limb of 758 normal healthy patients (390 men, 368 women; mean age 58.5 ± 16.4 years) with available data concerning angular values and retrieved from the SOMA database. The hip-knee-ankle angle (HKA), lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), posterior distal femoral angle (PDFA), posterior proximal tibial angle (PPTA) and non weight-bearing joint line convergence angle (nwJLCA) were then measured for each patient. Results were analysed for the entire cohort and based on gender, ethnicity and phenotype. The mean HKA was 179.4° ± 2.6°, LDFA: 85.8° ± 2.0°, MPTA: 85.6° ± 2.4°, PDFA: 85.2° ± 1.5°, PPTA: 83.8° ± 2.9° and nwJLCA: 1.09° ± 0.9°. Gender was associated with higher LDFA and lower HKA for men. Ethnicity was associated with greater proximal tibial vara and distal femoral valgus for Asian patients. Patients with an overall global varus alignment had more tibia vara and less femoral valgus than patients with an overall valgus alignment. Even if significant differences were found based on subgroup analysis (gender, ethnicity or phenotype), this study demonstrated that neutral alignment is the main morphological pattern in the healthy middle-aged population. This neutrality is the result from tibia vara compensated by an ipsilateral femoral valgus. III, retrospective cohort study.


Designing multi-epitope based peptide vaccine targeting spike protein SARS-CoV-2 B1.1.529 (Omicron) variant using computational approaches.
Millions of lives have been infected since the SARS-CoV-2 outbreak in 2019. The high human-to-human transmission rate has warranted a need for a vaccine to protect people. Although some vaccines are in use, due to the high mutation rate in the SARS-CoV-2 multiple variants, the current vaccines may not be sufficient to immunize people against new variant threats. One of the emerging concern variants is B1.1.529 (Omicron), which carries ~ 30 mutations in the Spike protein (S) of SARS-CoV-2 and is predicted to evade antibody recognition even from vaccinated people. We used a structure-based approach and an epitope prediction server to develop a Multi-Epitope based Subunit Vaccine (MESV) involving SARS-CoV-2 B1.1.529 variant spike glycoprotein. The predicted epitope with better antigenicity and non-toxicity was used for designing and predicting vaccine construct features and structure models. In addition, the MESV construct In silico cloning in the pET28a expression vector predicted the construct to be highly translational. The proposed MESV vaccine construct was also subjected to immune simulation prediction and was found to be highly antigenic and elicit a cell-mediated immune response. Therefore, the proposed MESV in the present study has the potential to be evaluated further for vaccine production against the newly identified B1.1.529 (Omicron) variant of concern. The online version contains supplementary material available at 10.1007/s11224-022-02027-6.


Sick from what? Trauma during the SARS-CoV-2 pandemic.
We present the case of two brothers with identical mechanisms of injury presenting simultaneously, one with SARS-Cov-2 respiratory failure and the other in hemorrhagic shock. Healthcare globally and in the United States met novel challenges during the unprecedented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) health crisis. The effect of SARS-CoV-2 on hospital and health care delivery systems has been widely reported. Elective surgical procedures were suspended; however, trauma and acute care services remained active and faced unique challenges during this pandemic. Trauma patients by their nature of injury require rapid assessment and treatment to include invasive emergency operations. Not only do trauma centers have to adapt to limited resources and new procedures limiting exposure, they are also met with the confounding issue of trauma patients concomitantly presenting with SARS-CoV-2 respiratory illness. Trauma care providers must now contend with SARS-CoV-2 on the differential for patients presenting with trauma. This is demonstrated by our case of two brothers with identical mechanisms of injury presenting simultaneously, one in shock from respiratory failure and the other hemorrhagic.


Diagnosis of a vulvar granular cell tumor by fine needle aspiration biopsy. A case report.
Granular cell tumor (GCT) (granular cell "myoblastoma") is an uncommon neoplasm that may mimic carcinoma both clinically and morphologically. Fine needle aspiration diagnosis of vulvar GNT has been described on only one prior occasion. A 74-year-old, black female presented with a mass in the left labia. Fine needle aspiration biopsy revealed rare intact cells; abundant, granular, cytoplasmic fragments; and bland, ovoid, stripped nuclei. The intact cells were arranged in loose aggregates. Each sampling was exquisitely painful to the patient despite the use of local anesthesia. Cytologists should be aware of the distinctive clinical and morphologic appearance of GCT. The cytologic findings of vulvar, GCT are identical to those described at other body sites. Definitive diagnosis before extirpation permits definitive therapy.


Dairy Cattle Euthanasia-Focus Groups Exploring the Perspectives of Brazilians Working in the Dairy Cattle Industry.
The objective of this study was to explore perspectives and attitudes about euthanasia specific to the Brazilian dairy cattle industry. Twenty-five Brazilian citizens (13 veterinarians, 4 animal scientists, 3 professors, 3 researchers, 1 dairy owner, and 1 caretaker) participated in one of three focus groups conducted and recorded online (10, 8, and 7 participants per group). Questions regarding euthanasia were posed by a moderator, and the focus group discussions were then transcribed verbatim for analysis. After the initial data analysis, themes were evaluated and collapsed into three major categories: Euthanasia Training and Farm and Human Components. A complex interconnection between the three main themes and multiple subthemes specific to dairy cattle euthanasia was also revealed. The lack of nationally recognized euthanasia guidelines for dairy cattle paired with ineffective and inaccessible euthanasia tools makes it difficult for dairy veterinarians to implement humane protocols for on-farm euthanasia. In addition, logistical factors, particularly, the financial cost of euthanasia and the human-animal bond, play a role in the failure to perform euthanasia when warranted. Future studies should focus on the development of science-based standards and producer training to improve the consistency of on-farm euthanasia in Brazilian dairy operations.


Associations between cognitive impairment and illness awareness in fully remitted bipolar outpatients.
The euthymic state of bipolar disorder is often characterized by impaired cognitive function. In this investigation, we hypothesized that subjective cognitive function is impaired and illness awareness is inadequate and we further explored the associations among cognitive complaints, objective cognitive functions, and current illness awareness in Japanese patients. Twenty-seven patients in remission and 27 healthy subjects were recruited in this study. The Japanese version of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) and Scale to Assess Unawareness in Mental Disorders (Japanese, SUMD-J) were used to assess each patient. All patients underwent neuropsychological tests for the assessment of objective cognitive functions. Only SUMD2.C (current awareness of the effects of medication) was significantly correlated with COBRA, and the objective cognitive assessments, Word Fluency Test and Stroop Test Reaction Time, represented significant correlations with SUMD1.C (current awareness of mental illness). In remitted bipolar outpatients, both the objective and subjective cognitive functions were found to be associated with illness awareness. However, subjective and objective cognitive functions differed in the related illness awareness subscales in fully remitted bipolar outpatients.


Challenges in the recognition and management of paediatric sepsis - The journey.
Paediatric sepsis remains a leading cause of childhood death. Morbidity is high, with up to one third of children affected developing ongoing, sometimes lifelong sequelae. To address the major burden of sepsis on child health, there is need for a unified approach to care, as outlined in the Australian National Action Plan for sepsis. While the Surviving Sepsis Campaign 2020 guidelines provided evidence-based recommendations for sepsis management in hospital, additional emphasis on families, pre-hospital recognition and post-sepsis care incorporating the multidisciplinary team is paramount to achieve quality patient outcomes. The role of families, paramedics and nurses in recognising and managing paediatric sepsis remains an under-represented area in current literature. The aim of this paper is to critically discuss key challenges surrounding the journey of paediatric sepsis, drawing on contemporary literature to highlight key areas pertinent to recognition and management of sepsis in children. Application of a holistic, patient-centred focus will provide an overview of paediatric sepsis, aiming to inform future development for enhanced healthcare delivery and identify critical areas for further research.


Retrograde femoral nailing: computed tomography angiogram demonstrates no relative safe zone for prevention of small diameter arterial vascular injury during proximal anteroposterior interlocking.
Reported iatrogenic injury to the proximal femoral vascular structures is rare after retrograde femoral nailing. Previous cadaveric dissections have recommended placement of proximal interlocking screws above the level of the lesser trochanter. This study is designed to define the arterial vascular anatomy anterior to the proximal medullary canal of the femur, which could be damaged with the placement of anteroposterior (AP) proximal interlocking screws. Computed tomography angiograms of the structures anterior to the proximal femur demonstrate the presence of arterial branches >2 mm diameter in 100% of study patients at or above the level of the lesser trochanter. No true safe zone corridor exists anteriorly for placement of AP interlocking screws in this region. Surgical technique modifications are suggested to minimize the potential risks of iatrogenic arterial injury during retrograde femoral nail AP proximal interlocking.


Prognostic Relevance of Cardiorespiratory Fitness as Assessed by Submaximal Exercise Testing for All-Cause Mortality: A UK Biobank Prospective Study.
To investigate whether the inverse associations of cardiorespiratory fitness (CRF) with all-cause and cardiovascular mortality in the general population vary among individuals who are at different levels of pretest risk. Cardiorespiratory fitness was assessed through submaximal bicycle tests in 58,892 participants aged 40 to 69 years who completed baseline questionnaires between January 1, 2006, and December 31, 2010, in the UK Biobank Prospective Study. Participants were categorized into risk categories, which determined allocation to an individualized bicycle protocol. The groups at minimal risk (category 1), small risk (category 2), and medium risk (category 3) were tested at 50%, 35% of the predicted maximal workload, and constant level, respectively. We investigated associations of CRF with mortality across different levels of pretest risk and determined whether CRF improves risk prediction. During a median follow-up of 5.8 years, 936 deaths occurred. Cardiorespiratory fitness was linearly associated with mortality risk. Comparing extreme fifths of CRF, the multivariable-adjusted hazard ratios (95% CIs) for mortality were 0.63 (0.52-0.77), 0.54 (0.36-0.82), 0.81 (0.46-1.43), and 0.58 (0.48-0.69) in categories 1, 2, and 3 and overall population, respectively. The addition of CRF to a 5-year mortality risk score containing established risk factors was associated with a C-index change (0.0012; P=.49), integrated discrimination improvement (0.0005; P<.001), net reclassification improvement (+0.0361; P=.005), and improved goodness of fit (likelihood ratio test, P<.001). Differences in 5-year survival were more pronounced across levels of age, smoking status, and sex. Cardiorespiratory fitness, assessed by submaximal exercise testing, improves mortality risk prediction beyond conventional risk factors and its prognostic relevance varies across cardiovascular risk levels.


Evaluation of the pharmacokinetic interaction between cimetidine or famotidine and cyclosporine in healthy men.
To investigate the potential interaction between cimetidine or famotidine and cyclosporine in healthy men. All subjects received oral cyclosporine at baseline, after the first week of 1 histamine2 (H2)-blocker, and a third time after a 1-week washout plus 1 week of the second H2-blocker. Blood samples were collected just before each dose of cyclosporine and for up to 36 hours afterward for pharmacokinetic analysis. A college of pharmacy in a university teaching hospital. The study population consisted of 8 healthy men at least 19 years of age. Cyclosporine concentrations in whole blood were measured using a polyclonal fluorescence polarization immunoassay. Cyclosporine pharmacokinetic parameters during each of the 3 treatment periods were compared. The average times to maximum cyclosporine concentrations were similar between baseline (3.2 h), cimetidine (2.9 h), and famotidine (3.6 h) dosing periods. There were no significant differences in area under the curve, half-life, or maximum concentration during the 3 dosing periods. Neither cimetidine or famotidine produced a significant change in the pharmacokinetics of single-dose oral cyclosporine in healthy men.


Oxidative stress damage in the liver of fish and rats receiving an intraperitoneal injection of hexavalent chromium as evaluated by chemiluminescence.
The livers fractions of Oreochromis niloticus (Tilapia) and Wistar rats taken from treated animals to single intraperitoneal doses of hexavalent chromium (K(2)Cr(2)O(7)), were analyzed for tert butyl hydroperoxide-initiated chemiluminescence (CL), lipid peroxidation using thiobarbituric acid reactive substances (TBARS), enzymes superoxide dismutase (SOD) and catalase activities, and the quantification of cytochromes P450 and b5. The CL time course curve was significantly higher in O. niloticus treated with Cr(VI) at all times studied. The maximum CL was observed after 24h of exposure. The CL mean ratio treated/control was 4.6 and the initial velocity (V(0)) increased 7.4 times at 24h of intoxication. The TBARS levels however increased only 24h after intoxication. The CL time course curve was significantly higher in rats treated with Cr(VI) as early as 3h after intoxication. The maximum CL occurred 24h after exposure. The CL mean ratio treated/control was 2.1 and the V(0) increased 3.8 times at 24h of intoxication. On the contrary, was not observed any increase in TBARS in this study. Compared to the controls, in fish, SOD activity increased significantly only 24h after of exposure. In rats, there was a significant increase in SOD activity after 3 and 24h of intoxication. There was no catalase activity, nor cytochrome P450 and cytochrome b5 variation in both species studied. Through CL approach, it was possible to detect oxidative stress as early as 15min in fish and 3h in rats. Also a marked oxidative stress was revealed by the increased CL parameters that at 24h of intoxication was accompanied by arose SOD activity in liver of O. niloticus and Wistar rats and increased TBARS in O. niloticus. In addition, it was possible to show higher levels of oxidative stress in fish compared to the rat in spite of the dose to be four times smaller. Furthermore, CL provide a sensitive method for possible use to detect earlier biological impact in contaminated environments.


Unraveling Ascaris suum experimental infection in humans.
Ascaris lumbricoides and Ascaris suum are two closely related parasites that infect humans and pigs. The zoonotic potential of A. suum has been a matter of debate for decades. Here we sought to investigate the potential human infection by A. suum and its immunological alterations. We orally infected five healthy human subjects with eggs embraced by A. suum. The infection was monitored for symptoms and possible respiratory changes, by an interdisciplinary health team. Parasitological, hematological analyses, serum immunoglobulin, cytokine profiles, and gene expression were evaluated during the infection. Our results show that A. suum is able to infect and complete the cycle in humans causing A. lumbricoides similar symptoms, including, cough, headache, diarrhea, respiratory discomfort and chest x-ray alterations coinciding with larvae migration in the lungs. We also observed activation of the immune system with production of IgM and IgG and a Th2/Th17 response with downregulation of genes related to Th1 and apoptosis. PCA (Principal componts analysis) show that infection with A. suum leads to a change in the immune landscape of the human host. Our data reinforce the zoonotic capacity of A. suum and bring a new perspective on the understanding of the immune response against this parasite.


Thromboangiitis Obliterans Biomarker Shifts in Different Acute Phase Stages: A Case Study.
Thromboangiitis obliterans (TAO) is a rare vasculopathy that is predominantly seen in young male smokers. Recently, new biomarkers have been shown to be useful in distinguishing TAO from acute phase TAO in an Asian study population. The present case study illustrates their application in a European patient during TAO exacerbation and their association with therapeutic performance.


Dictyocaulus viviparus: isolation and characterization of a recombinant antigen with potential for immunodiagnosis.
Crude adult worm antigen of Dictyocaulus viviparus was examined for specific antigens by SDS-PAGE and immunoblotting using sera from cattle experimentally infected with D. viviparus, vaccinated with a normal or a reduced dosage of the commercial lungworm vaccine, and helminth-free cattle. A D. viviparus-specific region M(r) 18,000 was identified and isolated. A lambda ZAP II cDNA expression library consisting of 4.4 x 10(5) recombinant clones (88% of the total number of clones) was constructed from D. viviparus adult worm mRNA. Rabbit antiserum to the M(r) 18,000 antigen was used to screen the cDNA library and eight positive clones were picked and allocated to the same antigenic family by sibling analysis. All clones were subcloned into the plasmid pGEX-2T, and the clone with highest expression yields was expressed as a glutathione S-transferase fusion protein (DvGST3-14) or, after cleavage with thrombin, as pure recombinant parasite protein (Dv3-14). The native parasite antigen encoded by the clone was identified. The immunodiagnostic potential of the recombinant proteins was assessed by immunoblotting.


Blackout 2003: preparedness and lessons learned from the perspectives of four hospitals.
The blackout in North America of August 2003 was one of the worst on record. It affected eight US states and parts of Canada for >24 hours. Additionally, two large US cities, Detroit, Michigan and Cleveland, Ohio, suffered from a loss of water pressure and a subsequent ban on the use of public supplies of potable water that lasted four days. A literature review revealed a paucity of literature that describes blackouts and how they may affect the medical community. This paper includes a review of after-action reports from four inner-city, urban hospitals supplemented accounts from the authors' hospital's emergency operations center (EOC). Some of the problems encountered, included: (1)lighting; (2) elevator operations; (3) supplies of water; (4) communication operations; (5) computer failure; (6) lack of adequate supplies of food; (7) mobility to obtain X-ray studies; (8) heating, air condition, and ventilation; (9) staffing; (10) pharmacy; (11) registration of patients; (12) hospital EOC; (13) loss of isolation facilities; (14) inadequate supplies of paper; (15) impaired ability to provide care for non-emergency patients; (16) sanitation; and (17) inadequate emergency power. The blackout of 2003 uncovered problems within the US hospital system, ranging from staffing to generator coverage. This report is a review of the effects that the blackout and water ban of 2003 had on hospitals in a large inner-city area. Also discussed are solutions utilized at the time and recommendations for the future. The blackout of 2003 was an excellent test of disaster/emergency planning, and produced many valuable lessons to be used in future events.


Recent advances on dual inhibitors targeting HIV reverse transcriptase associated polymerase and ribonuclease H.
Reverse transcriptase (RT) plays an indispensable role in the replication of human immunodeficiency virus (HIV) through its associated polymerase and ribonuclease H (RNase H) activities during the viral RNA genome transformation into proviral DNA. Due to the fact that HIV is a highly mutagenic virus and easily resistant to single-target RT inhibitors, dual inhibitors targeting HIV RT associated polymerase and RNase H have been developed. These dual inhibitors have the advantages of increasing efficacy, reducing drug resistance, drug-drug interactions, and cytotoxicity, as well as improving patient compliance. In this review, we summarize recent advances in polymerase/RNase H dual inhibitors focusing on drug design strategies, and structure-activity relationships and share new insights into developing anti-HIV drugs.


Addressing the Gender Gap in Research: Insights from a Women in Neuroscience Conference.
There has been growing interest in quantifying the proportion of women participating in scientific conferences, publications, and committees. Numbers reveal persistent disparities, but offer few cures to the root causes of the gender gaps in research. Toward remediation, we outline five lessons learned through organizing two conferences for Women in Neuroscience (WiN). These recommendations build on participants' comments, and aim to better support women in their scientific paths and help provide equal opportunity.


The effects of implementing phenomenology in a deep neural network.
There have been several recent attempts at using Artificial Intelligence systems to model aspects of consciousness (Gamez, 2008; Reggia, 2013). Deep Neural Networks have been given additional functionality in the present attempt, allowing them to emulate phenological aspects of consciousness by self-generating information representing multi-modal inputs as either sounds or images. We added these functions to determine whether knowledge of the input's modality aids the networks' learning. In some cases, these representations caused the model to be more accurate after training and for less training to be required for the model to reach its highest accuracy scores.


Sterilization of biological pathogens using supercritical fluid carbon dioxide containing water and hydrogen peroxide.
Novel noninvasive techniques for the removal of biological contaminants to generate clean or sterile materials are in demand by the medical, pharmaceutical and food industries. The sterilization method described here uses supercritical fluid carbon dioxide (SF-CO(2)) containing 3.3% water and 0.1% hydrogen peroxide (v/v/v) to achieve from four to eight log viability reduction of all tested microbial species, including vegetative cells, spores and biofilms. The sterilization method employs moderate pressure and temperature (80 atm, 50°C) and a short (30-minute) treatment time. The procedure kills various opportunistic pathogens that often persist in biofilm structures, fungal spores commonly associated with nosocomial infections, and Bacillus pumilus SAFR-032 endospores that are notoriously hard to eradicate by conventional sterilization techniques.


Striosomes and Matrisomes: Scaffolds for Dynamic Coupling of Volition and Action.
Striosomes form neurochemically specialized compartments of the striatum embedded in a large matrix made up of modules called matrisomes. Striosome-matrix architecture is multiplexed with the canonical direct-indirect organization of the striatum. Striosomal functions remain to be fully clarified, but key information is emerging. First, striosomes powerfully innervate nigral dopamine-containing neurons and can completely shut down their activity, with a following rebound excitation. Second, striosomes receive limbic and cognition-related corticostriatal afferents and are dynamically modulated in relation to value-based actions. Third, striosomes are spatially interspersed among matrisomes and interneurons and are influenced by local and global neuromodulatory and oscillatory activities. Fourth, striosomes tune engagement and the motivation to perform reinforcement learning, to manifest stereotypical behaviors, and to navigate valence conflicts and valence discriminations. We suggest that, at an algorithmic level, striosomes could serve as distributed scaffolds to provide formats of the striatal computations generated through development and refined through learning. We propose that striosomes affect subjective states. By transforming corticothalamic and other inputs to the functional formats of the striatum, they could implement state transitions in nigro-striato-nigral circuits to affect bodily and cognitive actions according to internal motives whose functions are compromised in neuropsychiatric conditions.


The local administration of parathyroid hormone encourages the healing of bone defects in the rat calvaria: Micro-computed tomography, histological and histomorphometric evaluation.
To evaluate the effect of a single-dose local administration of PTH on bone healing in rat calvarial bone defects by means of micro-computed tomography, histological and histomorphometric analysis. Critical-size cranial osteotomy defects were created in 42 male rats. The animals were randomly divided into 3 groups. In the C Group, the bone defect was only filled with a blood clot. In the S Group, it was filled with a collagen sponge and covered with bovine cortical membrane. In the PTH Group, the defect was filled with a collagen sponge soaked with PTH and covered with bovine cortical membrane. The groups were further split in two for euthanasia 15 and 60days post-surgery. Data was statistically analyzed with t-tests for independent samples or the nonparametric Mann-Whitney test when applicable. Intragroup comparisons were analyzed with paired t-tests (p<0.05). Micro-CT analysis results did not demonstrate statistically significant intergroup differences. At 15days post-surgery, the histomorphometric analysis showed that the PTH Group exhibited a significantly higher percentage of bone formation compared with the S Group. At 60days post-surgery, a higher percentage of new bone was observed in the PTH group. The results suggest that the local administration of PTH encouraged the bone healing in critical-size calvarial defects in rats.


Regulation of the organic pollution level in anaerobic digesters by using off-line COD measurements.
A sampled delayed scheme is proposed to regulate the organic pollution level in anaerobic digestion processes by using off-line COD measurements. The proposed scheme is obtained by combining an error feedback control with a steady state estimator to track constant references and attenuate process load disturbances. The controller performance is tested experimentally for the treatment of tequila vinasses over a period of 68days under different set-point values and several uncertain scenarios which include badly known kinetic parameters and load disturbances. Experimental results show that the COD concentration can be effectively regulated under the influence of set-point changes and high load disturbances by using only a daily off-line COD measurement, which makes the industrial application of the proposed control scheme feasible.


'Coexisting pituitary adenoma and suprasellar meningioma-a coincidence or causation effect: report of two cases and review of the literature'.
Coexistence of pituitary adenoma (PA) and another type of brain tumor is a very rare clinical scenario. Even though such a presentation can be an incidental event but a thorough review of the literature will be made to elucidate the possible mechanisms and treatment options in similar cases. Two cases of concomitant sellar and suprasellar/diaphragmatic tumors are reported. A 37-year-old lady with prolactinoma and a suprasellar diaphragmatic meningioma and a 42-year-old acromegalic man with suprasellar/diaphragmatic meningioma and a PA. Both meningiomas were removed transcranially. The prolactinoma could be managed medically and the growth hormone secreting adenoma was removed trans-sphenoidally. The visual problems and hormonal imbalances of both patients improved postoperatively. The literature is reviewed on this topic and the possible pathogenesis and management protocol of similar lesions are discussed.


Sulcal and gyral crown cortical grey matter involvement in multiple sclerosis: A magnetisation transfer ratio study.
Histopathology has demonstrated extensive cortical grey matter (GM) demyelination in multiple sclerosis (MS), and suggests that sulcal folds may be preferentially affected, particularly in progressive MS. This has not been confirmed in vivo, and it is not known if it is relevant to clinical status. To determine sulcal and gyral crown magnetisation transfer ratio (MTR) in MS cortical GM, and the MTR associations with clinical status. We measured sulcal and gyral crown cortical GM MTR values in 61 MS patients and 32 healthy controls. Disability was measured using Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores. MTR values were reduced in sulcal and gyral crown regions in all MS subtypes, more so in secondary progressive (SP) MS than relapsing remitting (RR) MS, and similarly in primary progressive (PP) MS and RRMS. Sulcal MTR was lower than gyral crown MTR in controls, PPMS and RRMS patients, but not in SPMS. MTR correlated with clinical status in RRMS and SPMS, but not PPMS. Cortical pathology, as reflected by MTR, is present in all MS subtypes and most pronounced in SPMS. A preferential disease effect on sulcal cortical regions was not observed. Cortical MTR abnormalities appear to be more clinically relevant in relapse-onset rather than progressive-onset MS.


[Fast determination of polybrominated diphenyl ethers in human milk using gas chromatography-negative chemical ionization/mass spectrometry].
A method for the quantitative determination of 8 polybrominated diphenyl ethers (PBDEs) in human milk was established using gas chromatography-negative chemical ionization/mass spectrometry (GC-NCI/MS). After extraction by Soxhlet extractor, the lipid in the extract was removed by acidic silica, and the analyte was further purified by the multilayer silica-alumina column. The concentrations of BDE28, BDE47, BDE99, BDE100, BDE153, BDE154, BDE183 and BDE209 in human milk were fast determined by GC-NCI/MS in selected ion monitoring (SIM) mode on a 7 m column. The quantitative analysis was performed by isotope dilution method for BDE209 and internal standard method for other PBDEs. The limits of detection (LODs) of PBDEs in the lipid ranged from 1.74 to 6.35 pg/g. The recoveries of the spiked PBDEs were between 61.5% and 108% and their relative standard deviations (RSDs) (n = 6) were between 2.06% and 10.1%. The method was further validated by the analysis of the reference materials of human milk. It was demonstrated that it is a low cost, rapid and reliable alternative for the trace analysis of selected PBDEs, especially for BDE209 in human milk.


The caveolin-1 binding domain of HIV-1 glycoprotein gp41 is an efficient B cell epitope vaccine candidate against virus infection.
Caveolin-1 is a scaffolding protein that organizes and concentrates specific ligands within the caveolae membranes. We identified a conserved caveolin-1 binding motif in the HIV-1 transmembrane envelope glycoprotein gp41 and designed several synthetic peptides, referred to as CBD1, corresponding to the consensus caveolin-1 binding domain in gp41. In rabbits, these peptides elicit the production of antibodies that inhibit infection of primary CD4(+) T lymphocytes by various primary HIV-1 isolates. Interestingly, gp41 exists as a stable complex with caveolin-1 in HIV-infected cells. Anti-CBD1 peptide antibodies, therefore, might be functional by inhibiting the potential interaction of gp41 with caveolin-1. Because of their capacity to elicit antibodies that inhibit the different clades of HIV-1, CBD1-based peptides may represent a novel synthetic universal B cell epitope vaccine candidate for HIV/AIDS. Moreover, such peptides could also have an application as a therapeutic vaccine since CBD1-specific antibodies are rare in HIV-infected individuals from several geographic origins.


Analysis and prediction of COVID-19 trajectory: A machine learning approach.
The outbreak of Coronavirus 2019 (COVID-19) has impacted everyday lives globally. The number of positive cases is growing and India is now one of the most affected countries. This paper builds predictive models that can predict the number of positive cases with higher accuracy. Regression-based, Decision tree-based, and Random forest-based models have been built on the data from China and are validated on India's sample. The model is found to be effective and will be able to predict the positive number of cases in the future with minimal error. The developed machine learning model can work in real-time and can effectively predict the number of positive cases. Key measures and suggestions have been put forward considering the effect of lockdown.


Severe coarctation of the aorta without a severely elevated echocardiographic pressure gradient: a case highlighting the importance of aortic Doppler flow profile.
An asymptomatic 5-year-old male was diagnosed with severe coarctation of the aorta despite normal peak flow velocity with pathology identified on the basis of Doppler flow profile.


The factors affecting the distribution of babesiosis in dogs in Poland.
The aim of this paper was to determine the factors affecting the development of canine babesiosis in Poland. The studies included 800 animals from 16 polish voivodeships-districts (50 from each voivodeship) with suspected piroplasmosis. Hematological and molecular tests confirmed infections in 158 animals. Analysis of the genetic material using the Real-Time Sybr Green HRM technique showed that 96 dogs were infected with Babesia canis 18S RNA-A and 62 with B. canis 18S RNA-B. It was observed that the disease occurs more often in eastern Poland (OR: 8.91; CI: 5.7-13.8), in males (OR: 1.04; CI: 0.7-1.5) and especially in rural areas (OR: 1.7; CI: 1.2-2.4). More prone to infection were pure-bred dogs (OR: 2.24; CI: 1.6-3.2), young animals under 1 year old (OR: 0.73; CI: 0.4-1.5), animals that had suffered from babesiosis in the past (OR: 17.9; CI: 10.9-29.2) and those that had not received preventive measures against ectoparasites (OR: 0.32; CI: 0.2-0.5). Knowledge of the factors facilitating the development of canine babesiosis helps to understand the causal connection between the dogs' exposure to the pathogen and the development of the disease and to limit the occurrence of the infection in these animals, to diagnose it early and to start proper treatment before serious complications develop.


Traumatic Atlantoaxial Dislocation with Type II Odontoid Fractures: A Case Report.
Odontoid fracture frequently ensues after a cervical trauma, and most commonly at the junction between the dens and the body (type II odontoid fracture). This report is focused on a 24-years-old male patient with right-sided hemiparesis, resulting from traumatic atlantoaxial dislocation with type II odontoid fracture. Cervical CT-scanning showed a spondylolisthesis of the C1-C2 complex with type II odontoid fracture, and the injury was treated using posterior reduction and internal stabilization. Therefore, hemiparesis was reduced, and during the follow-up period, our patients were disease-free. Early diagnosis and the appropriate management of atlantoaxial trauma is a possible approach towards preventing severe neurological deficits.


Dental sex dimorphism: Using odontometrics and digital jaw radiography.
Estimating the gender from the human skeletal remains can guide the forensic investigator in revealing the missing person's identity. (1) To determine the utility of the various parameters taken on the orthopantomographs (mandible) and of odontometrics on tooth remains to estimate the gender. (2) To determine the most dimorphic parameter taken on the radiograph as well as tooth (odontometrics) in the study taken. (1) A retrospective study was planned on 200 subjects (100 males and 100 females) in the age group of 18-30 years and the following parameters (maximum ramus height, bigonion width, and bicondylar breadth) were measured on the orthopantomograph. (2) A prospective clinical study was planned on 200 subjects (100 males and 100 females) in the age group of 18-30 years, to measure the mesio-distal width of permanent maxillary central incisors and canines directly in the patient's mouth, using Digital Vernier calipers. The mean, range, and standard deviation were calculated for each variable in the study. The Z-score test was done to find out the magnitude of sexual dimorphism for each parameter in each part of the study. Maximum ramus height proved to be the most dimorphic parameter depicting the utility of mandible for the estimation of gender of the deceased. Permanent maxillary central incisor proved to be more dimorphic than the maxillary canines, depicting it to be population specific. Measurements taken on the mandible proved to be useful in the estimation of gender of the deceased. In cases of fragmentary or missing mandible, odontometrics can be used. Hence, teeth proved to be an adjunct tool in the determination of gender of the deceased.


"A prospective study of assessment of neurocognitive function in illiterate patients with gliomas treated with chemoradiation": Assessment of neurocognitive function in gliomas.
Neurocognitive functioning (NCF) is an important component of quality of life (QoL) in glioma patients. The neurocognitive toxicity from irradiation of brain tumours may be related to damage to neural progenitor cells (NPC). The aim of our study was to assess the NCF in illiterate glioma patients. This was a prospective study done in glioma patients admitted for adjuvant treatment. Illiterate and semiliterate post op glioma patients with ECOG PS ≤ 3 were included. Neurocognitive assessment was done using Addenbrooke's Cognitive Examination (ACE-III) questionnaire prior to the start of RT and at 6month and 12 month follow up. The scores were correlated to the doses to sub ventricular zone (SVZ) and sub granular zone (SGZ) regions. 20 patients were recruited.16 patients were illiterate and four patients were semiliterate. Median of the mean dose to the SVZ I/L (ipsilateral) was 48.5 Gy and SGZ I/L was 39.5 Gy. In patients who received ≤49 Gy mean dose to SVZ I/L, there was statistically significant improvement in memory, fluency, language and total ACE scores at six months. In patients with SGZ I/L mean dose ≤40 Gy, there was improvement in memory, language, and total ACE score at six months. Similar trend continued at 12 months follow up. NCF assessment by ACE III questionnaire is a useful tool even in illiterate patients. Lower RT doses to the ipsilateral SVZ and SGZ showed significant improvement in total ACE scores at 6 months and improvement in specific domains at 6 and 12 months.


Conjoint cognitive and emotional death-preparedness states and their changes within cancer patients' last 6 months.
Cognitive prognostic awareness (PA) and emotional preparedness for death are distinct but related concepts that have rarely been investigated conjointly and without considering the dynamic nature of death preparedness. To fill this gap, this secondary-analysis study identified distinct patterns/states of death preparedness and their changes within cancer patients' last 6 months. Distinct death-preparedness states, determined by conjoint cognitive PA and emotional preparedness for death, as well as their changes between consecutive times were identified and estimated, respectively, by latent transition modeling with hidden Markov modeling among 383 cancer patients within their last 6 months. Four death-preparedness states (prevalence) were initially identified: no death preparedness (17.1%), cognitive death preparedness only (23.3%), emotional death preparedness only (39.9%), and sufficient death preparedness (19.7%). Patients in the no-death-preparedness state had neither accurate PA nor adequate emotional preparedness for death. The sufficient-death-preparedness state was characterized by both accurate PA and adequate emotional preparedness for death. In the cognitive- and emotional-death-preparedness-only states, patients were accurately aware of their prognosis and adequately emotionally prepared for their forthcoming death only, respectively. As death approached, state prevalence fluctuated within a narrow range for the no- and sufficient-death-preparedness states, whereas prevalence of cognitive- and emotional-death-preparedness-only states increased and decreased substantially, respectively. Cancer patients heterogeneously experienced conjoint cognitive PA and emotional preparedness for death, and prevalence of death-preparedness states changed substantially as death approached. Effective interventions are warranted to cultivate cognitive PA and facilitate emotional death-preparedness to improve end-of-life-care quality, thereby helping patients achieve a good death.


Neutrophils delay repair process in Wallerian degeneration by releasing NETs outside the parenchyma.
Although inflammation is indispensable for the repair process in Wallerian degeneration (WD), the role of neutrophils in the WD repair process remains unclear. After peripheral nerve injury, neutrophils accumulate at the epineurium but not the parenchyma in the WD region because of the blood-nerve barrier. An increase or decrease in the number of neutrophils delayed or promoted macrophage infiltration from the epineurium into the parenchyma and the repair process in WD. Abundant neutrophil extracellular traps (NETs) were formed around neutrophils, and its inhibition dramatically increased macrophage infiltration into the parenchyma. Furthermore, inhibition of either MIF or its receptor, CXCR4, in neutrophils decreased NET formation, resulting in enhanced macrophage infiltration into the parenchyma. Moreover, inhibiting MIF for just 2 h after peripheral nerve injury promoted the repair process. These findings indicate that neutrophils delay the repair process in WD from outside the parenchyma by inhibiting macrophage infiltration via NET formation and that neutrophils, NETs, MIF, and CXCR4 are therapeutic targets for peripheral nerve regeneration.


Association between stress and bilateral symmetrical alopecia in free-ranging Formosan macaques in Mt. Longevity, Taiwan.
Since 2013, a high incidence of bilateral symmetrical alopecia has been observed in free-ranging Formosan macaques (Macaca cyclopis) in Mt. Longevity, Taiwan. We hypothesized that stress induces alopecia in this population. To verify our hypothesis, we evaluated the histopathological characteristics of skin biopsy and used a validated enzyme immunoassay (EIA) for fecal glucocorticoid metabolite (FGM) analysis, which act as an indicator of stress experienced by the individual. Follicular densities were lower (2.1-3.0 mm2) in individuals with symmetrical alopecia than in those with normal hair conditions (4.7 mm2). Furthermore, anagen to catagen/telogen ratios were lower in individuals with alopecia (0-1.4) than in those with normal hair (4.0). The histopathological characteristics of alopecia were similar to those of telogen effluvium, which indicates that stress is one of the possible etiologies. On the basis of the analytical and biological validation of EIAs for FGM analysis, 11β-hydroxyetiocholanolone was considered suitable for monitoring adrenocortical activity in both sexes of Formosan macaques. The mean concentrations (standard error; sample size) of 11β-hydroxyetiocholanolone were 2.02 (0.17; n = 10) and 1.41 (0.10; n = 31) μg/g for individuals with and without alopecia, respectively. Furthermore, the results of logistic regression analysis show that 11β-hydroxyetiocholanolone (p = 0.012) concentration was positively associated with alopecia. Thus, stress was the most likely to trigger symmetrical alopecia in Formosan macaques in Mt. Longevity. Although stress can decrease the fitness of an individual, considering the population status of Formosan macaques in Taiwan is stable and alopecia was only observed in our study area, which is isolated from other populations, the impact on the total population of Formosan macaque in Taiwan is limited. Nonetheless, stress-induced immunosuppression and alopecia might affect the local abundance and increase zoonosis risk due to frequent human-macaque contact in Mt. Longevity. Future studies are suggested to focus on the causative factor of stress and the effects of stress and alopecia on the health and welfare in the Formosan macaques.


Primary low-grade B-cell lymphoma of MALT-type occurring in the liver: a study of two cases.
Primary non-Hodgkin's lymphomas of the liver are rare. One specific clinico-pathological entity has been identified as hepatosplenic gamma/delta T-cell lymphoma. Recently, another distinct primary lymphoma of the liver has been recognised as primary low-grade hepatic B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), based on a study comprising four cases. We analysed two additional cases of this particular non-Hodgkin's lymphoma, not only by morphology and phenotyping, but also by genotyping and cytogenetic analysis. This type of non-Hodgkin's lymphoma is characterised by a dense lymphoid infiltrate, localised in the portal tracts, and is associated with lympho-epithelial lesions of the bile ducts, thereby mimicking hepatitis or an inflammatory bile duct disorder. In one of our cases, translocation t(3;14)(q27;q32) was identified as the sole cytogenetic abnormality. A high incidence of trisomy 3 has been associated with marginal zone B-cell lymphomas, and fluorescence in situ hybridisation as well as comparative genomic hybridisation studies have shown frequent involvement of the long arm of chromosome 3. Nevertheless, t(3;14)(q27;q32) involving BCL6 gene, located at 3q27, has not yet been found. Our findings suggest a role for the BCL6 gene in the histogenesis of this particular lymphoma.


Click chemistry inspired one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles and their Src kinase inhibitory activity.
Two classes of 1,4-disubstituted 1,2,3-triazoles were synthesized using one-pot reaction of α-tosyloxy ketones/α-halo ketones, sodium azide, and terminal alkynes in the presence of aq PEG (1:1, v/v) using the click chemistry approach and evaluated for Src kinase inhibitory activity. Structure-activity relationship analysis demonstrated that insertion of C(6)H(5)- and 4-CH(3)C(6)H(4)- at position 4 for both classes and less bulkier aromatic group at position 1 in class 1 contribute critically to the modest Src inhibition activity (IC(50) = 32-43 μM) of 1,4-disubstituted 1,2,3-triazoles.


AICAR and Compound C regulate food intake independently of AMP-activated protein kinase in lines of chickens selected for high or low body weight.
AMP-activated protein kinase (AMPK) functions to maintain cellular and body energy balance. Our aim was to investigate the effect of intracerebroventricular (ICV) administration of AMPK stimulator AICAR and AMPK inhibitor Compound C on food intake in lines of chickens that had undergone long-term selection from a common founder population for high (HWS) or low (LWS) body weight. AICAR caused a quadratic dose-dependent decrease in food intake in LWS but not HWS chicks. Compound C caused a quadratic dose-dependent increase in food intake in HWS but not in LWS chicks. Key aspects of the AMPK pathway, including upstream kinases mRNA expression, AMPK subunit α mRNA expression and phosphorylation, and a downstream target acetyl CoA carboxylase (ACC) phosphorylation were not affected by either AICAR or Compound C in either line. The exception was a significant inhibitory effect of AICAR on ACC phosphorylation ratio due to increased total ACC protein content without changing phosphorylated ACC protein levels. Thus, the anorexigenic effect of AICAR in LWS chicks and orexigenic effect of Compound C in HWS chicks resulted from activation or inhibition of other kinase pathways separate from AMPK. These results suggest genetic variation in feeding response for central AICAR and Compound C in chickens, which may contribute to the different body weights between the HWS and LWS lines.


Role of Receptor Interacting Protein (RIP) kinases in cancer.
The Receptor Interacting Protein (RIP) kinase family consists of seven Serine/Threonine kinases, which plays a key signaling role in cell survival and cell death. Each RIP family member contains a conserved kinase domain and other domains that determine the specific kinase function through protein-protein interactions. RIP1 and RIP3 are best known for their critical roles in necroptosis, programmed necrosis and a non-apoptotic inflammatory cell death process. Dysregulation of RIP kinases contributes to a variety of pathogenic conditions such as inflammatory diseases, neurological diseases, and cancer. In cancer cells, alterations of RIP kinases at genetic, epigenetic and expression levels are frequently found, and suggested to promote tumor progression and metastasis, escape of antitumor immune response, and therapeutic resistance. However, RIP kinases can be either pro-tumor or anti-tumor depending on specific tumor types and cellular contexts. Therapeutic agents for targeting RIP kinases have been tested in clinical trials mainly for inflammatory diseases. Deregulated expression of these kinases in different types of cancer suggests that they represent attractive therapeutic targets. The focus of this review is to outline the role of RIP kinases in cancer, highlighting potential opportunities to manipulate these proteins in cancer treatment.


High-resolution magnetic resonance imaging in isolated, traumatic oculomotor nerve palsy: A case report.
Traumatic, isolated oculomotor nerve palsy is a rare clinical finding and only few reports demonstrate associated magnetic resonance imaging (MRI) findings. Here, we present the case of a 70-year-old woman with left-sided oculomotor nerve palsy following a mild head trauma due to an e-bike accident. Post-traumatic cerebral computed tomography revealed punctiform hemorrhage in the left interpeduncular cistern and the following MRI confirmed an intraneural hemorrhage of the left oculomotor nerve. Nine weeks later, the follow-up MRI showed progressive atrophy and contrast-enhancement of the left oculomotor nerve. To support functional recovery, a treatment with intravenous corticosteroids was started. Six months later, the patient presented with improved oculomotor nerve function and partial recovery of ptosis and diplopia. In accordance, MRI demonstrated recurrent contrast-enhancement of the atrophic nerve. In conclusion, high-resolution MRI allows the reliable delineation of the oculomotor nerve and can support diagnosis in trauma patients with isolated oculomotor nerve palsy.


[Problems applying DIN EN 12780 for the detection of Pseudomonas aeruginosa in water from natural swimming pools and surface water].
Pseudomonas aeruginosa (P. aeruginosa) is a relevant pathogen to bathers and, therefore, water from natural swimming pools is analyzed for its presence. P. aeruginosa can be detected regularly in surface waters. Currently the methods described in DIN EN 12780 are recommended for the quantitative analysis of water from natural swimming pools, although this standard was developed for bottled water. The present study examines whether the recommendation is satisfactory. In 93 water samples from five natural swimming pools (Naturschwimmteiche), 3226 presumptive P. aeruginosa colonies were detected. Of the 3226 colonies, 101 were directly confirmed due to their formation of pyocyanin. From the remaining 3125 colonies, 349 representative samples were isolated and examined further. Using the criteria of DIN EN 12780 fluorescense and ammonia formation from acetamide, another 45 colonies were considered to be P. aeruginosa. 71% (32) of these 45 non-pyocyanin-forming strains could not be confirmed by the APINE system. None of the 32 strains grew at 42 degrees C, which is a characteristic feature of P. aeruginosa as mentioned in a note of DIN EN 12780. In 20 of the original samples, P. aeruginosa numbers exceeded the recommended limit value of 10/100 ml. Eleven cases (55 %) were caused by P. aeruginosa, which were not confirmed taxonomically. Due to insufficient selectivity, the method according to DIN EN 12780 is not applicable for the testing of surface waters and water from natural swimming pools. The high number of false positive results for P. aeruginosa questions the standard even further. It is suggested that for surface water samples growth of P. aeruginosa at 42 degrees C has to be checked as an additional confirmation characteristics of P. aeruginosa until a reliable standard is published.


Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia.
Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte-monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.