Modelling the field personnel resources to control foot-and-mouth disease outbreaks in New Zealand.
The objective of the study was to simulate New Zealand's foot-and-mouth disease (FMD) operational plan to determine personnel requirements for an FMD response and understand how the numbers of front-line staff available could affect the size and duration of FMD outbreaks, when using stamping-out (SO) measures with or without vaccination. The model utilized a national dataset of all known livestock farms. Each simulation randomly seeded infection into a single farm. Transmission mechanisms included direct and indirect contacts, local and airborne spread. Prior to each simulation, the numbers of personnel available for front-line tasks (including contact tracing, surveillance of at-risk farms, depopulation and vaccination) were set randomly. In a random subset of simulations, vaccination was allowed to be deployed as an adjunct to SO. The effects of personnel numbers on the size and duration of epidemics were explored using machine learning methods. In the second stage of the study, using a subset of iterations where numbers of personnel were unconstrained, the number of personnel used each day were quantified. When personnel resources were unconstrained, the 95th percentile and maximum number of infected places (IPs) were 78 and 462, respectively, and the 95th percentile and maximum duration were 69 and 217 days, respectively. However, severe constraints on personnel resources allowed some outbreaks to exceed the size of the UK 2001 FMD epidemic which had 2026 IPs. The number of veterinarians available had a major influence on the size and duration of outbreaks, whereas the availability of other personnel types did not. A shortage of veterinarians was associated with an increase in time to detect and depopulate IPs, allowing for continued transmission. Emergency vaccination placed a short-term demand for additional staff at the start of the vaccination programme, but the overall number of person days used was similar to SO-only strategies. This study determined the optimal numbers of front-line personnel required to implement the current operational plans to support an FMD response in New Zealand. A shortage of veterinarians was identified as the most influential factor to impact disease control outcomes. Emergency vaccination led to earlier control of FMD outbreaks but at the cost of a short-term spike in demand for personnel. In conclusion, a successful response needs to have access to sufficient personnel, particularly veterinarians, trained in response roles and available at short notice.


Multicenter Comparison of the Safety and Efficacy of Clopidogrel Versus Ticagrelor for Neuroendovascular Stents.
Dual antiplatelet therapy (DAPT) is commonly employed for neuroendovascular stenting due to the significant risk of thromboembolism. Clopidogrel and aspirin are most often selected as initial DAPTs; however, there is limited literature available to support guidance of DAPT in this setting. The objective of this study was to evaluate safety and efficacy in patients whose final regimen included either DAPT with aspirin and clopidogrel (DAPT-C) or DAPT with aspirin and ticagrelor (DAPT-T). This was a multicenter, retrospective cohort of patients who underwent neuroendovascular stenting and received DAPT between July 1, 2017, and October 31, 2020. Study participants were allocated into groups based on discharge DAPT regimen. The primary outcome was incidence of stent thrombosis at 3-6 months on DAPT-C versus DAPT-T, as defined by the presence of thrombus on imaging or new onset stroke. Secondary outcomes included major and minor bleeding and death within 3-6 months after the procedure. Five hundred and seventy patients were screened across 12 sites. Of those, 486 were included (DAPT-C n = 360, DAPT-T n = 126). There was no difference in the primary outcome of stent thrombosis between the DAPT-C and DAPT-T groups (8% vs. 8%, p = 0.97) and no difference in any of the secondary safety outcomes. Using DAPT-C or DAPT-T regimens in a broad population of neuroendovascular stenting procedures appears to have similar safety and efficacy profiles. Further prospective evaluation is warranted to streamline the practice of DAPT selection and monitoring to determine the impact on clinical outcomes.


One-Year All-Cause Mortality of Patients Diagnosed as Having In-Hospital Pulmonary Embolism After Modern Elective Joint Arthroplasty Is Low And Unaffected By Radiologic Severity.
We studied the 1-year complication rate of patients diagnosed as having a pulmonary embolism (PE) after elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) surgery and the distribution of emboli in the pulmonary circulation, and determined if a relationship exists between the location of the PE and age, gender, body mass index, preoperative predisposing factors, American Society of Anesthesiology classification, type of surgery, prophylaxis, hospital stay, transfer to a higher level of care, and mortality. Two hundred sixty-nine patients who developed an in-hospital PE proved by computed tomography pulmonary angiography after elective THA or TKA between 2005 and 2012 were studied. The most proximal location of the emboli was central in 62, segmental in 139, and subsegmental in 68. Nineteen patients (7%) developed a bleeding complication during PE treatment. Twenty-nine patients (11%) were readmitted during the first year. Two patients (0.74%) died: one had a segmental PE after TKA. He died 11 months after surgery due to an autopsy-proven sepsis. The second patient developed a segmental PE after THA. She was anticoagulated, developed an intracranial bleed, and died 8 months after surgery. Multivariate analysis showed that demographic variables, American Society of Anesthesiology class, preoperative comorbidities (with the exception of arrhythmia), and the presence of preoperative predisposing factors had no effect in the location of the PE. The 1-year mortality rate of these patients is low. Death can be caused by bleeding complications secondary to anticoagulation or by unrelated conditions. This information may aid clinicians while counseling patients who developed a PE after surgery, particularly those with small subsegmental emboli.


Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase.
TWINKLE is a nucleus-encoded human mitochondrial (mt)DNA helicase. Point mutations in TWINKLE are associated with heritable neuromuscular diseases characterized by deletions in the mtDNA. To understand the biochemical basis of these diseases, it is important to define the roles of TWINKLE in mtDNA metabolism by studying its enzymatic activities. To this end, we purified native TWINKLE from Escherichia coli. The recombinant TWINKLE assembles into hexamers and higher oligomers, and addition of MgUTP stabilizes hexamers over higher oligomers. Probing into the DNA unwinding activity, we discovered that the efficiency of unwinding is greatly enhanced in the presence of a heterologous single strand-binding protein or a single-stranded (ss) DNA that is complementary to the unwound strand. We show that TWINKLE, although a helicase, has an antagonistic activity of annealing two complementary ssDNAs that interferes with unwinding in the absence of gp2.5 or ssDNA trap. Furthermore, only ssDNA and not double-stranded (ds)DNA competitively inhibits the annealing activity, although both DNAs bind with high affinities. This implies that dsDNA binds to a site that is distinct from the ssDNA-binding site that promotes annealing. Fluorescence anisotropy competition binding experiments suggest that TWINKLE has more than one ssDNA-binding sites, and we speculate that a surface-exposed ssDNA-specific site is involved in catalyzing DNA annealing. We propose that the strand annealing activity of TWINKLE may play a role in recombination-mediated replication initiation found in the mitochondria of mammalian brain and heart or in replication fork regression during repair of damaged DNA replication forks.


Lipoteichoic acids from Staphylococcus aureus stimulate proliferation of human non-small-cell lung cancer cells in vitro.
Pulmonary infections are frequent complications in lung cancer and may worsen its outcome and survival. Inflammatory mediators are suspected to promote tumor growth in non-small-cell lung cancer (NSCLC). Hence, bacterial pathogens may affect lung cancer growth by activation of inflammatory signalling. Against this background, we investigated the effect of purified lipoteichoic acids (LTA) of Staphylococcus aureus (S. aureus) on cellular proliferation and liberation of interleukin (IL)-8 in the NSCLC cell lines A549 and H226. A549 as well as H226 cells constitutively expressed TLR-2 mRNA. Even in low concentrations, LTA induced a prominent increase in cellular proliferation of A549 cells as quantified by automatic cell counting. In parallel, metabolic activity of A549 cells was enhanced. The increase in proliferation was accompanied by an increase in IL-8 mRNA expression and a dose- and time-dependent release of IL-8. Cellular proliferation as well as the release of IL-8 was dependent on specific ligation of TLR-2. Interestingly, targeting IL-8 by neutralizing antibodies completely abolished the LTA-induced proliferation of A549 cells. The pro-proliferative effect of LTA could also be reproduced in the squamous NSCLC cell line H226. In summary, LTA of S. aureus induced proliferation of NSCLC cell lines of adeno- and squamous cell carcinoma origin. Ligation of TLR-2 followed by auto- or paracrine signalling by endogenously synthesized IL-8 is centrally involved in LTA-induced tumor cell proliferation. Therefore, pulmonary infections may exert a direct pro-proliferative effect on lung cancer growth.


Mesoscopic surfactant organization and membrane protein crystallization.
The paucity of detailed X-ray crystallographic structures of integral membrane proteins arises from substantive technical obstacles in the overexpression of multimilligram quantities of protein, and in the crystallization of purified protein-detergent complexes (PDCs). With rare exception, crystal contacts within the lattice are mediated by protein-protein interaction, and the detergent surrounding the protein behaves as a disordered solvent. The addition and use of surfactants that display mesoscopic self-assembly behavior in membrane protein crystallization experiments presents a novel alternative strategy. Well-ordered crystals of the water channel human aquaporin-1 (hAQP1) that diffract to 4 A resolution have been obtained with this approach.


Associations do not energize behavior: on the forgotten legacy of Kurt Lewin.
Hundred years ago, Kurt Lewin published a series of articles in which he vehemently argued against the idea that associations between stimuli and responses motivate behavior. This article reviews his empirical work and theory and the cogency of Lewin's conclusion according to modern standards. We conclude that Lewin's criticism of the contiguity principle of associationism is still valid, and is now supported by a broad range of theories on learning, motivation, and action control. Implications for modern dual-system theory and modern theories on motivated action and (instructed) task sets are discussed.


Neoliberalism and its implications for mental health in the UK.
This article sets out to outline the tenets of neoliberalism and globalization, prior to the identification of the implications of neoliberalism for the British health system since 1979. The article then focuses on the applications and implications of neoliberalism for the British mental health system in terms of service organization and management, and the impact these changes in direction had on the three existing service sectors: users, carers and professionals. The discussion and the conclusion highlight the significance of these developments in the mental health system in the rather hybrid context of health, mental health, and social care policy and practice in the United Kingdom.


Synthesis and characterization of ZnO nanostructures using palm olein as biotemplate.
A green approach to synthesize nanomaterials using biotemplates has been subjected to intense research due to several advantages. Palm olein as a biotemplate offers the benefits of eco-friendliness, low-cost and scale-up for large scale production. Therefore, the effect of palm olein on morphology and surface properties of ZnO nanostructures were investigated. The results indicate that palm olein as a biotemplate can be used to modify the shape and size of ZnO particles synthesized by hydrothermal method. Different morphology including flake-, flower- and three dimensional star-like structures were obtained. FTIR study indicated the reaction between carboxyl group of palm olein and zinc species had taken place. Specific surface area enhanced while no considerable change were observed in optical properties. Phase-pure ZnO particles were successfully synthesized using palm olein as soft biotemplating agent by hydrothermal method. The physico-chemical properties of the resulting ZnO particles can be tuned using the ratio of palm olein to Zn cation.


Tandem Domains with Tuned Interactions Are a Powerful Biological Design Principle.
Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation. In a cell, there are many copies of the same protein, all experiencing these perturbations in a dynamic fashion and fluctuating through different conformations and activity states. According to the "conformational selection and population shift" theory, ligand binding selects a particular conformation. This perturbs the ensemble and induces a population shift. In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the "Double-Conformational Selection Model", which demonstrates how two tandem ligand-binding domains interact to regulate protein function. Here we explain how tandem domains with tuned interactions-but not single domains-can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control.


Spatial pattern and environmental drivers of breast cancer incidence in Chinese women.
Breast cancer (BC) had the highest incidence of all cancers in Chinese women. However, studies on spatial pattern and environmental drivers of BC were still lacked as they were either limited in a small area or few considered the comprehensive impact of multiple risk factors. In this study, we firstly performed spatial visualization and the spatial autocorrelation analysis based on Chinese women breast cancer incidence (BCI) data of 2012-2016. Then, we explored the environmental drivers related to BC by applying univariate correlation analysis and geographical detector model. We found that the BC high-high clusters were mainly distributed in the eastern and central regions, such as Liaoning, Hebei, Shandong, Henan, and Anhui Provinces. The BCI in Shenzhen was significantly higher than other prefectures. Urbanization rate (UR), per capita GDP (PGDP), average years of school attainment (AYSA), and average annual wind speed (WIND) had higher explanatory power on spatial variability of the BCI. PM10, NO2, and PGDP had significant nonlinear enhanced effect on other factors. Besides, normalized difference vegetation index (NDVI) was negatively associated with BCI. Therefore, high socioeconomic status, serious air pollution, high wind speed, and low vegetation cover were the risk factors for BC. Our study may able to provide evidence for BC etiology research and precise identification of areas requiring focused screening.


[Clinical study on effect of bushen shengxue paste in treating renal anemia patients].
To evaluate the therapeutical mechanism of Bushen Shengxue Paste (BSSXP) on anemia. Chronic renal failure induced anemia patients were treated with BSSXP, clinical manifestation, anemia and renal function as indicators were observed in patients. The erythropoietin (EPO) and inhibition of colony-forming unit-erythrocyte (CFU-E) in patients' serum were determined by CFU-E in vitro. The patients' symptoms, renal function and anemia were improved after administration with BSSXP 1-2 course. EPO in serum was slightly increased. The inhibition of CFU-E in patient's serum was significantly decreased. BSSXP could improve the anemia degree, its mechanism might be through clearing the inhibitor of CFU-E in serum.


Hyperexcitability and impaired intracortical inhibition in patients with fragile-X syndrome.
Fragile-X syndrome (FXS) is characterized by neurological and psychiatric problems symptomatic of cortical hyperexcitability. Recent animal studies identified deficient γ-aminobutyricacid (GABA) inhibition as a key mechanism for hyperexcitability in FXS, but the GABA system remains largely unexplored in humans with the disorder. The primary objective of this study was to assess GABA-mediated inhibition and its relationship with hyperexcitability in patients with FXS. Transcranial magnetic stimulation (TMS) was used to assess cortical and corticospinal inhibitory and excitatory mechanisms in 18 patients with a molecular diagnosis of FXS and 18 healthy controls. GABA-mediated inhibition was measured with short-interval intracortical inhibition (GABAA), long-interval intracortical inhibition (GABAB), and the corticospinal silent period (GABAA+B). Net intracortical facilitation involving glutamate was assessed with intracortical facilitation, and corticospinal excitability was measured with the resting motor threshold. Results showed that FXS patients had significantly reduced short-interval intracortical inhibition, increased long-interval intracortical inhibition, and increased intracortical facilitation compared to healthy controls. In the FXS group, reduced short-interval intracortical inhibition was associated with heightened intracortical facilitation. Taken together, these results suggest that reduced GABAA inhibition is a plausible mechanism underlying cortical hyperexcitability in patients with FXS. These findings closely match those observed in animal models, supporting the translational validity of these markers for clinical research.


Analysis of smoking and LPO in ALS.
Smoking has been suggested as one of the risk factor for amyotrophic lateral sclerosis (ALS) development. In order to investigate whether adverse effects of cigarette smoke in ALS have any association with increase in oxidative stress, disease severity, lipid hydroperoxides (LPO) and superoxide dismutase-1 (SOD1) levels were measured in biofluids of smoker and never smoker ALS patients and clinically correlated. Serum and CSF from sporadic ALS patients (n=50) diagnosed with El Escorial criteria were collected in the study. Serum (n=50) and CSF (n=42) were also collected from normal healthy controls. The LPO levels were estimated using commercially available kits. Enzyme-linked immunosorbent assays (ELISAs) were used to quantitate SOD1. Their levels were further analyzed among smoker and never smoker subjects. Significantly elevated LPO in sera and CSF of ALS patients were observed (p<0.05). There was considerably increased LPO in sera and CSF of smoker ALS subjects matched with disease severity as compared to never smoker ALS (p<0.05). ALS group did not show any alteration in SOD1 when compared to controls (p>0.05). In addition, no change has been observed in SOD1 levels in ALS subjects who smoke (p>0.05). Increased LPO and unaltered SOD1 in ALS patients may suggest the neuro-pathological association of LPO with ALS disease independent of SOD1. With current findings, it may be proposed that LPO levels might constitute as probable biomarker for smoker ALS patients, however, it cannot be concluded without larger gender matched studies. Additional investigations are needed to determine whether LPO upregulation is primary or secondary to motor neuron degeneration in ALS.


Efficacy and Safety of Leuprolide Acetate 6-Month Depot for the Treatment of Central Precocious Puberty: A Phase 3 Study.
Treatment options for central precocious puberty (CPP) are important for individualization of therapy. We evaluated the efficacy and safety of 6-month 45-mg leuprolide acetate (LA) depot with intramuscular administration. LA depot was administered at weeks 0 and 24 to treatment-naïve (n = 27) or previously treated (n = 18) children with CPP in a phase 3, multicenter, single-arm, open-label study (NCT03695237). Week 24 peak-stimulated luteinizing hormone (LH) suppression (<4 mIU/mL) was the primary outcome. Secondary/other outcomes included basal sex hormone suppression (girls, estradiol <20 pg/mL; boys, testosterone <30 ng/dL), suppression of physical signs, height velocity, bone age, patient/parent-reported outcomes, and adverse events. All patients (age, 7.8 ± 1.27 years) received both scheduled study doses. At 24 weeks, 39/45 patients (86.7%) had LH suppressed. Six were counted as unsuppressed; 2 because of missing data, 3 with LH of 4.35-5.30 mIU/mL and 1 with LH of 21.07 mIU/mL. Through 48 weeks, LH, estradiol, and testosterone suppression was achieved in ≥86.7%, ≥97.4%, and 100%, respectively (as early as week 4 for LH and estradiol and week 12 for testosterone). Physical signs were suppressed at week 48 (girls, 90.2%; boys, 75.0%). Mean height velocity ranged 5.0 to 5.3 cm/year post-baseline in previously treated patients and declined from 10.1 to 6.5 cm/year at week 20 in treatment-naïve patients. Mean bone age advanced slower than chronological age. Patient/parent-reported outcomes remained stable. No new safety signals were identified. No adverse event led to treatment discontinuation. Six-month intramuscular LA depot demonstrated 48-week efficacy with a safety profile consistent with other GnRH agonist formulations.


Detection and quantification of breast arterial calcifications on mammograms: a deep learning approach.
Breast arterial calcifications (BAC) are a sex-specific cardiovascular disease biomarker that might improve cardiovascular risk stratification in women. We implemented a deep convolutional neural network for automatic BAC detection and quantification. In this retrospective study, four readers labelled four-view mammograms as BAC positive (BAC+) or BAC negative (BAC-) at image level. Starting from a pretrained VGG16 model, we trained a convolutional neural network to discriminate BAC+ and BAC- mammograms. Accuracy, F1 score, and area under the receiver operating characteristic curve (AUC-ROC) were used to assess the diagnostic performance. Predictions of calcified areas were generated using the generalized gradient-weighted class activation mapping (Grad-CAM++) method, and their correlation with manual measurement of BAC length in a subset of cases was assessed using Spearman ρ. A total 1493 women (198 BAC+) with a median age of 59 years (interquartile range 52-68) were included and partitioned in a training set of 410 cases (1640 views, 398 BAC+), validation set of 222 cases (888 views, 89 BAC+), and test set of 229 cases (916 views, 94 BAC+). The accuracy, F1 score, and AUC-ROC were 0.94, 0.86, and 0.98 in the training set; 0.96, 0.74, and 0.96 in the validation set; and 0.97, 0.80, and 0.95 in the test set, respectively. In 112 analyzed views, the Grad-CAM++ predictions displayed a strong correlation with BAC measured length (ρ = 0.88, p < 0.001). Our model showed promising performances in BAC detection and in quantification of BAC burden, showing a strong correlation with manual measurements. Integrating our model to clinical practice could improve BAC reporting without increasing clinical workload, facilitating large-scale studies on the impact of BAC as a biomarker of cardiovascular risk, raising awareness on women's cardiovascular health, and leveraging mammographic screening. • We implemented a deep convolutional neural network (CNN) for BAC detection and quantification. • Our CNN had an area under the receiving operator curve of 0.95 for BAC detection in the test set composed of 916 views, 94 of which were BAC+ . • Furthermore, our CNN showed a strong correlation with manual BAC measurements (ρ = 0.88) in a set of 112 views.


GABA-like immunoreactivity in the chick basilar papilla and the lagenar macula.
Gamma-aminobutyric acid (GABA)-like immunoreactivity in the chick basilar papilla and lagenar macula was studied by using anti-serum against GABA coupled with glutaraldehyde to bovine serum albumin. GABA-like immunoreactivity was localized selectively in the cytoplasm of both tall and short hair cells in the basilar papilla, and in the hair cell cytoplasm of the lagenar macula. This immunocytochemical finding suggests that GABA may be an afferent neurotransmitter from the hair cell to the primary afferent neuron in the auditory organs of avians and is consistent with previous findings which suggest that GABA may act as an afferent neurotransmitter in the avian vestibular organs as well. However, the distribution pattern of GABA-like immunoreactivity in the afferent system is quite different from the distribution pattern previously described in the mammalian inner ear where GABA-like immunoreactivity is found exclusively within the efferent system.


Comprehensive profiling of phenolic compounds by HPLC-DAD-ESI-QTOF-MS/MS to reveal their location and form of presence in different sorghum grain genotypes.
In this study, comprehensive profiling of the phenolic compounds in sorghum grain was achieved by analysing the free and bound extracts of sorghum bran and kernel fractions from five Australian sorghum genotypes (1 white, 2 red, 1 brown and 1 black coloured), using HPLC-DAD-ESI-QTOF-MS/MS. A total of 110 phenolic compounds were annotated, out of which 56 were reported for the first time in sorghum grain. Compounds with matched authentic standards were quantified/semi-quantified. Multiple factor analysis (MFA) was performed and heatmaps generated, which provided direct visualisation of the distribution of individual phenolic compounds/subclasses between the sorghum samples. The results indicated that phenolic compounds were concentrated on the bran, and free and bound extracts had different phenolic composition. The phenolic compound/subclass profile varied greatly among sorghum genotypes. Brown sorghum genotype (IS131C) had the highest concentration of total phenolic contents, and the bran fraction of brown sorghum had the most abundant and diverse phenolic composition among all tested samples. This study provides the most comprehensive phenolic profile of Australian representative sorghum grains up to date.


Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area.
To examine the integrity of sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO) in postmortem brains of narcolepsy type 1 patients. Postmortem examination of five narcolepsy and eight control brains. VLPO galanin neuron count did not differ between narcolepsy patients (11,151 ± 3,656) and controls (13,526 ± 9,544). A normal number of galanin-immunoreactive VLPO neurons in narcolepsy type 1 brains at autopsy suggests that VLPO cell loss is an unlikely explanation for the sleep fragmentation that often accompanies the disease.


The politics of abortion: a historical perspective.
An analysis of the capture of the Republican party and the national agenda from the late 1970s into the 1990s by a coalition of political and religious conservatives.


Thrombolytic therapy for acute ischemic stroke: why the majority of patients remain ineligible for treatment.
Thrombolytic therapy has been advocated as an effective treatment for acute ischemic stroke. In an attempt to promote maximum benefit while reducing the risk of hemorrhagic complications, numerous exclusions to the use of thrombolytic therapy for acute ischemic stroke have been promulgated. This study was conducted to identify the number of acute ischemic stroke patients eligible for thrombolytic therapy and to determine the reasons those deemed ineligible were excluded. This observational study was conducted from September 15, 1996, to May 1, 1997, at an emergency department with an annual census of 70,000. Patients with a chief complaint suggestive of acute ischemic stroke were categorized as "eligible" if thrombolytic therapy was not contraindicated and could be initiated within 3 hours of symptom onset. Patients were deemed "ineligible" if the time to thrombolytic therapy would have exceeded 3 hours, or if other specific contraindications to thrombolytic therapy were present. For all categories, 95% confidence intervals (95% CI) were determined. Of the 214 patients with acute ischemic stroke who were screened, 6 (2.8%+/-2.2%) were eligible. Ninety-five patients (44%+/-7%) were excluded solely on the basis of the time interval from onset of symptoms to eligibility for thrombolytic therapy exceeding 3 hours. Other common reasons for exclusion included resolution of symptoms in 31 patients (14%+/-4%), intracranial hemorrhage as determined by head computed tomography in 22 (10%+/-4%), and minor symptoms in 20 (9%+/-4%). The majority of acute ischemic stroke patients do not meet accepted criteria for thrombolytic therapy. Most are ineligible because of delays in obtaining treatment. Strategies should be devised to reduce the time to treatment if thrombolytic therapy is to achieve widespread use in the treatment of acute ischemic stroke.


Phase I study of 5-fluorouracil and leucovorin by a 14-day circadian infusion in metastatic adenocarcinoma patients.
Initial experimental and clinical studies have indicated that 5-fluorouracil (5-FU) toxicity can be reduced by delivering 5-FU at around 4 a.m. More recent data have suggested that the toxicity might be reduced even more with delivery at around 9-10 p.m. The current study determined the maximum tolerated dose (MTD) for 5-FU and leucovorin (LV) delivered as a continuous circadian infusion over 14 days every 28 days, with the peak of the infusion occurring at around 3-4 a.m. The peak drug delivery was shifted to 9-10 p.m. in all patients developing toxicity of > or = grade II (Eastern Cooperative Oncology Group) to determine if this timing further reduced toxicity and enabled increased dose intensity. A total of 14 patients with metastatic adenocarcinoma received an admixture of 5-FU and LV via a programmable portable infusion pump, with 62.5% of the 24-h dose being given over 7 h around the infusion peak. The starting dose level of 5-FU (200 mg/m2 daily) and LV (5 mg/m2 daily) was that established as the highest tolerable dose rate in a previously reported phase I study using a 14-day flat infusion of 5-FU and LV. The LV dose was first escalated to 20 mg/m2 daily, followed by escalations of the 5-FU dose. A total of 51 courses were evaluable for toxicity. The dose-limiting toxicity was oral mucositis and hand-foot syndrome. More dose intensity could be delivered using a circadian infusion peaking at around 3-4 a.m. than was possible with a flat infusion of these drugs. Toxicity was reduced even further with peak drug delivery at around 9-10 p.m. The recommended dose for phase II studies using this schedule is 250 mg/m2 5-FU daily and 20 mg/m2 LV daily with the peak of the infusion occurring at 9-10 p.m. This is a 300% and 25% higher dose for LV and 5-FU, respectively, than was found to be safe for a flat infusion.


Bibliometric analysis of the scientific production as regards statin use for ophthalmological symptoms of myasthenia gravis.
The first symptoms of myasthenia gravis (MG) usually involve weakness of the ocular muscles, making it relevant that ophthalmologists have updated information on studies as regards its relationship with the consumption of drugs, such as statins. A bibliometric analysis was performed using the Scopus database and by a search strategy in the selection of documents containing descriptors related to statins in the «Title» («TI») field and the descriptors «ophthalm *', «myast *', «visual *' in other fields of the document (period 1986-2015). The results showed that, while the number of scientific publications on ocular effects of statins has grown lineally (n=838; y=2.267x-4507.1; r=0.7221; time of duplication: 4.66 years, and rate of annual growth: 50.06%), the specific publications about MG have experienced an exponential growth (n=38; y=2E-262e0.3001x; r=0.3892; time of duplication: 2.95 years, and rate of annual growth: 46.25%) without reaching the saturation postulated in Price theory of the expansion of the scientific literature. The majority of publications relating to MG are reports of cases linked to a worsening of the MG symptoms, and simvastatin and atorvastatin are the agents mentioned in most of the publications. These results should enable ophthalmologists to expand their knowledge concerning the evolution of studies on statins and MG, pointing out the relevance of such causal relationships.


Effect of compound Kushen injection on T-cell subgroups and natural killer cells in patients with locally advanced non-small-cell lung cancer treated with concomitant radiochemotherapy.
To observe effect of compound Kushen injection on T-cell subgroups and NK cells in patients with locally advanced non-small-cell lung cancer (NSCLC) treated with concomitant radiochemotherapy. We randomly divided 60 patients with locally advanced NSCLC who were treated at our hospital between May 2011 and May 2013 into a treatment group and a control group by drawing. The treatment group (n = 30) received concomitant radiochemotherapy plus compound Keshen injection, and the control group (n = 30) received only radiochemotherapy. After treatment, levels of CD3+, CD4+, CD4+/CD8+ and CD16+/CD56+ cells had significantly increased, and CD8+ cells had significantly decreased, in the treatment group compared with both their pretreatment levels and with levels in the control group. In the control group, post-treatment levels of CD3 +, CD4 +, CD4 +/CD8 + and CD16+/CD56+ cells were not significantly changed from pretreatment levels. The two groups did not significantly differ in their rates of toxicity reactions (P> 0.05). Compound Kushen injections can increase immunologic function in patients with locally advanced non-small cell lung cancer who receive concomitant radiochemotherapy.


BOARD-FTD-PACC: a graphical user interface for the synaptic and cross-frequency analysis derived from neural signals.
In order to understand the link between brain functional states and behavioral/cognitive processes, the information carried in neural oscillations can be retrieved using different analytic techniques. Processing these different bio-signals is a complex, time-consuming, and often non-automatized process that requires customization, due to the type of signal acquired, acquisition method implemented, and the objectives of each individual research group. To this end, a new graphical user interface (GUI), named BOARD-FTD-PACC, was developed and designed to facilitate the visualization, quantification, and analysis of neurophysiological recordings. BOARD-FTD-PACC provides different and customizable tools that facilitate the task of analyzing post-synaptic activity and complex neural oscillatory data, mainly cross-frequency analysis. It is a flexible and user-friendly software that can be used by a wide range of users to extract valuable information from neurophysiological signals such as phase-amplitude coupling and relative power spectral density, among others. BOARD-FTD-PACC allows researchers to select, in the same open-source GUI, different approaches and techniques that will help promote a better understanding of synaptic and oscillatory activity in specific brain structures with or without stimulation.


Regulation of the TCRalpha repertoire by the survival window of CD4(+)CD8(+) thymocytes.
T cell receptor (TCR) alpha alleles undergo primary and secondary rearrangement in double-positive (DP) thymocytes. By analyzing TCRalpha rearrangement in orphan nuclear receptor RORgamma-deficient mice, in which the DP lifespan is shorter, and in Bcl-x(L)-transgenic mice, in which the DP lifespan is extended, we show that the progression of secondary V(alpha) to J(alpha) rearrangements is controlled by DP thymocyte survival. In addition, because Bcl-x(L) induces a bias towards 3' J(alpha) usage in peripheral T cells, we conclude that the programmed cell death of DP thymocytes is not simply a consequence of failed positive selection. Rather, it limits the progression of rearrangement along the J(alpha) locus and the opportunities for positive selection, thereby regulating the TCRalpha repertoire.


A mutation in mannose-phosphate-dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy.
Congenital disorders of glycosylation type I (CDG-I) are inborn errors of metabolism, generally characterized by multisystem clinical manifestations, including developmental delay, hepatopathy, hypotonia, and skin, skeletal, and neurological abnormalities. Among others, dolichol-phosphate-mannose (DPM) is the mannose donor for N-glycosylation as well as O-mannosylation. DOLK-CDG, DPM1-CDG, DPM2-CDG, and DPM3-CDG are defects in the DPM synthesis showing both CDG-I abnormalities and reduced O-mannosylation of alpha-dystroglycan (αDG), which leads to muscular dystrophy-dystroglycanopathy. Mannose-phosphate-dolichol utilization defect 1 (MPDU1) plays a role in the utilization of DPM. Here, we report two MPDU1-CDG patients without skin involvement, but with massive dilatation of the biliary duct system and dystroglycanopathy characteristics including hypotonia, elevated creatine kinase, dilated cardiomyopathy, buphthalmos, and congenital glaucoma. Biochemical analyses revealed elevated disialotransferrin in serum, and analyses in fibroblasts showed shortened lipid linked oligosaccharides and DPM, and reduced O-mannosylation of αDG. Thus, MPDU1-CDG can be added to the list of disorders with overlapping biochemical and clinical abnormalities of CDG-I and dystroglycanopathy. Mannose-phosphate-dolichol utilization defect 1 patients can have overlapping biochemical and clinical abnormalities of congenital disorders of glycosylation type I and dystroglycanopathy.


Influence of parotid-sparing radiotherapy on xerostomia in head and neck cancer patients.
Radiotherapy (RT) for head and neck cancers causes permanent salivary gland dysfunction (SGD) and xerostomia. We have previously demonstrated the effectiveness of parotid-sparing RT on salivary function. The aim of this was to characterize the relationship between radiation dosages to parotid glands, SGD, xerostomia, and impaired quality of life (QOL). Ninety-three patients received unilateral (n=38) and bilateral (n=44) neck RT with parotid-sparing techniques, or standard three-field technique RT (n=11). Unstimulated and stimulated parotid saliva was collected pre-RT and 1 year post-RT. Assessment of QOL and xerostomia was conducted with three questionnaires. The results demonstrated that reduced radiation dosages to parotid glands were strongly associated with percentage of baseline parotid flow rates measured at 1 year post-RT. Unilateral and bilateral neck RT with parotid-sparing techniques were successful in preserving salivary output, compared to standard three beam RT techniques. Lower radiation dose to contralateral parotid glands was associated with greater percentage of baseline salivary flow rates at 1 year post-RT, fewer xerostomic complaints, and an enhanced QOL.


[Skin lesions in small mammals parasitized by Psorergates apodemi and P. dissimilis (Gheyletoidea: Psorergatidae)].
Histopathology in the sites of localization and parasiting of the mites Psorergates apodemi Fain et al., 1966 and P. dissimilis Fain et al., 1966 on the Ural field mouse Apodemus uralensis (Pallas) and the bank vole Clethrionomys glareolus (Schreber) is described. The mites affected all epidermis cell layers down to the cambium layer and caused hyperkeratosis.


Fenestration of bone flap during decompressive craniotomy for subdural hematoma.
Persistent/recurrent extra-axial hemorrhage may occur after decompression of a subdural hematoma (SDH) followed by an immediate replacement of bone flap. A fenestration of the bone flap may encourage extra-axial fluid absorption; however, the literature has not explored this technique. Forty-four consecutive patients who underwent surgical decompression of SDH with immediate replacement of bone flap were divided into two groups: Fenestration (F), n = 33, and no fenestration (NF), n = 11. Fenestration involves placement of twist drill holes 1-2 cm apart throughout the bone flap. Clinical data (age, sex, history of antiplatelet/anticoagulation [AA], and presence of drains) were collected. The size of bone flap, postoperative volume, and midline shift (MLS) were measured. A univariate analysis was performed for continuous variables; Fisher's exact test was performed for categorical variables. For postoperative volume, NF group exhibited 94.4 ± 15.5 cm(3), while F group exhibited 47.3 ± 15.5 cm(3) (P = 0.04); no AA exhibited 62.9 ± 12.3 cm(3), while AA exhibited 100.5 ± 19.0 cm(3) (P = 0.07); no drains exhibited 110.1 ± 29.6 cm(3), while drains exhibited 63.0 ± 9.1 cm(3) (P = 0.14). For postoperative MLS, NF group exhibited 4.8 ± 1.1 mm, while F group exhibited 2.5 ± 1.1 mm (P = 0.16); no AA exhibited 2.3 ± 1.0 mm, while AA exhibited 5.8 ± 1.4 mm (P = 0.048); no drains exhibited 4.6 ± 2.2 mm, while drains exhibited 3.8 ± 0.7 mm (P = 0.70). Accounting for fenestration status and AA status: For F group, AA status did not correlate with postoperative volume or MLS significantly; for NF group, history of AA exhibited higher postoperative value 129.2 ± 26.5 cm(3), compared to no history of AA at 59.5 ± 16.2 cm(3) (P = 0.03). Our results suggest that fenestration prior to the immediate replacement of bone flap after surgical decompression of SDH has the potential to reduce extra-axial fluid accumulation.


The European Health Union: European Union's Concern about Health for All. Concepts, Definition, and Scenarios.
The COVID-19 pandemic brought visibility and intensified the discussions on the European Union's (EU) health mandate. The proposals of the European Commission (EC) to move towards a European Health Union (EHU) can be seen as a starting point towards more integration in health. However, the definition of what the EHU will look like is not clear. This paper searches to find a common definition, and/or features for this EHU through a systematic literature review performed in May 2021. "European Union's concern about health for all" is suggested as a definition. The main drivers identified to develop an EHU are: surveillance and monitoring, crisis preparedness, funding, political will, vision of public health expenditures, population's awareness and interest, and global health. Based on these findings, five scenarios were developed: making a full move towards supranational action; improving efficiency in the actual framework; more coordination but no real change; in a full intergovernmentalism direction; and fragmentation of the EU. The scenarios show that the development of a EHU is possible inside the current legal framework. However, it will rely on increased coordination and has a focus on cross-border health threats. Any development will be strongly linked to political choices from Member States.


A baseline study of microplastics in the burrowing crab (Neohelice granulata) from a temperate southwestern Atlantic estuary.
Growing evidence has demonstrated that microplastics (MPs) are available for a wide range of marine organisms, with filter-feeding bivalves and crabs being especially vulnerable. The crab Neohelice granulata is considered a key and structuring species in the Bahía Blanca Estuary (BBE) (SW Atlantic) and its ecological role makes this species especially vulnerable to several pollutants. In this study, male specimens of N. granulata and water samples were collected at three sites in the BBE for the presence of MPs. Different types of MPs were found in all the crabs and the water column samples, although the most frequent were fibers <500-1500 μm, mainly blue. This is the first study to identify MPs in the gills and digestive tract of N. granulata. Moreover, gills presented higher total abundances of MPs than the digestive tract, which suggests that in this case the main uptake of MPs would be by adherence to the gills.


Stability of arterial to end-tidal carbon dioxide gradients during postoperative cardiorespiratory support.
The changes in the arterial to end-tidal carbon dioxide gradient. P(a-ET)CO2, were studied in postoperative cardiac surgery patients from the time of admission to the intensive care unit, during changing cardiorespiratory support, up to the time of tracheal extubation. Individual factors evaluated for their effects on P(a-ET)CO2 included rate of mechanical ventilation, infusion of vasoactive agents (nitroglycerin, nitroprusside, dopamine, dobutamine, and metariminol), and associated changes in haemodynamic pathophysiology (cardiac index, pulmonary artery pressure, pulmonary vascular resistance index, systemic vascular resistance index, and pulmonary capillary wedge pressure). After approval by the Clinical Investigation Committee, 59 patients, age 63 +/- 9 (41 to 75) yr, were studied and 382 individual gradient determinations made. Mean P(a-ET)CO2 was 5.47 +/- 5.21 mmHg, with the mean PaCO2, 36.51 +/- 5.89 mmHg and mean ETCO2, 31.04 +/- 6.44 mmHg. For the population as a whole, the correlation between PaCO2 and ETCO2 determined by regression analysis was maintained (R = 0.644, P less than 0.001). Comparison of the individual and population correlation coefficients by Student's t test showed no significant difference, but a normal population distribution of the gradients (P less than 0.05). None of the variables assessed could be determined to influence P(a-ET)CO2 significantly. For many of the individual patients, however, the relationship between PaCO2 and ETCO2 did not maintain a significant correlation throughout the study period. In the postoperative cardiac surgery patient population P(a-ET)CO2 follows a normal distribution and PaCO2 and ETCO2 maintain a statistically significant correlation. However, when evaluating individual patients, this relationship has wide variability.


Long-term course of surgically induced astigmatism after a 5.0 mm sclerocorneal valve incision.
To study surgically induced astigmatism (SIA) after a sutureless 5.0 mm sclerocorneal valve incision. Department of Ophthalmology, University of Vienna, Vienna, Austria. This study evaluated SIA in 34 cases of sutureless cataract surgery with a 5.0 mm superior sclerocorneal valve incision and implantation of a poly(methyl methacrylate) intraocular lens. Keratometry was measured with a Zeiss keratometer in all cases preoperatively, and 1 day, 1 week, 1 and 3 months, and 1 and 5 years postoperatively. Surgically induced astigmatism, calculated by Cravy's vector analysis, showed an initial mean with-the-rule shift of 0.35 diopter (D), followed by an against-the-rule shift to a mean of -0.30 D after 1 month. One year postoperatively, mean SIA was -0.46 D. Between 1 and 5 years postoperatively, there was a statistically significant increase in mean SIA calculated by Cravy's vector analysis; SIA increased from -0.46 D after 1 year to -0.76 D after 5 years postoperatively. A small, although statistically significant, amount of postoperatively induced astigmatism occurred 5 years after a sutureless 5.0 mm sclerocorneal valve incision.


Quantitative evaluation of myocardial stress/rest 201TL SPECT: results of a ROI-based method in 108 patients with CHD.
ROI-based polar maps (33 ROIs) were employed to evaluate quantitatively stress/rest myocardial 201Tl SPECT in 108 patients with angiographically proven coronary heart disease (CHD) in comparison with 30 controls. Sensitivity in detecting a CHD with stenoses of greater than 50% of luminal diameter was determined versus normal regional values (+/- 2.5 SD) employing vitality (VI) and wash-out corrected redistribution (RD). The method was evaluated referring to the severity of the disease, to the number of ROIs displaying changes [(a) 1 ROI, (b) greater than 2 ROIs], to validity of VI, RD or a combination thereof, and for specificity. Wash-out values were found to depend on degree of stress individually achieved and thus were not used as a threshold criterion. Sensitivity in supply areas with old myocardial infarctions was 95% (a) and 86% (b), resp. With no infarction, it was 96% (a) and 79% (b), resp. VI in stenosis greater than 75% was more sensitive than RD. However, combined evaluation of VI and RD yielded sensitivities from 91-100% (a) and 77-94% (b), resp. for different main supply areas. In stenosis less than 50% with normal VI, RD was positive in 18-31%. Specificity turned out to be 91% (a) and 97% (b), resp. We conclude that the method presented is reliable to quantify numerically 201Tl kinetics in myocardial SPECT, aimed at detecting and describing CHD.


Interleukin 1 inhibits T cell receptor-mediated apoptosis in immature thymocytes.
T cell receptor signaling has been implicated in an intrathymic process of cell selection in which potentially harmful autoreactive precursors are deleted before they emigrate to the periphery. Recent work has shown that immature thymocytes undergo apoptosis, or programmed cell death, upon stimulation via the T cell antigen receptor, and it has been suggested that this mechanism may mediate deletion of the self-reactive clones during T cell development. Here we report that the accessory cell-derived T cell growth hormone interleukin-1 prevents T cell receptor-mediated thymocyte apoptosis by a mechanism that appears to involve protein kinase C activation. This effect may be relevant to the positive signaling that spares the appropriate precursors during the generation of functional T lymphocytes.


Identification of scaffold proteins for improved endogenous engineering of extracellular vesicles.
Extracellular vesicles (EVs) are gaining ground as next-generation drug delivery modalities. Genetic fusion of the protein of interest to a scaffold protein with high EV-sorting ability represents a robust cargo loading strategy. To address the paucity of such scaffold proteins, we leverage a simple and reliable assay that can distinguish intravesicular cargo proteins from surface- as well as non-vesicular proteins and compare the EV-sorting potential of 244 candidate proteins. We identify 24 proteins with conserved EV-sorting abilities across five types of producer cells. TSPAN2 and TSPAN3 emerge as lead candidates and outperform the well-studied CD63 scaffold. Importantly, these engineered EVs show promise as delivery vehicles in cell cultures and mice as demonstrated by efficient transfer of luminal cargo proteins as well as surface display of different functional entities. The discovery of these scaffolds provides a platform for EV-based engineering.


Coexistence of two chromatin structures in sperm nuclei of the bivalve mollusc Protothaca thaca.
The chromatin of the spermatozoa from the bivalve mollusc Protothaca thaca, has a peculiar composition in which coexist core histones with sperm-specific proteins H1 and Pt1, the latter being a protein exhibiting features intermediate between histones and protamines. In this paper, we report an analysis of chromatin organization using micrococcal nuclease digestion, salt fractionation of soluble chromatin derived from nuclease digestion and crosslinking experiments. The results obtained indicate that it is possible to obtain two types of chromatin, one which is soluble, more accessible to micrococcal nuclease action and which does not contain Pt1, and another insoluble type, more resistant to micrococcal nuclease and enriched in protein Pt1. The crosslinking experiments show that the protein Pt1 interacts with itself and with core histones but not with sperm-specific H1. These results have led us to propose a special structural arrangement for this chromatin. Based in the data reported here we propose the coexistence in the genome of P. thaca of two interspersed chromatin domains, one nucleosomal and the other nonnucleosomal containing protein Pt1.


Assuring safety without animal testing: the case for the human testis in vitro.
From 15 to 17 June 2011, a dedicated workshop was held on the subject of in vitro models for mammalian spermatogenesis and their applications in toxicological hazard and risk assessment. The workshop was sponsored by the Dutch ASAT initiative (Assuring Safety without Animal Testing), which aims at promoting innovative approaches toward toxicological hazard and risk assessment on the basis of human and in vitro data, and replacement of animal studies. Participants addressed the state of the art regarding human and animal evidence for compound mediated testicular toxicity, reviewed existing alternative assay models, and brainstormed about future approaches, specifically considering tissue engineering. The workshop recognized the specific complexity of testicular function exemplified by dedicated cell types with distinct functionalities, as well as different cell compartments in terms of microenvironment and extracellular matrix components. This complexity hampers quick results in the realm of alternative models. Nevertheless, progress has been achieved in recent years, and innovative approaches in tissue engineering may open new avenues for mimicking testicular function in vitro. Although feasible, significant investment is deemed essential to be able to bring new ideas into practice in the laboratory. For the advancement of in vitro testicular toxicity testing, one of the most sensitive end points in regulatory reproductive toxicity testing, such an investment is highly desirable.


Empty follicle syndrome after GnRHa triggering versus hCG triggering in COS.
This study aimed to explore the incidence of empty follicle syndrome (EFS) in oocyte donors who had final oocyte maturation triggered with GnRHa and to compare the incidence of EFS in this group of patients with IVF patients who had final oocyte maturation with hCG. Data including 2034 oocyte donation cycles and 1433 IVF cycles performed between years 2009 and 2010 was retrospectively analyzed to identify cases of EFS in each group. The incidence of EFS in the two groups did not differ significantly, 3.5% versus 3.1%, (n.s.). This large retrospective analysis indicates that the incidence of EFS is not increased after GnRHa triggering as compared to hCG triggering.


Monitoring dendritic cell and cytokine biomarkers during remission prior to relapse in patients with FLT3-ITD acute myeloid leukemia.
Relapse occurs frequently after treatment of acute myeloid leukemia (AML) patients with the FMS-like tyrosine kinase 3-internal tandem duplication (ITD) mutation. The availability of immunologic biomarkers to predict patients at high risk could allow clinicians to accelerate alternative treatments such as stem cell transplantation, immunotherapy, or novel drugs. We have previously reported that first diagnostic (FD) ITD(+) AML showed immunophenotypic and functional characteristics of arrested dendritic cell (DC) precursors. In this study, we show that the high frequency of precursor DCs in 16 FD ITD(+) AML samples (Lin(-)/HLA-DR(+)/CD11c(+)/CD123(+)) was associated with a lack of terminal DCs (myeloid DCs: BDCA-1(+) or BDCA-3(+); plasmacytoid DC: BDCA-2(+)). We further evaluated prospectively the peripheral blood complete remission (CR) samples obtained from 11 ITD(+) AML patients after chemotherapy regarding the frequency of DCs and their pattern of cytokine production. Whereas the aberrant frequencies of precursor and terminal plasmacytoid DCs resolved during remission, the myeloid DC compartment did not fully recover. For an available cohort of patients (n = 4) who could be monitored over a period of >15 months after FD, we identified IL-10, TNF-α, IL-6, and IL-1β as cytokines produced by the CR samples at high levels a few months prior to relapse. Cell-free supernatant of an FD ITD(+) AML sample stimulated monocytes obtained from two healthy donors to secrete IL-10, TNF-α, IL-6, and IL-1β. Thus, we hypothesize that ITD(+) AML minimal residual disease can act directly as dysfunctional antigen-presenting cells or indirectly by production of factors that convert monocytes into myeloid-derived suppressor cells secreting cytokines that promote immune evasion. Monitoring these immunologic biomarkers could improve prediction of relapse.


Micro- and nanofibrillated cellulose from virgin and recycled fibers: A comparative study of its effects on the properties of hygiene tissue paper.
This study aims to understand the effect of micro- and nanofibrillated cellulose (MNFC) on the tensile index, softness, and water absorbency of tissue paper. MNFC was produced from four different fiber sources. The results show that MNFC acts as an effective strength enhancer at the expense of a reduced water absorbency and softness. The impact of the fiber source on MNFC manufacturing cost and the trade-off with performance was also investigated. MNFCs produced from southern bleached hardwood kraft, northern bleached softwood kraft, and deinked pulp exhibited similar performance trends with the MNFC from the deinked pulp having a significantly lower cost. This suggests that MNFCs with similar degrees of fibrillation may be used interchangeably regardless of the fiber source, revealing the possibility to minimize MNFC manufacturing costs based on fiber selection. MNFC produced from bleached Eucalyptus kraft showed the lowest degree of fibrillation and the lowest strength improvements among the MNFCs evaluated.


Effects of Triton WR 1339 and orotic acid on lipid metabolism in rats.
In order to investigate the effect of hepatic cholesterol flux on biliary bile acids, Triton WR 1339 and orotic acid were administered to rats, and the biliary cholesterol, phospholipids and bile acids were analyzed together with serum lipoproteins and hepatic lipids. Triton, which raised serum very low density lipoprotein and lipid levels and decreased serum high density lipoprotein liver lipid levels, increase the biliary cholic acid group/chenodeoxycholic acid group ratio (CA/CDCA) in the bile without affecting the total amount of bile acids and the other biliary lipids. Orotic acid, which decreased serum lipid and lipoprotein concentrations and increased liver lipid levels, increased the biliary excretion of cholesterol and phospholipids, but produced no significant change in the total amount of bile acids and in the CA/CDCA ratio in bile.


Accurate prediction of histological grading of intraductal papillary mucinous neoplasia using deep learning.
Risk stratification and recommendation for surgery for intraductal papillary mucinous neoplasm (IPMN) are currently based on consensus guidelines. Risk stratification from presurgery histology is only potentially decisive owing to the low sensitivity of fine-needle aspiration. In this study, we developed and validated a deep learning-based method to distinguish between IPMN with low grade dysplasia and IPMN with high grade dysplasia/invasive carcinoma using endoscopic ultrasound (EUS) images. For model training, we acquired a total of 3355 EUS images from 43 patients who underwent pancreatectomy from March 2015 to August 2021. All patients had histologically proven IPMN. We used transfer learning to fine-tune a convolutional neural network and to classify "low grade IPMN" from "high grade IPMN/invasive carcinoma." Our test set consisted of 1823 images from 27 patients, recruiting 11 patients retrospectively, 7 patients prospectively, and 9 patients externally. We compared our results with the prediction based on international consensus guidelines. Our approach could classify low grade from high grade/invasive carcinoma in the test set with an accuracy of 99.6 % (95 %CI 99.5 %-99.9 %). Our deep learning model achieved superior accuracy in prediction of the histological outcome compared with any individual guideline, which have accuracies between 51.8 % (95 %CI 31.9 %-71.3 %) and 70.4 % (95 %CI 49.8-86.2). This pilot study demonstrated that deep learning in IPMN-EUS images can predict the histological outcome with high accuracy.


Post-rejection ureteral obstruction owing to ureteral adherence to graft inferior pole.
We describe 2 renal transplant patients with increasing plasma creatinine levels after resolution of acute rejection episodes. Antegrade pyelography demonstrated adherence of the ureter to the inferior pole of the kidney with partial obstruction in both cases, which was confirmed at operation.


Association of select vitamin D receptor gene polymorphisms with the risk of tobacco-related cancers - a meta-analysis.
The observed increase in morbidity and mortality due to tobacco-related cancers, especially those in the respiratory system and esophagus, is becoming a public health challenge. Smoking cigarettes is one of the main risk factors predisposing individuals to many types of cancers. The aim of this study was to determine the role of select vitamin D receptor (VDR) gene polymorphisms as risk factors in tobacco-related cancers. The MEDLINE and ResearchGate databases were used to search for articles up to June 2017, and 12 articles including 26 studies concerning FokI, ApaI, TaqI and BsmI polymorphisms and lung, neck, head, esophageal and oral cancers were chosen. In total, 5 113 cases and 5 657 controls were included in the pooled analysis. We found a significant relationship between tobacco-related cancers and the occurrence of the "t" allele in the TaqI polymorphism of VDR. The occurrence of the "t" allele reduced the risk of tobacco-related cancers by 17% (OR = 0.83, 0.72-0.96 95% CI, p-value = 0.0114). Our analysis revealed that there is a correlation between the TaqI polymorphism of VDR and the risk of tobacco-related cancers.


Connected speech markers of amyloid burden in primary progressive aphasia.
Positron emission tomography (PET) amyloid imaging has become an important part of the diagnostic workup for patients with primary progressive aphasia (PPA) and uncertain underlying pathology. Here, we employ a semi-automated analysis of connected speech (CS) with a twofold objective. First, to determine if quantitative CS features can help select primary progressive aphasia (PPA) patients with a higher probability of a positive PET amyloid imaging result. Second, to examine the relevant group differences from a clinical perspective. 117 CS samples from a well-characterised cohort of PPA patients who underwent PET amyloid imaging were collected. Expert consensus established PET amyloid status for each patient, and 40% of the sample was amyloid positive. Leave-one-out cross-validation yields 77% classification accuracy (sensitivity: 74%, specificity: 79%). Our results confirm the potential of CS analysis as a screening tool. Discriminant CS features from lexical, syntactic, pragmatic, and semantic domains are discussed.


Long-term clinical outcomes of statin use for chronic heart failure: a meta-analysis of 15 prospective studies.
The effect of statin treatment on the long-term prognosis in patients with chronic heart failure (CHF) remains uncertain. This study aimed to answer the question by a meta-analysis. The Cochrane databases, MEDLINE and EMBASE, were systematically searched. The eligibility of prospective studies that assigned CHF patients to receive statin treatment and a control (no statin treatment), had defined prognostic outcomes as primary endpoint, and had a minimal follow-up of 12 months was determined. Fifteen studies involving 45,110 patients were included in the analysis. Additional statin treatment was associated with reduced all-cause mortality (risk ratios [RR] = 0.71, 95% confidence intervals [CI] 0.61-0.83) and reduced rehospitalisation rate for heart failure (RR = 0.84, 95% CI 0.74-0.96). Statin treatment, however, had little impact on pump failure mortality, cardiovascular mortality, and sudden cardiac death. Atorvastatin treatment appeared to facilitate to reduce all-cause mortality (lnRR = 0.61, p = 0.05) and rehospitalisation for heart failure (lnRR = 0.44, p = 0.04) compared with non-atorvastatin therapy. Based on the available data, statins persistently decreased all-cause mortality and the incidence of rehospitalisation for heart failure in CHF patients, and the benefits might be partially associated with use of specific statin.


Serotonin 1a receptor and associated G-protein activation in schizophrenia and bipolar disorder.
Abnormalities in the serotonergic signalling system, including the serotonin 1a receptor, have been implicated in the pathogenesis of schizophrenia and bipolar 1 disorder. However, there is no consensus on whether the density of the serotonin 1a receptor and/or the activity of the G-proteins linking the receptor to the intracellular cascade are altered in these disease states. To address these issues, tissue obtained postmortem from four cortical regions was used to measure [3H] 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) binding and 8-OH-DPAT-stimulated guanosine 5'-[gamma-thio]triphosphate (GTPgammaS) binding to determine if either parameter is altered in schizophrenia or bipolar I disorder. There was an effect of diagnosis on the level of [3H] 8-OH-DPAT binding that may indicate a global change in the density of serotonin 1a receptors, although this effect did not reach significance in any individual brain region. The activation of serotonin 1a receptors did not differ significantly with diagnoses. However, in the outer cortical layers, there appeared to be a dissociation between the number of receptors available and the extent of ligand-induced GTPgammaS binding, suggesting considerable receptor reserve. In addition, comparing gender independent of diagnoses, a decrease in the levels of serotonin 1a receptors was observed in the cortex of female subjects. These data indicates that there may be subtle changes in serotonin 1a receptors across the cortex in schizophrenia or bipolar I disorder and suggests a gender discordance in receptor levels.


Spectroscopic investigations on the orientation of 1,4-dibromonaphthalene on silver nanoparticles.
Silver nanoparticles (Ag NPs) have been prepared by solution combustion method with glycine as fuel. Silver nanoparticles were characterized by X-Ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM) and UV-visible spectroscopy. The prepared silver nanoparticles exhibit cubic crystalline structure with grain size of 59 nm. HRTEM image shows that the silver nanoparticles have strain and four-fold symmetry formed by twinning in the crystal structure. The optical adsorption spectrum shows that the surface plasmon resonance peak of silver is observed at 380 nm. The orientation of 1,4-dibromonaphthlaene (1,4-DBrN) on silver nanoparticles has been inferred from nRs and SERS spectral features. The absence of a C-H stretching vibrations, the observed high intense C-H out-of-plane bending modes and high intense C-Br stretching vibration suggest that the 1,4-DBrN molecule may be adsorbed in a 'stand-on' orientation to the surface.


Ontogeny of IgM and IgM-bearing cells in rainbow trout.
We have studied the ontogenic development of immunoglobulin M (IgM) and of IgM-bearing cells in the rainbow trout, Oncorhynchus mykiss. Lymphocytes showing cytoplasmic IgM were first observed in embryos at 12 days before hatch (14 degrees C). At this stage, no cells positive for surface IgM were present. Lymphocytes bearing surface IgM were observed at 8 days before hatch (14 degrees C). Unfertilized trout eggs contained detectable amounts of IgM (11.2 +/- 2.6 micrograms/g of egg weight), indicating that transfer of IgM from mother to embryo can occur in salmonids. The levels of IgM from whole fish increase slowly after the appearance of intraembryonic cells that express surface IgM. The amount of IgM/g of tissue peaks around hatch, but this parameter shows lower values up to 2 months after hatch.


Limited applicability and implementation of the international oncology treatments guidelines in low- and middle-income countries, an example from the Mediterranean area borders.
The quality of cancer care in the modern era is based on a precise diagnosis and personalized therapy according to patients and their disease based on validated guidelines with a high level of evidence. During cancer patients' management, the objective is first to make an accurate diagnosis and then offer the best treatment, validated beforehand in a multidisciplinary board meeting, with the best benefit/risk ratio. In the context of many low- and middle-income countries, the limited available means do not allow an adequate offer, resulting in non-optimal patients' care. In addition, in many low- and middle-income countries, priority can be given to other types of disease than cancer, which may considerably reduce allocation of specific resources to cancer care. Thus, the limited availability of systemic therapy, radiotherapy machines, brachytherapy and technological development may come up against another difficulty, that of geographical distribution of the means in the countries or a lack of expertise due to insufficient training programs. For all these reasons, the implementation of the guidelines established in Western countries could be impossible for many low- and middle-income countries which, moreover, have to face a completely different epidemiology of cancers compared to developed countries. In this work, we will discuss through a few examples of common cancers on both borders of the Mediterranean area, the applicability of the guidelines and the limits of their implementation for optimal cancer care.


Renal cell carcinoma in children and young adults.
Renal cell carcinoma (RCC) is a relatively uncommon tumor in childhood. Its biologic behavior and prognostic factors have rarely been documented. We report treatment and survival of 4 children (aged 8, 9, 11, and 14 years) who had RCC, along with a review of the literature to analyze the frequency of major symptoms, clinical stage, and prognostic factors based on 130 published cases of RCC in individuals younger than 20 years of age. Two of our cases had renal tumors detected by ultrasound screening, and all 4 cases were followed for a considerable length of time and were alive and free of disease after treatment. An analysis of these 130 published cases of pediatric RCC showed tumor staging and cell type to be the factors that affected patient survival. Tumors composed of granular cells or mixed cells, or at advanced stages, had a poor prognosis. Age, sex, tumor size, symptom duration, and cellular pattern were not related to patient prognosis. Children older than 10 years of age, who have an abdominal mass, flank pain, and/or hematuria should alert clinicians to consider the possibility of RCC. The importance of early diagnosis of renal tumors, using ultrasound as a tool of screening, is emphasized, since surgical treatment leads to a favorable prognosis only in the early stage of RCC.


Shear stress regulates the SNAP23-mediated endothelial secretion of VWF through the GPR68/PKA/vimentin mechanotransduction pathway.
Von Willebrand Factor (VWF) can promote platelet adhesion to the post-atherosclerotic regions to initiate thrombosis. The synthesis and secretion of VWF are important functions of endothelial cells (ECs). However, the mechanism through which blood flow regulates endothelial secretion of VWF remains unclear. We utilized a parallel-plate flow apparatus to apply fluid shear stress to human umbilical vein endothelial cells (HUVECs). Compared with pulsatile shear stress that mimics laminar flow in the straight parts of arteries or upstream of atherosclerotic stenosis sites, short-term exposure to oscillatory shear stress (OS) that mimics disturbed flow increased VWF secretion independent of affecting synaptosomal-associated protein 23 (SNAP23) expression and promoted the translocation of SNAP23 to the cell membrane. Vimentin associated with SNAP23, and this association was enhanced by OS or histamine. Acrylamide, a reagent that disrupts vimentin intermediate filaments, prevented histamine/OS-induced SNAP23 translocation, as well as VWF secretion. Immunofluorescence analysis revealed that the polarity of the vimentin intermediate filament network decreased after stimulation with histamine or OS. In addition, inhibition of protein kinase A (PKA) or G protein coupled receptor 68 (GPR68) eliminated the histamine/OS-induced phosphorylation of vimentin at Ser38 and secretion of VWF. Furthermore, syntaxin 7 might assist with the translocation of SNAP23 to the cell membrane, thus playing a role in promoting VWF secretion. The GPR68/PKA/vimentin signaling pathway may represent a novel mechanism for the regulation of SNAP23-mediated VWF secretion by ECs under OS and provide strategies for the prevention of atherosclerosis-related thrombosis.


Magnetic MXene-based molecularly imprinted electrochemical sensor for methylmalonic acid.
A novel magnetic Ti3C2Tx-MXene/Fe3O4 composite was prepared from Ti3C2Tx and magnetic Fe3O4. The characterizations by electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM) exhibited that the Ti3C2Tx/Fe3O4 nanomaterial presented an outstanding conductivity and a large specific area, which could improve the electron transfer rate, leading to the amplification of the sensor's signal. Furthermore, an ultrasensitive molecularly imprinted electrochemical sensor based on MXene/Fe3O4 composites was fabricated for detecting methylmalonic acid (MMA) with high selectivity. The current intensity of differential pulse voltammetry of the sensor presented a good linear relationship with the logarithm of MMA concentration ranging from 9 × 10-15 mol L-1 to 9 × 10-13 mol L-1. The detection limit of the sensor was 2.33 × 10-16 mol L-1. The fabricated sensor was utilized for detecting MMA in human serum samples with excellent recoveries. Therefore, this method significantly improved the sensitivity of detection, and constitutes an affordable sensing platform for trace detection of organic carboxylic acid.


Helminth parasites of stellate sturgeon Acipenser stellatus Pallas, 1771 and Persian sturgeon Acipenser persicus Borodin, 1897 (Pisces: Acipenseridae) from the South-East Caspian Sea.
A total of 182 specimens of two sturgeon species, stellate sturgeon Acipenser stellatus (N=112) and Persian sturgeon Acipenser persicus (N=70), from three coastal stations in the South-East Caspian Sea were examined for endohelminth parasites. Four helminth species were recorded: Cucullanus sphaerocephala (Nematoda: Cucullanidae) and Skrjabinopsolus semiarmatus (Digenea: Acanthocolpidae), found in both host species, and Leptorhynchoides plagicephalus (Acanthocephala: Rhadinorhynchidae) and Amphilina foliacea (Cestodaria: Amphilinidae), found only in A. stellatus. The most abundant parasites were C. sphaerocephala and S. semiarmatus in A. persicus and A. stellatus, respectively. Canonical discriminant analysis was applied for separating host species using parasite numbers data, Brillouin index of diversity, and species richness. By this means, 83% of the hosts were assigned to their correct a priori groups. The different feeding habits and habitat preferences of the two hosts are probably the major factors accounting for the difference in their parasite burdens.


A Novel Mouse Model of Idiopathic Nephrotic Syndrome Induced by Immunization with the Podocyte Protein Crb2.
The cause of podocyte injury in idiopathic nephrotic syndrome (INS) remains unknown. Although recent evidence points to the role of B cells and autoimmunity, the lack of animal models mediated by autoimmunity limits further research. We aimed to establish a mouse model mimicking human INS by immunizing mice with Crb2, a transmembrane protein expressed at the podocyte foot process. C3H/HeN mice were immunized with the recombinant extracellular domain of mouse Crb2. Serum anti-Crb2 antibody, urine protein-to-creatinine ratio, and kidney histology were studied. For signaling studies, a Crb2-expressing mouse podocyte line was incubated with anti-Crb2 antibody. Serum anti-Crb2 autoantibodies and significant proteinuria were detected 4 weeks after the first immunization. The proteinuria reached nephrotic range at 9-13 weeks and persisted up to 29 weeks. Initial kidney histology resembled minimal change disease in humans, and immunofluorescence staining showed delicate punctate IgG staining in the glomerulus, which colocalized with Crb2 at the podocyte foot process. A subset of mice developed features resembling FSGS after 18 weeks. In glomeruli of immunized mice and in Crb2-expressing podocytes incubated with anti-Crb2 antibody, phosphorylation of ezrin, which connects Crb2 to the cytoskeleton, increased, accompanied by altered Crb2 localization and actin distribution. The results highlight the causative role of anti-Crb2 autoantibody in podocyte injury in mice. Crb2 immunization could be a useful model to study the immunologic pathogenesis of human INS, and may support the role of autoimmunity against podocyte proteins in INS.


Corrigendum: Research on the mechanism and prevention of hypertension caused by apatinib through the RhoA/ROCK signaling pathway in a mouse model of gastric cancer.
[This corrects the article DOI: 10.3389/fcvm.2022.873829.].


Endovascular versus open repair in patients with abdominal aortic aneurysm: a claims-based data analysis in Japan.
Endovascular aortic repair (EVAR) evolved through competition with open aortic repair (OAR) as a safe and effective treatment option for appropriately selected patients with abdominal aortic aneurysm (AAA). Although endoleaks are the most common reason for post-EVAR reintervention, compliance with lifelong regular follow-up imaging remains a challenge. Retrospective data analysis. The Japan Medical Data Center (JMDC), a claims database with anonymous data linkage across hospitals, consists of corporate employees and their families of ≤75 years of age. The analysis included participants in the JMDC who underwent EVAR or OAR for intact (iAAA) or ruptured (rAAA) AAA. Patients with less than 6 months of records before the aortic repair were excluded. Overall survival and reintervention rates. We identified 986 cases (837 iAAA and 149 rAAA) from JMDC with first aortic repairs between January 2015 and December 2020. The number of patients, median age (years (IQR)), follow-up (months) and post-procedure CT scan (times per year) were as follows: iAAA (OAR: n=593, 62.0 (57.0-67.0), 26.0, 1.6, EVAR: n=244, 65.0 (31.0-69.0), 17.0, 2.2), rAAA (OAR: n=110, 59.0 (53.0-59.0), 16.0, 2.1, EVAR: n=39, 62.0 (31.0-67.0), 18.0, 2.4). Reintervention rate was significantly higher among EVAR than OAR in rAAA (15.4% vs 8.2%, p=0.04). In iAAA, there were no group difference after 5 years (7.8% vs 11.0%, p=0.28), even though EVAR had initial advantage. There were no differences in mortality rate between EVAR and OAR for either rAAA or iAAA. Claims-based analysis in Japan showed no statistically significant difference in 5-year survival rates of the OAR and EVAR groups. However, the reintervention rate of EVAR in rAAA was significantly higher, suggesting the need for regular post-EVAR follow-up with imaging. Therefore, international collaborations for long-term outcome studies with real-world data are warranted.


The delicate balance of macrophages in colorectal cancer; their role in tumour development and therapeutic potential.
Most tumours are heavily infiltrated by immune cells. This has been correlated with either a good or a bad patient prognosis, depending on the (sub) type of immune cells. Macrophages represent one of the most prominent leukocyte populations in the majority of tumours. Functions of macrophages range from cytotoxicity, to stimulation of tumour growth by secretion of cytokines, growth and angiogenic factors, or suppressing immune responses. In most tumours macrophages are described as cells with immune suppressing, and wound healing properties, which aids tumour development. Yet, increasing evidence shows that macrophages are potent inhibitors of tumour growth in colorectal cancer. Macrophages in this respect show high plasticity. The presence of high macrophage numbers in the tumour may therefore become advantageous, if cells can be reprogrammed from tumour promoting macrophages into potent effector cells. Enhancing cytotoxic properties of macrophages by microbial products, pro-inflammatory cytokines or monoclonal antibody therapy are promising possibilities, and are currently tested in clinical trials.


Vaccinium arctostaphylos, a common herbal medicine in Iran: molecular and biochemical study of its antidiabetic effects on alloxan-diabetic Wistar rats.
The purpose of this study was to define antidiabetic effects of fruit of Vaccinium arctostaphylos L. (Ericaceae) which is traditionally used in Iran for improving of health status of diabetic patients. Firstly, we examined the effect of ethanolic extract of Vaccinium arctostaphylos fruit on postprandial blood glucose (PBG) after 1, 3, 5, 8, and 24h following a single dose administration of the extract to alloxan-diabetic male Wistar rats. Also oral glucose tolerance test was carried out. Secondly, PBG was measured at the end of 1, 2 and 3 weeks following 3 weeks daily administration of the extract. At the end of treatment period the pancreatic INS and cardiac GLUT-4 mRNA expression and also the changes in the plasma lipid profiles and antioxidant enzymes activities were assessed. Finally, we examined the inhibitory activity of the extract against rat intestinal α-glucosidase. The obtained results showed mild acute (18%) and also significant chronic (35%) decrease in the PBG, significant reduction in triglyceride (47%) and notable rising of the erythrocyte superoxide dismutase (57%), glutathione peroxidase (35%) and catalase (19%) activities due to treatment with the extract. Also we observed increased expression of GLUT-4 and INS genes in plant extract treated Wistar rats. Furthermore, in vitro studies displayed 47% and 56% inhibitory effects of the extract on activity of intestinal maltase and sucrase enzymes, respectively. Findings of this study allow us to establish scientifically Vaccinium arctostaphylos fruit as a potent antidiabetic agent with antihyperglycemic, antioxidant and triglyceride lowering effects.


Nucleotide sequencing of 5' and 3' termini of bovine viral diarrhea virus by RNA ligation and PCR.
Genomic RNA was extracted from cytopathic (CP) bovine viral diarrhea virus (BVDV) strain NADL, CP strain 72, and noncytopathic (NCP) strain SD-1 purified by ultracentrifugation. Assuming the presence of a cap structure, de-blocking of the 5' capped end of the genomic RNA was done by treatment with tobacco acid pyrophosphatase (TAP). Following decapping, the RNA molecules were ligated using T4 RNA ligase and the ligated tandem RNA templates were then amplified by primer-directed amplification (PCR). cDNA synthesis was done using reverse transcriptase with random primers and cDNA amplification was done using a negative sense primer 231-248 and a positive sense primer 12434-12451. The nucleotide sequence of the amplified product was determined by double-stranded sequencing using the Sanger di-deoxy chain termination method and an additional 'CCCCC' nucleotide sequence was identified at the ligation site. Following dATP tailing of cDNA and amplification across the 5' terminus and nucleotide sequencing, no additional nucleotides were identified on the 5' terminus. The 5' terminus as published by Collett et al., 1988b was confirmed as previously reported. Therefore, the 3' terminus includes an additional 'CCCCC' nucleotide sequence to that previously reported. Identical results were obtained when the BVDV genomic RNA was not decapped prior to RNA ligation and amplification.


Mixed models of alcoholism. Definitions, etiology, treatment and prognosis in health education textbooks.
The information on alcoholism presented in college-level health education textbooks was compared with eight models of alcoholism. No model was cited consistently; diverse knowledge bases, models of alcoholism and moral views were implicit in the texts. The utility of the models is also discussed.


Ichthyosis vulgaris showing features of the autosomal dominant and X-linked recessive variants in the same family.
A family in which the mother and six of her sons present an ichthyosis of the vulgaris type has been analysed clinically, histologically and electron microscopically. Phenotypically the ichthyosis in the mother is purely of the dominant type, while that in all the affected sons shows, to varying degrees, features of both the dominant and X-linked recessive variants. The findings are interpreted as reasonably good evidence that the mother has transmitted to all her affected sons both the autosomal dominant and the X-linked recessive genes for ichthyosis. Although genetically this is a most unusual situation, it corresponds best to our findings.


Dynamic nuclear polarization of quadrupolar nuclei using cross polarization from protons: surface-enhanced aluminium-27 NMR.
The surface of γ-alumina nanoparticles can be characterized by dynamic nuclear polarization (DNP) surface-enhanced NMR of (27)Al. DNP is combined with cross-polarization and MQ-MAS to determine local symmetries of (27)Al sites at the surface.


Human fused NKG2D-IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells.
Interleukin (IL)-15 plays an important role in natural killer (NK) and CD8+ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coli. DsNKG2D-IL-15 could efficiently bind to major histocompatibility complex class I chain-related protein A (MICA) of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8+ T cells. We transplanted human gastric cancer (SGC-7901) cells into nude mice and mouse melanoma cells with ectopic expression of MICA (B16BL6-MICA) into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56+ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-IL-15 treatment. Human dsNKG2D-IL-15 also delayed the growth of transplanted melanoma (B16BL6-MICA) by activating and recruiting mouse NK and CD8+ T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.Cellular & Molecular Immunology advance online publication, 14 September 2015; doi:10.1038/cmi.2015.81.


Emotion regulation profiles in psychogenic non-epileptic seizures.
Psychogenic non-epileptic seizures (PNES) are frequently encountered in epilepsy referral centers, yet there is limited understanding of the emotion processing style in this psychiatrically heterogeneous population. Understanding profiles of emotion regulation in PNES will provide further evidence of the psychogenic nature of the disorder and will potentially inform psychotherapeutic interventions. Fifty-five patients with PNES underwent a neuropsychiatric evaluation and completed self-report questionnaires that measured difficulties in emotion regulation, psychopathology severity and quality of life. Through the use of cluster analysis, two groups were identified; Cluster 1 represented a highly emotion dysregulated group while Cluster 2 represented a low emotion dysregulated group. Additional analyses revealed that each group significantly differed from normative data. Finally, Cluster 1 was significantly associated with several measures of psychiatric symptoms, higher rates of comorbid psychiatric diagnoses and impairment in quality of life. These findings suggest that patients with PNES may be subject to high levels of emotion dysregulation, severe psychiatric symptomatology and impaired quality of life, or to low emotion dysregulation characterized by emotional unawareness or avoidance. These profiles clearly differ from normative data regarding emotion regulation and their identification may help tailor psychotherapeutic interventions.


Synthesis and discovery of ω-3 polyunsaturated fatty acid- alkanolamine (PUFA-AA) derivatives as anti-inflammatory agents targeting Nur77.
In this work, three series of ω-3 polyunsaturated fatty acid-alkanolamine derivatives (PUFA-AAs) were synthesized, characterized and their anti-inflammatory activity in vivo was evaluated. Compounds 4a, 4f, and 4k exhibited marked anti-inflammatory activity in LPS-stimulated RAW 264.7 cells. The most promising compound 4k dose-dependently suppressed the cytokines with IC50 values in the low micromolar range. Further, 4k exhibited potential in vitro Nur77-binding affinity (Kd = 6.99 × 10-6 M) which is consistent with the result of docking studies. Next, the anti-inflammatory mechanism of 4k was found to be through NF-κB signal pathway in a Nur77-dependent manner. Moreover, we also observed 4k significantly inhibited LPS-induced expression of cytokines (IL-6, TNF-α, and IL-1β) through suppressing NF-κB activation and attenuated LPS-induced inflammation in mouse acute lung injury (ALI) model. In conclusion, the study strongly suggests that the PUFA-AA derivatives can be particularly as new Nur77 mediators for further treatment in inflammatory diseases.


Predicting risk of AF in ischaemic stroke using sinus rhythm ECG abnormalities: A meta-analysis.
To identify ECG changes in sinus rhythm that may be used to predict subsequent development of new AF. We identified prospective and retrospective cohort or case control studies evaluating ECG patterns from a 12-lead ECG in sinus rhythm taken in hospital or community predicting subsequent development of new AF. For each identified ECG predictor, we then identify absolute event rates and pooled risk ratios (RR) using an aggregate level random effects meta-analysis. We identified 609,496 patients from 22 studies. ECG patterns included P wave terminal force V1 (PTFV1), interatrial block (IAB) and advanced interatrial block (aIAB), abnormal P wave axis (aPWA), PR prolongation and atrial premature complexes (APCs). Pooled risk ratios reached significance for each of these; PTFV1 RR 1.48 (95% CI 1.04-2.10), IAB 2.54 (95% CI 1.64-3.93), aIAB 4.05 (95% CI 2.64-6.22), aPWA 1.89 (95% CI 1.25-2.85), PR prolongation 2.22 (95% CI 1.27-3.87) and APCs 3.71 (95% CI 2.23-6.16). Diabetes reduced the predictive value of PR prolongation. APC and aIAB were most predictive of AF, while IAB, PR prolongation, PTFV1 and aPWA were also significantly associated with development of AF. These support their use in a screening tool to identify at risk cohorts who may benefit from further investigation, or following stroke, with empirical anticoagulation.


Protein synthesis by synaptosomes from rat brain: the effect of centrifugal forces.
1. Synaptosomal protein synthesis has been found to differ depending on whether synaptosomes are recovered from the sucrose gradients by centrifuging at 20,000 g or at 150,000 g. 2. The fraction obtained at 20,000 g incorporated 60% more amino acid into proteins after 30 min of incubation than the one obtained in the same period of time at 150,000 g. 3. The respiratory capacity of synaptosomes obtained at 20,000 g in the presence or absence of glucose as substrate, is also better preserved than that of those obtained at 150,000 g. 4. It is shown that the yield, enzymic content, and nucleic acid composition is the same in both fractions. 5. These results cannot be explained by the presence of inhibitory factors in the 150,000 g fraction or by the presence of better preserved free mitochondria in the 20,000 g fraction. 6. Our findings are best explained by postulating that the synaptosomal metabolic activity is damaged when synaptosomes are pelleted at too high a speed.


Is there a role for organic trace element supplements in transition cow health?
Optimal transition cow health is the key to success of the subsequent lactation, and increasing attention has been focused on management and nutritional practices that support it. Physiological stress during the transition period alters the efficiency of the immune system, making the lactating dairy cow more susceptible to infectious diseases, such as mastitis and metritis, with subsequent impairment of reproductive performance. Trace elements have a specific role in free radical control at the cellular level and influence the anti-oxidant/free radical balance. Dietary trace elements must be available for absorption throughout the whole of the digestive process until they reach the final site of absorption in the small intestine. Negative interactions between minerals can occur and, as the intestinal environment lowers the absorption of ionic minerals, chelation technology has been developed to increase mineral bioavailability. Organic trace elements have been used in dairy cow experiments, resulting in significant improvements in udder health, lameness and reproductive performance.


Two New Cytotoxic Maytansinoids Targeting Tubulin from Trewia nudiflora.
Two new maytansinoids, N-methyltreflorine (1: ) and methyltrewiasine (2: ), were isolated from the dried fruits of Trewia nudiflora, together with three known congeners (3: - 5: ). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1: and 2: was determined by X-ray crystallographic analysis. Compounds 1: - 5: exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 - 11, and MCF-7, with IC50 values ranging from 0.12 to 11 nM. Compounds 1: and 4: also showed inhibitory activity against the MCF-7/ADR cell line with IC50 values of 13 and 28 nM, respectively. Compounds 1: and 2: significantly inhibited tubulin polymerization in vitro with IC50 values of 3.6 and 3.2 µM, respectively.


A neuronal system of movement control via muscle spindle secondaries.
A recently discovered spinal interneuronal system of movement control is briefly described. It includes a population of midlumbar interneurones with a predominant monosynaptic input from secondary muscle spindle afferents but supplied with information via several other afferent and descending neuronal systems as well. The neurones are in direct contact with both motoneurones and other interneurones. The evidence in favour for their involvement in locomotion is briefly summarized.


Effect of age on immunological response in the first year of antiretroviral therapy in HIV-1-infected adults in West Africa.
To assess the effect of aging on the immunological response to antiretroviral therapy (ART) in the West African context. The change in CD4 T-cell count was analysed according to age at the time of ART initiation among HIV-infected patients enrolled in the International epidemiological Database to Evaluate AIDS (IeDEA) Collaboration in the West African region. CD4 gain over 12 months of ART was estimated using linear mixed models. Models were adjusted for baseline CD4 cell count, sex, baseline clinical stage, calendar period and ART regimen. The total number of patients included was 24,107, contributing for 50,893 measures of CD4 cell count in the first year of ART. The baseline median CD4 cell count was 144 cells/μl [interquartile range (IQR) 61-235]; median CD4 cell count reached 310 cells/μl (IQR 204-443) after 1 year of ART. The median age at treatment initiation was 36.3 years (10th-90th percentiles = 26.5-50.1). In adjusted analysis, the mean CD4 gain was significantly higher in younger patients (P < 0.0001). At 12 months, patients below 30 years recovered an additional 22 cells/μl on average [95% confidence interval (CI) 2-43] compared to patients at least 50 years. Among HIV-infected adults in West Africa, the immunological response after 12 months of ART was significantly poorer in elderly patients. As the population of treated patients is likely to get older, the impact of this age effect on immunological response to ART may increase over time.


Successful orthotopic transplantation of a fresh tricuspid valve homograft in a human.
We report a successful transplantation of a human tricuspid valve in a human. We used a fresh tricuspid homograft with its chordae tendineae and papillary muscles, harvested 5 days earlier under sterile conditions from a multiorgan donor a few minutes after cardiectomy (the heart was not suitable for cardiac transplantation) and immediately stored at 4 degrees C. We elected to implant the homograft in a young heroin addict. Our experience demonstrates that the implantation of an atrioventricular homograft in the orthotopic position is technically feasible and can achieve good results, at least in the short term.


Use of primary cultures and continuous cell lines to study effects on astrocytic regulatory functions.
1. Current opinions on the mechanisms for glutamate-mediated neurotoxicity are reviewed. The protective role of astrocytic high-affinity glutamate transport is also discussed. 2. Low-density seeding of primary astrocytes from rat hemispheres was found to result in the development of reactive-like astrocytes. Typical glial signs of amyotrophic lateral sclerosis (ALS) could not be induced in astrocyte cultures by serum from ALS-patients. 3. Glutamate (100 mumol/L) was found to induce an increase in respiratory activity in primary cultures of astrocytes. This stimulation appeared to be related to the co-transport of Na2+ with glutamate and a resulting activation of Na2+/K(+)-ATPase. Both basal respiration and glutamate-stimulated oxygen consumption was inhibited by organic solvents. 4. Preliminary results show that heavy metals cause an increase in the mitochondrial DNA content at concentrations that have no effect on growth rate or morphology in a glial cell line. This increase was accompanied by an inhibition of oxygen consumption and an increased production of lactate at unaltered ATP levels.