Myeloid lineage of high proliferative potential human smooth muscle outgrowth cells circulating in blood and vasculogenic smooth muscle-like cells in vivo.
Emerging experimental data supports a circulating precursor origin for some smooth muscle cells that participate in vasculogenesis but uncertainty exists on the precise phenotype and lineage of these vascular precursors. We determined the lineage of human smooth muscle outgrowth cells (SOC) derived from circulating blood mononuclear cells and smooth muscle-like cells present in regions of vasculogenesis in diseased arteries. Immunophenotypic characterization of SOC was performed using FACS and immunofluorescence (IF). An SOC hierarchy was determined based on in vitro clonogenic and proliferative potential. Lineage of smooth muscle-like cells in vasculogenic regions in vivo was also determined by dual IF for myeloid and smooth muscle specific markers combined with FISH for the X and Y chromosome in diseased vessel of human subjects who had undergone gender mismatched cardiac transplantation. We show here that primary high proliferative potential smooth muscle outgrowth cells (HPP-SOC) expanded in culture from human peripheral blood mononuclear cells (PBMC) and recipient-derived chimeric smooth muscle cells participating in vasculogenesis in vivo share a myeloid phenotype (CD68 and CD14 positivity). Moreover, HPP-SOC in vitro are distinct in being negative for several myeloid markers such as CD11b, CD13 and CD33, and CD45 surface antigens and chimeric SMC in vivo show no evidence of cell fusion propensity. This study provides evidence of a possible myeloid subpopulation origin for smooth muscle outgrowth cells in blood and vasculogenic smooth muscle-like cells in the intima and adventitial microvasculature of diseased arteries. These data have significant implications for understanding the role myeloid cells play in smooth muscle cell biology and vascular remodelling.


Sixth BHD Symposium and First International Upstate Kidney Cancer Symposium: latest scientific and clinical discoveries.
The Sixth BHD Symposium and First International Upstate Kidney Cancer Symposium concluded in September 2015, in Syracuse, NY, USA. The program highlighted recent findings in a variety of areas, including drug development, therapeutics and surgical management of patients with BHD and multi-focal renal tumors, as well as multidisciplinary approaches for patients with localized, locally advanced and metastatic renal cell carcinoma.


The HOTAIR/miR-214/ST6GAL1 crosstalk modulates colorectal cancer procession through mediating sialylated c-Met via JAK2/STAT3 cascade.
The regulatory non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), emerge as pivotal markers during tumor progression. Abnormal sialylated glycoprotein often leads to the malignancy of colorectal cancer (CRC). Differential levels of HOTAIR and ST6GAL1 are analyzed by qRT-PCR. Functionally, CRC cell proliferation, aggressiveness and apoptosis are measured through relevant experiments, including CCK8 assay, colony formation assay, transwell assay, western blot and flow cytometry. Dual-luciferase reporter gene assay and RIP assay confirm the direct interaction between HOTAIR and miR-214. The lung metastasis, liver metatstasis and xenografts nude mice models are established to show the in vivo effect of HOATIR. Here, differential levels of HOTAIR and ST6GAL1 are primarily observed in CRC samples and cells. Upregulated HOTAIR and ST6GAL1 are crucial predictors for poor CRC prognosis. Altered level of ST6GAL1 modulates CRC malignancy. Furthermore, ST6GAL1 and HOTAIR are confirmed as the direct targets of miR-214, and ST6GAL1 is regulated by HOTAIR via sponging miR-214. ST6GAL1 induces the elevated metabolic sialylation of c-Met, which is co-mediated by HOTAIR and miR-214. Sialylated c-Met affects the activity of JAK2/STAT3 pathway. The regulatory role of HOTAIR/miR-214/ST6GAL1 axis also impacts CRC procession. In addition, HOTAIR mediates lung metastasis, liver metastasis and tumorigenesis in vivo. ShHOTAIR and AMG-208 are combined to inhibit tumorigenesis for successful drug development. The HOTAIR/miR-214/ST6GAL1 axis commands the CRC malignancy by modifying c-Met with sialylation and activating JAK2/STAT3 pathway. Our study presents novel insights into CRC progression and provided prospective therapeutic target for CRC.


Heterogeneous Circles for Liver Allocation.
In February 2020, the Organ Procurement and Transplantation Network replaced donor service area-based allocation of livers with acuity circles, a system based on three homogeneous circles around each donor hospital. This system has been criticized for neglecting to consider varying population density and proximity to coast and national borders. Using Scientific Registry of Transplant Recipients data from July 2013 to June 2017, we designed heterogeneous circles to reduce both circle size and variation in liver supply/demand ratios across transplant centers. We weighted liver demand by Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) because higher MELD/PELD candidates are more likely to be transplanted. Transplant centers in the West had the largest circles; transplant centers in the Midwest and South had the smallest circles. Supply/demand ratios ranged from 0.471 to 0.655 livers per MELD-weighted incident candidate. Our heterogeneous circles had lower variation in supply/demand ratios than homogeneous circles of any radius between 150 and 1,000 nautical miles (nm). Homogeneous circles of 500 nm, the largest circle used in the acuity circles allocation system, had a variance in supply/demand ratios 16 times higher than our heterogeneous circles (0.0156 vs. 0.0009) and a range of supply/demand ratios 2.3 times higher than our heterogeneous circles (0.421 vs. 0.184). Our heterogeneous circles had a median (interquartile range) radius of only 326 (275-470) nm but reduced disparities in supply/demand ratios significantly by accounting for population density, national borders, and geographic variation of supply and demand. Large homogeneous circles create logistical burdens on transplant centers that do not need them, whereas small homogeneous circles increase geographic disparity. Using carefully designed heterogeneous circles can reduce geographic disparity in liver supply/demand ratios compared with homogeneous circles of radius ranging from 150 to 1,000 nm.


The interaction of pentosan polysulphate (SP54) with human neutrophil elastase and connective tissue matrix components.
The binding of pentosan polysulphate (SP54) to human polymorphonuclear leucocyte elastase (PMNE) and some of its natural and synthetic substrates has been investigated. Using an ion exchange (DE52) assay system the binding of SP54 to PMNE was found to be 100 times stronger than to collagen or proteoglycan (PG). While the order for in vitro binding of the drug to purified substrates was found to be PG greater than gelatin greater than type I collagen, in vivo experiments indicated that SP54 was localized in tissues rich in collagen. Using gel-exclusion chromatography it was shown that these tissues also contained proteinaceous components other than PG and collagen which interacted with SP54. These results indicate that the potent inhibitor activity of SP54 against PMNE (50% inhibition at 1.7 X 10(-7)M) probably occurs by a specific interaction with the enzyme rather than by substrate binding inhibition, although the latter interaction may be important for localising the drug in these tissues.


Neutrophil recruitment inhibitory factor: a possible candidate for a novel cytokine.
Inhibitory effect upon neutrophil migration to the inflammatory focus was previously detected in the cell-free incubation fluid of lipopolysaccharide (LPS)-stimulated macrophage monolayers. In the present study we showed that the neutrophil recruitment inhibitory activity from this supernatant was mainly detected in a fraction (P2) obtained by gel filtration chromatography on Sephacryl S-300. P2 fraction was able to inhibit 'in vivo' neutrophil emigration induced by different inflammatory stimuli, but it did not affect 'in vitro' neutrophil chemotaxis induced by FMLP. When injected intravenously, P2 inhibited oedema induced by carrageenin or immunological stimulus but not the oedema induced by dextran, thus affecting cell-dependent inflammatory responses. It was observed that P2 also induced neutrophil migration when injected locally in peritoneal cavities. This activity was significantly reduced by pretreatment of the animals with dexamethasone. Cytokines, such as IL-8 and TNF-alpha that are known to exhibit inhibitory effect upon neutrophil migration, were not detected in P2 fraction by highly sensitive assays. Overall the results suggest the existence of a novel cytokine exhibiting 'in vivo' neutrophil inhibitory activity, referred as NRIF.


RELATIONSHIP BETWEEN SELENIUM NUTRITIONAL STATUS AND MARKERS OF LOW-GRADE CHRONIC INFLAMMATION IN OBESE WOMEN.
Low-grade chronic inflammation is one of the main disorders that characterize adipose tissue dysfunction in obesity and is an important element in the pathogenesis of several comorbidities. In this context, selenium is an essential micronutrient that exerts important anti-inflammatory functions, and the role of selenium in controlling inflammation associated with obesity is not well defined. Thus, this study aimed to evaluate the relationship between markers of the nutritional status of selenium and low-grade chronic inflammation in obese women. This cross-sectional study included 81 women aged between 18 and 50 years, who were divided into two groups according to body mass index (BMI): the obesity group (n = 38) and normal weight group (n = 43). Selenium intake was assessed by 3-day diet records. The plasma, erythrocyte, and urinary selenium concentrations were determined using inductively coupled plasma optical emission spectrometry. The analysis of serum cytokines interleukin (IL)-8, IL-1β, IL-6, IL-10, and tumor necrosis factor alpha (TNFα) was performed using flow cytometry. The results of this study revealed that the obese women had higher dietary intake of selenium than eutrophic women. However, obese participants showed decreased selenium concentrations in plasma and erythrocytes, in parallel with increased concentrations of selenium in the urine. Regarding the inflammatory parameters, obese women exhibited higher concentrations of IL-6 and lower concentrations of the cytokines IL-8, IL-1β, and TNFα than eutrophic women. In the binary logistic regression analysis, erythrocyte selenium was considered an independent predictor of the serum concentrations of cytokine IL-8 in obese women, reflecting the anti-inflammatory action of this micronutrient.


Chaperonin TRiC/CCT Recognizes Fusion Oncoprotein AML1-ETO through Subunit-Specific Interactions.
AML1-ETO is the translational product of a chimeric gene created by the stable chromosome translocation t (8;21)(q22;q22). It causes acute myeloid leukemia (AML) by dysregulating the expression of genes critical for myeloid cell development and differentiation and recently has been reported to bind multiple subunits of the mammalian cytosolic chaperonin TRiC (or CCT), primarily through its DNA binding domain (AML1-175). Through these interactions, TRiC plays an important role in the synthesis, folding, and activity of AML1-ETO. Using single-particle cryo-electron microscopy, we demonstrate here that a folding intermediate of AML1-ETO's DNA-binding domain (AML1-175) forms a stable complex with apo-TRiC. Our structure reveals that AML1-175 associates directly with a specific subset of TRiC subunits in the open conformation.


A pseudo sinus tachycardia originating from the right superior pulmonary vein. Successful ablation by a simplified, targeted ablation strategy.
We report the case of a young woman suffering from a permanent ectopic atrial tachycardia originating from the right superior pulmonary vein and mimicking a sinus tachycardia on the ECG. Using only 2 quadripolar catheters after a transseptal approach, the focus was successfully mapped to the posterior wall of the right superior pulmonary vein. The focus was successfully ablated during the same procedure using a 4-mm tip-irrigated catheter.


[Dynamics of dysplastic hip remodelling during the first month of a child's life in an ultrasonographic image].
Remodelling of dysplastic hip in the first four weeks of life in 51 children treated with abduction diapers has been assessed sonographically. An improvement has been found in every case. The best results have been achieved in type IIIa hips, the worst in type IV (after Graf).


Schistosoma mattheei in the ox: clinical pathological observations.
Twenty-eight Friesian calves were infected between seven and 11 months of age with 5000 to 45,000 cercariae of Schistosoma mattheei. They developed anaemia, lymphopaenia and hypoalbuminaemia during the period of acute clinical illness after the infection became patent, and lymphocyte counts remained depressed after clinical recovery. Neutrophil counts rose and later fell before returning to normal. Eosinophilia and hypergammaglobulinaemia were marked during the period of recovery. The changes in haemoglobin, neutrophils and serum proteins were proportional to the level of infection. The eosinophil response was reduced in animals subjected to nutritional stress. The aetiology of the changes is discussed.


iPSCs derived from esophageal atresia patients reveal SOX2 dysregulation at the anterior foregut stage.
A series of well-regulated cellular and molecular events result in the compartmentalization of the anterior foregut into the esophagus and trachea. Disruption of the compartmentalization process leads to esophageal atresia/tracheoesophageal fistula (EA/TEF). The cause of EA/TEF remains largely unknown. Therefore, to mimic the early development of the esophagus and trachea, we differentiated induced pluripotent stem cells (iPSCs) from EA/TEF patients, and iPSCs and embryonic stem cells from healthy individuals into mature three-dimensional esophageal organoids. CXCR4, SOX17 and GATA4 expression was similar in both patient-derived and healthy endodermal cells. The expression of the key transcription factor SOX2 was significantly lower in the patient-derived anterior foregut. We also observed an abnormal expression of NKX2.1 (or NKX2-1) in the patient-derived mature esophageal organoids. At the anterior foregut stage, RNA sequencing revealed the critical genes GSTM1 and RAB37 to be significantly lower in the patient-derived anterior foregut. We therefore hypothesize that a transient dysregulation of SOX2 and the abnormal expression of NKX2.1 in patient-derived cells could be responsible for the abnormal foregut compartmentalization.


Arsenic cancer risk confounder in southwest Taiwan data set.
Quantitative analysis for the risk of human cancer from the ingestion of inorganic arsenic has been based on the reported cancer mortality experience in the blackfoot disease (BFD) -endemic area of southwest Taiwan. Linear regression analysis shows that arsenic as the sole etiologic factor accounts for only 21% of the variance in the village standardized mortality ratios for bladder and lung cancer. A previous study had reported the influence of confounders (township, BFD prevalence, and artesian well dependency) qualitatively, but they have not been introduced into a quantitative assessment. In this six-township study, only three townships (2, 4, and 6) showed a significant positive dose-response relationship with arsenic exposure. The other three townships (0, 3, and 5) demonstrated significant bladder and lung cancer risks that were independent of arsenic exposure. The data for bladder and lung cancer mortality for townships 2, 4, and 6 fit an inverse linear regression model (p < 0.001) with an estimated threshold at 151 microg/L (95% confidence interval, 42 to 229 microg/L) . Such a model is consistent with epidemiologic and toxicologic literature for bladder cancer. Exploration of the southwest Taiwan cancer mortality data set has clarified the dose-response relationship with arsenic exposure by separating out township as a confounding factor. Key words: arsenic, blackfoot disease, bladder cancer, cancer risk, confounder, dose-response relationship, southwest Taiwan, threshold model.


Recent Advances in Shape-Controlled Synthesis of Noble Metal Nanoparticles by Radiolysis Route.
This paper focuses on the recent advances on radiolysis-assisted shape-controlled synthesis of noble metal nanostructures. The techniques and protocols for producing desirable shapes of noble metal nanoparticles are discussed through introducing the critical parameters which can influence the nucleation and growth mechanisms. Nucleation rate plays a vital role on the crystallinity of seeds while growth rate of different seeds' facets determines the final shape of resultant nanoparticles. Nucleation and growth rate both can be altered with factors such as absorbed dose, capping agents, and experimental environment condition to control the final shape. Remarkable physical and chemical properties of synthesized noble metal nanoparticles by controlled morphology have been systematically evaluated to fully explore their applications.


Optimal cycling time trial position models: aerodynamics versus power output and metabolic energy.
The aerodynamic drag of a cyclist in time trial (TT) position is strongly influenced by the torso angle. While decreasing the torso angle reduces the drag, it limits the physiological functioning of the cyclist. Therefore the aims of this study were to predict the optimal TT cycling position as function of the cycling speed and to determine at which speed the aerodynamic power losses start to dominate. Two models were developed to determine the optimal torso angle: a 'Metabolic Energy Model' and a 'Power Output Model'. The Metabolic Energy Model minimised the required cycling energy expenditure, while the Power Output Model maximised the cyclists׳ power output. The input parameters were experimentally collected from 19 TT cyclists at different torso angle positions (0-24°). The results showed that for both models, the optimal torso angle depends strongly on the cycling speed, with decreasing torso angles at increasing speeds. The aerodynamic losses outweigh the power losses at cycling speeds above 46km/h. However, a fully horizontal torso is not optimal. For speeds below 30km/h, it is beneficial to ride in a more upright TT position. The two model outputs were not completely similar, due to the different model approaches. The Metabolic Energy Model could be applied for endurance events, while the Power Output Model is more suitable in sprinting or in variable conditions (wind, undulating course, etc.). It is suggested that despite some limitations, the models give valuable information about improving the cycling performance by optimising the TT cycling position.


Impaired calcification around matrix vesicles of growth plate and bone in alkaline phosphatase-deficient mice.
The presence of skeletal hypomineralization was confirmed in mice lacking the gene for bone alkaline phosphatase, ie, the tissue-non-specific isozyme of alkaline phosphatase (TNAP). In this study, a detailed characterization of the ultrastructural localization, the relative amount and ultrastructural morphology of bone mineral was carried out in tibial growth plates and in subjacent metaphyseal bone of 10-day-old TNAP knockout mice. Alizarin red staining, microcomputerized tomography (micro CT), and FTIR imaging spectroscopy (FT-IRIS) confirmed a significant overall decrease of mineral density in the cartilage and bone matrix of TNAP-deficient mice. Transmission electron microscopy (TEM) showed diminished mineral in growth plate cartilage and in newly formed bone matrix. High resolution TEM indicated that mineral crystals were initiated, as is normal, within matrix vesicles (MVs) of the growth plate and bone of TNAP-deficient mice. However, mineral crystal proliferation and growth was inhibited in the matrix surrounding MVs, as is the case in the hereditary human disease hypophosphatasia. These data suggest that hypomineralization in TNAP-deficient mice results primarily from an inability of initial mineral crystals within MVs to self-nucleate and to proliferate beyond the protective confines of the MV membrane. This failure of the second stage of mineral formation may be caused by an excess of the mineral inhibitor pyrophosphate (PPi) in the extracellular fluid around MVs. In normal circumstances, PPi is hydrolyzed by the TNAP of MVs' outer membrane yielding monophosphate ions (Pi) for incorporation into bone mineral. Thus, with TNAP deficiency a buildup of mineral-inhibiting PPi would be expected at the perimeter of MVs.


Comparison of the therapeutic effects between stem cells and exosomes in primary ovarian insufficiency: as promising as cells but different persistency and dosage.
Primary ovarian insufficiency (POI) refers to the loss of ovarian function under the age of 40 and results in amenorrhea and infertility. Our previous studies have shown that transplantation of mesenchymal stem cells (MSCs) and MSC-derived exosomes in chemotherapy-induced POI mouse ovaries can reverse the POI and eventually achieve pregnancy. Based on our recent studies, MSC-derived exosomes have almost equal therapeutic potentials as transplanted MSCs. However, it is still unclear whether exosomes can completely replace MSCs in POI treatment. For the reliable application of cell-free treatment for POI patients using exosomes, there is a need to understand whether there is any outcome and effectiveness difference between MSC and MSC-derived exosome treatment. Comparing the therapeutic effect of intravenous injection using MSCs and equal amounts of exosomes in a POI mouse model will reveal the difference between the two therapeutic resources. In this study, we induced POI in C57/BL6 mice by chemotherapy (CXT) using a standard protocol. We then injected four different doses of MSCs or equal amounts of commercialized MSC-derived exosomes by retro-orbital injection post-CXT. After MSC/exosome treatment, tissue and serum samples were harvested to analyze molecular changes after treatment, while other mice in parallel experiments underwent breeding experiments to compare the restoration of fertility. Both the MSC- and exosome-treated groups had a restored estrous cycle and serum hormone levels compared to untreated POI mice. The pregnancy rate in the MSC-treated group was 60-100% after treatment, while the pregnancy rate in the exosome-treated group was 30-50% after treatment. Interestingly, in terms of long-term effects, MSC-treated mice still showed a 60-80% pregnancy rate in the second round of breeding, while the exosome-treated group became infertile again in the second round of breeding. Although there were some differences in the efficacy between MSC treatment and exosome treatment, both treatments were able to achieve pregnancy in the POI mouse model. In conclusion, we report that MSC-derived exosomes are a promising therapeutic option to restore ovarian function in POI conditions similar to treatment with MSCs.


Body size, fatness, and leanness of Mexican American children in Brownsville, Texas: changes between 1972 and 1983.
Changes in the height, weight, body mass index, triceps skinfold, and arm and estimated midarm muscle circumferences in lower socioeconomic Mexican American children, 6 through 17 years of age, from Brownsville, Texas, were documented on the basis of surveys done in 1972 and 1983. With the exception of height in youths ages 14-17, all parameters show gains at most ages, and in particular an increase in fatness. Brownsville Mexican American youth are similar in height, weight, and the body mass index to Mexican American youth in other areas of Texas. These trends confirm the large proportion of relatively short but heavy children among Mexican Americans.


Exploring novel sero-epidemiological tools-Effect of different storage conditions on longitudinal stability of microarray slides comprising influenza A-, measles- and Streptococcus pneumoniae antigens.
In this study we evaluated the long-term stability of a microarray-based serological screening platform, containing antigens of influenza A, measles and Streptococcus pneumoniae, as part of a preparedness research program aiming to develop assays for syndromic disease detection. Spotted microarray slides were kept at four different storage regimes with varying temperature and humidity conditions. We showed that under the standard storage condition in a temperature-controlled (21°C) and desiccated environment (0% relative humidity), microarray slides remained stable for at least 22 months without loss of antigen quality, whereas the other three conditions (37°C, desiccated; Room temperature, non-desiccated; Frozen, desiccated) produced acceptable results for some antigens (influenza A, S.pneumoniae), but not for others (measles). We conclude that these arrays for multiplex antibody testing can be prepared and stored for prolonged periods of time, which aids laboratory-preparedness and facilitates sero-epidemiological studies.


Core-shell magnetic CFO@COF composites toward peroxymonosulfate activation for degradation of sulfamethoxazole from aqueous solution: A comparative study and mechanistic consideration.
A core-shell covalent organic framework encapsulated Co1.2Fe1.8O4 magnetic particles (CFO@COF) was designed and prepared successfully to activate peroxymonosulfate (PMS) for sulfamethoxazole (SMX) degradation. It displays amazing catalytic reactivity since the unique interior structure and synergistic effect between COF shell and CFO core, reaching 99.8% removal of SMX (10 mg/L) within 30 min and 90.8% TOC removal. The synergy between bimetals vests high reactivity to CFO core. And the outer COF shell can stabilize the CFO core under intricate reaction conditions to restrain the leaching of Co ions (decreased from 0.75 to 0.25 mg/L). Further investigation compared the activation mechanism in two different system, CFO/PMS system and CFO@COF/PMS system. The result showed that the radical mechanism controlled by SO4⋅- guided the SMX degradation in CFO/PMS system whereas the 1O2 played a pivotal role in CFO@COF/PMS system called non-radical leading. The influences of various factors on degradation experiments and SMX degradation pathway were also studied. Most importantly, risk assessment in CFO@COF/PMS/SMX system was estimated via "ecological structure activity relationships". In most case, the toxicities of intermediates were lower than the initial samples, which confirmed the effectiveness of CFO@COF/PMS/SMX system in the reduction of toxicity of SMX.


Tunica vaginalis flap for the management of disabling Peyronie's disease: surgical technique, results, and complications.
To discuss the surgical technique for tunica vaginalis flap (TVF) in the management of disabling Peyronie's disease and to evaluate the results and complications. Twelve patients underwent the TVF technique. Through a scrotal incision, the most dependent part of the tunica was dissected from the testicle and epididymis. The flap measured at least 4 cm in width and its upper extremity was left attached to the cremasteric muscle. Subsequently, the flap was brought underneath a groin skin bridge to cover the dorsal penile defect. All patients were pain free. Seven patients (58.3%) were able to achieve a satisfactory erection with good vaginal penetration. Five patients (41.7%) were unable to perform sexually secondary to disabling chordee in 3 patients, glanular hypoesthesia in 1 patient, and venous leakage in 1 patient. TVF is an adequate alternative for correction of distortions of Peyronie's plaque in patients with disabling disease. TVF is at present our first choice in the management of this disease. If penetration is still impaired following recurrent curvature, a Nesbit ventral plication can be used as a secondary procedure.


Adherence to cardiovascular medications: lessons learned and future directions.
Approximately 50% of patients with cardiovascular disease and/or its major risk factors have poor adherence to their prescribed medications. Finding novel methods to help patients improve their adherence to existing evidence-based cardiovascular drug therapies has enormous potential to improve health outcomes while potentially reducing health care costs. The goal of this report is to provide a review of the current understanding of adherence to cardiovascular medications from the point of view of prescribing clinicians and cardiovascular researchers. Key topics addressed include: (1) definitions of medication adherence; (2) prevalence and impact of non-adherence; (3) methods for assessing medication adherence; 4) reasons for poor adherence; and 5) approaches to improving adherence to cardiovascular medications. For each of these topics, the report seeks to identify important gaps in knowledge and opportunities for advancing the field of cardiovascular adherence research.


Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.
The authors are conducting clinical trials of the HER-2/neu E75-peptide vaccine in clinically disease-free breast cancer (BC) patients. Their phase 1-2 trials revealed that the E75 + granulocyte-macrophage colony-stimulating factor (GM-CSF) vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8(+) T cells. They assessed the need for and response to a booster after completion of primary vaccination series. BC patients enrolled in the E75 vaccine trials who were ≥6 months from completion of their primary vaccination series were offered boosters with E75 + GM-CSF. Patients were monitored for toxicity. E75-specific CD8(+) T cells were quantified using the human leukocyte antigen-A2:immunoglobulin G dimer before and after boosting. Fifty-three patients received the vaccine booster. Median time from primary vaccination series was 9 months (range, 6-35 months), and median residual E75-specific immunity was 0.70% (range, 0-3.49%) CD8(+) lymphocytes. Elevated residual immunity (ERI) (CD8(+) E75-specific T cells >0.5%) was seen in 94.4% of patients at 6 months from primary vaccination series versus 48% of patients at >6 months (P = .002). The booster was well tolerated, with only grade 1 and 2 toxicity observed. Local reactions were more robust in patients receiving the booster at 6 months from primary vaccination series compared with those at >6 months (99.4 ± 6.1 mm vs 81.8 ± 4.1 mm, P = .01). In patients lacking ERI, 85% had increased ERI after vaccination (P = .0014). The HER-2/neu E75 peptide vaccine E75 stimulates specific immunity in disease-free BC patients. However, immunity wanes with time. A vaccine booster is safe and effective in stimulating E75-specific immunity in those patients without ERI. These results suggest that the booster may be most effective at 6 months after completion of the primary vaccination series.


Allosteric modulation of GABA(A) receptor subtypes:effects on visual recognition and visuospatial working memory in rhesus monkeys [corrected].
Non-selective positive allosteric modulators (PAMs) of GABAA receptors (GABAARs) are known to impair anterograde memory. The role of the various GABAAR subtypes in the memory-impairing effects of non-selective GABAAR PAMs has not been fully elucidated. The current study assessed, in rhesus monkeys, effects of modulation of α1, α2/3, and α5GABAARs on visual recognition and spatial working memory using delayed matching-to-sample (DMTS) and self-ordered spatial search (SOSS) procedures, respectively. The DMTS procedure (n=8) involved selecting a previously presented 'sample' image from a set of multiple images presented after a delay. The SOSS procedure (n=6) involved touching a number of boxes without repeats. The non-selective GABAAR PAM triazolam and the α1GABAA preferential PAMS zolpidem and zaleplon reduced accuracy in both procedures, whereas the α5GABAA preferential PAMs SH-053-2'F-R-CH3 and SH-053-2'F-S-CH3, and the α2/3GABAA preferential PAM TPA023B were without effects on accuracy or trial completion. The low-efficacy α5GABAAR negative allosteric modulator (NAM) PWZ-029 slightly increased only DMTS accuracy, whereas the high-efficacy α5GABAAR NAMs RY-23 and RY-24 did not affect accuracy under either procedure. Finally, the slopes of the accuracy dose-effect curves for triazolam, zolpidem, and zaleplon increased with box number in the SOSS procedure, but were equivalent across DMTS delays. The present results suggest that (1) α1GABAARs, compared with α2/3 and α5GABAARs, are primarily involved in the impairment, by non-selective GABAAR PAMs, of visual recognition and visuospatial working memory in nonhuman primates; and (2) relative cognitive impairment produced by positive modulation of GABAARs increases with number of locations to be remembered, but not with the delay for remembering.


High resolution CT of the lung parenchyma with pathologic correlation.
The authors describe a technique for directly correlating high resolution CT scans and gross and histologic sections of the lung. They conclude that HRCT provides anatomic detail comparable to that seen on gross tissue inspection.


Designing payments for GPs to improve the quality of diabetes care.
Three features are essential in designing the flexible funding payments and pay-for-performance elements.


Negative association between free triiodothyronine level and international normalized ratio in euthyroid subjects with acute myocardial infarction.
To investigate the relationship between free triiodothyronine (FT3) and the international normalized ratio (the ratio of the prothrombin time of a patient to the normal sample, INR) in Chinese euthyroid subjects with acute ST-segment elevation myocardial infarction (STEMI). A total of 231 consecutive patients (177 males, 54 females) with STEMI were enrolled. Anthropometric and laboratory measurements, including heart rate, respiratory rate, blood pressure, body temperature, platelet count, INR, prothrombin time, activated partial thromboplastin time, FT3, free thyroxine (FT4), and thyroid-stimulating hormone, were collected from all the patients. The levels of FT3 and FT4 were measured with a full-automatic immune analyzer. The INR was determined using a coagulation analyzer. Patients were classified into 4 groups according to their quartile FT3 and FT4 levels: 0.40-3.09 (n=52), 3.10-3.69 (n=56), 3.70-4.29 (n=64) and 4.30-7.10 (n=59) for FT3; 4.9-14.8 (n=57), 14.9-16.8 (n=58), 16.9-18.7 (n=57) and 18.8-29.0 (n=59) for FT4. Subjects with a high FT3 level had significantly lower values of INR than those with a low FT3 level (P=0.01). Multiple linear regression analysis revealed decreased serum FT3 as an independent risk factor for elevated INR values (β=-0.139, P=0.025). The value of INR was similar among the 4 groups according to the quartile FT4 levels (P=0.36). Free triiodothyronine was negatively associated with INR in the patients with acute STEMI and normal thyroid function.


Epigenetic effects of graphene oxide and its derivatives: A mini-review.
Graphene oxide (GO), an engineered nanomaterial, has a two-dimensional structure with carbon atoms arranged in a hexagonal array. While it has been widely used in many industries, such as biomedicine, electronics, and biosensors, there are still concerns over its safety. Recently, many studies have focused on the potential toxicity of GO. Epigenetic toxicity is an important aspect of a material's toxicological profile, since changes in gene expression have been associated with carcinogenicity and disease progression. In this review, we focus on the epigenetic alterations caused by GO, including DNA methylation, histone modification, and altered expression of non-coding RNAs. GO can affect DNA methyltransferase activity and disrupt the methylation of cytosine bases in DNA strands, leading to alteration of genome expression. Modulation of histones by GO, targeting histone deacetylase and demethylase, as well as dysregulation of miRNA and lncRNA expression have been reported. Further studies are required to determine the mechanisms of GO-induced epigenetic alterations.


Thrombocyte decrease and hemoglobin level as simple non-inflammatory predictors of anastomotic leakage in rectal-cancer surger.
The study aimed to determine a simple diagnostic test that could predict the risk of anastomotic leakage in early postoperative period. A single-center, retrospective study was conducted. The electronic medical records of patients who underwent resection for rectal tumor between January 1, 2016, and December 31, 2021, in University Hospital Olomouc, were reviewed. The data included risk factors for leakage and laboratory parameters commonly obtained. The decrease in platelets was significant as for the possibility of being a marker of anastomotic leakage; OR = 0.980 (p = 0.036). A decrease of 34 or higher predicts leakage with a sensitivity of 45 % (95 % CI: 23.1-68.5 %) and specificity of 81.1 % (95 % CI: 75.2-86.1 %). Postoperative leukocyte blood level (OR = 1.134; p = 0.019) and leukocyte level on postoperative day 1 (OR = 1.184; p = 0.023) were significant predictors for leakage. WBC values ≥ 8.8 predict leakage with a sensitivity of 70.0 % (95 % CI: 45.7-88.1 %) and specificity of 55.3 % (95 % CI: 48.4-62.0 %). Hemoglobin blood level ≤ 79.5 predicts leakage with a sensitivity of 70.0 % (95 % CI: 45.7-88.1 %) and specificity of 62.2 % (95 % CI: 55.5-68.7 %). Despite the fact that the specificity and sensitivity of the followed parameters are low, they could serve as markers useful for early diagnosis or suspicion for leakage (Tab. 5, Fig. 3, Ref. 14).


Multi-institutional study of peritoneal sarcomatosis from uterine sarcoma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Uterine sarcoma (US) is a rare tumor representing 1% of female genital tract malignancies. Peritoneal sarcomatosis (PS) after US, diminishes median overall survival (OS) and progression-free survival (PFS) with cytoreductive surgery (CRS) alone, with or without systemic chemotherapy is <1 year and 6 months, respectively. A multi-institutional review of PS from US was conducted to evaluate CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) and effects on survival outcomes. A retrospective review of 36 patients from 7 specialized international centers was performed. Selection criteria included PS of uterine origin with CRS/HIPEC treatment. Clinical data were analyzed. OS and PFS were estimated with Kaplan-Meier method. Thirty-six patients underwent a total 38 HIPEC procedures performed from 2005 to 2014; 35 previous treatment and 1 primary treatment. Twenty-nine (81%) LMS patients, 3 (8%) endometrial stromal sarcoma (ESS), 3 (8%) adeneosarcoma (AS), and 1 (3%) categorized as other. Median PCI was 16 (range: 2-39), 10 patients had PCI ≥20. Thirty-four patients (94%) had complete cytoreduction (CC 0-1), 19 patients recurred. CRS/HIPEC OS at 1, 3, and 5-years was 75%, 53%, and 32% respectively, with median OS of 37 months (CI 95%: 20-54). PFS in 32 patients with CC at 1, 3, and 5-years was 67%, 32% and 32%, respectively with median PFS of 18.9 months (CI 95%: 6.7-31). CRS/HIPEC is a promising treatment modality for patients with PS. Histological subtype may influence survival. A global prospective registry of patients to further assess the efficacy of CRS/HIPEC is needed.


Prostaglandin D2, a neuromodulator.
The distribution of prostaglandin D synthetase activity was determined in various tissues of rat by using the supernatant fraction (10,000 x g, 20 min) of the homogenates. The highest activity was found in brain, spinal cord, and alimentary tract. The activity was uniquitously distributed in all parts of brain, and the highest specific activity was found in hypothalamus and thalamus. Homogenates of two neuroblastoma cell lines were found to produce prostaglandin D2, whereas a glioma cell line was almost inactive. Prostaglandin D2 is a potent and specific activator of the adenylate cyclase system of cultured neuroblastoma cells, suggesting the possibility that it may act as a neuromodulator in the central nervous system.


Future trends in the development of safer nonsteroidal anti-inflammatory drugs.
Gastrointestinal (GI) adverse events, ranging from mild to life-threatening, are well-recognized sequelae to nonsteroidal anti-inflammatory drug (NSAID) use. Recent improvements in our knowledge of the mechanisms responsible for NSAID-associated gastropathy have enabled several experimental approaches to decreasing the risk of these events. Whereas such strategies as preassociation of NSAIDs to zwitterionic phospholipids to prevent NSAID-mucosal interactions and concomitant administration of trefoil peptides to stimulate mucosal defense pathways represent novel approaches, their clinical feasibility remains to be determined. Other strategies that appear more immediately promising in the reduction of NSAID-associated GI toxicity are the coupling of NSAIDs to nitric oxide (NO)-releasing compounds and the introduction of NSAIDs that are preferential or specific for cyclo-oxygenase-2 (COX-2), the isoform implicated in the inflammatory response. Clinical trials of several specific COX-2 inhibitors, as well as European clinical data for a preferential COX-2 inhibitor, meloxicam, suggest that COX-2 inhibitors provide an advantage over standard NSAIDs in terms of GI tolerability. However, as recent observations have implicated COX-2 as an integral component in the maintenance of physiologic homeostasis, careful scrutiny of both the beneficial and the deleterious effects of the selective COX-2 inhibitors is requisite before their approval and widespread use. Furthermore, based on the physiologic importance of COX-2, the preferential inhibitors may ultimately prove to represent the optimal compromise for the treatment of various arthritides.


Warming during embryogenesis induces a lasting transcriptomic signature in fishes.
Exposure to elevated temperatures during embryogenesis can influence the plasticity of tissues in later life. Despite these long-term changes in plasticity, few differentially expressed genes are ever identified, suggesting that the developmental programming of later life plasticity may occur through the modulation of other aspects of transcriptomic architecture, such as gene network organisation. Here, we use network modelling approaches to demonstrate that warm temperatures during embryonic development (developmental warming) have consistent effects in later life on the organisation of transcriptomic networks across four diverse species of fishes: Scyliorhinus canicula, Danio rerio, Dicentrarchus labrax, and Gasterosteus aculeatus. The transcriptomes of developmentally warmed fishes are characterised by an increased entropy of their pairwise gene interaction networks, implying a less structured, more 'random' set of gene interactions. We also show that, in zebrafish subject to developmental warming, the entropy of an individual gene within a network is associated with that gene's probability of expression change during temperature acclimation in later life. However, this association is absent in animals reared under 'control' conditions. Thus, the thermal environment experienced during embryogenesis can alter transcriptomic organisation in later life, and these changes may influence an individual's responsiveness to future temperature challenges.


Factors associated with upper limb function in breast cancer survivors.
Breast cancer survivors may have side effects from treatment, such as impaired upper limb function after surgery, which may be affected by a range of factors. To analyze the association between upper limb function and strength, fear avoidance, and central sensitization symptoms among breast cancer survivors, and to explore how these variables are associated with upper limb function. Validation cohort. Institutional practice at a public hospital. One hundred seventy-four breast cancer survivors who had been undergone surgery for a primary tumor. Not applicable. Upper limb function was measured by the Upper Limb Functional Index (ULFI-Sp). Independent outcomes were: handgrip strength, which was measured using a Jamar dynamometer on the dominant side; fear avoidance, measured using the Fear-Avoidance Components Scale (FACS-Sp); and central sensitization symptoms, which were measured using the Central Sensitisation Inventory (CSI-Sp). A linear regression model explaining the ULFI-Sp results was constructed with the variables. The regression model was significant (F = 46.826; p < .0001), and explained 45% of the variance of the ULFI values. All variables showed strong associations with upper limb function. Greater upper limb function is associated with higher grip strength, lower fear-avoidance behavior and fewer central sensitization symptoms among breast cancer survivors. These variables explained 45% of the upper limb function in the regression model, and concur with earlier research showing that factors such as central sensitization symptoms and kinesiophobia negatively affect upper limb function in such patients. Clinicians should therefore take into account strength, fear avoidance, and central sensitization symptoms when considering interventions aimed at improving upper limb function among breast cancer survivors.


Pancreatic acinar cell carcinoma presenting as acute pancreatitis.
Acinar cell carcinoma (ACC) is a rare pancreatic neoplasm, and its presentation with acute pancreatitis has not been reported previously. A 70-year-old man presented with acute pancreatitis, and a spiral CT scan showed a 5-cm tumour in the body of the pancreas. Distal pancreatectomy was performed, and histological examination showed an ACC. This is a newly reported mode of presentation for a rare pancreatic tumour.


Comparison of automatic and voluntary chewing patterns and performance.
Chewing, like respiration, is ordinarily performed as an automatic motor act, yet both can be voluntarily controlled. No in-depth analyses of voluntary chewing exist. Therefore, we have analyzed on a cycle-by-cycle basis voluntarily controlled chewing, and compared it with automatic chewing. We assessed the performance during voluntarily controlled chewing by obtaining constant error and variable error scores. Nine healthy adults with full dentition were subjects (Ss). Their three-dimensional jaw movements and movement times were derived from Kinesiograph recordings obtained while chewing a standard piece of gum on the right side of the mouth. Burst durations and onset latencies of masseter activity were obtained from surface-recorded EMGs. Frequency during automatic chewing was obtained from data recorded while the subject viewed a film. Next, the subject chewed in time with a metronome set at this "automatic" rate. Intrasubject variability among 30 consecutive chewing cycles during voluntary was less than during automatic chewing. In every S gape and ipsilateral jaw excursions and the variability of burst durations of masseter activity were less during voluntary than during automatic chewing, showing that both the spatial and temporal aspects of the two types of chewing differ significantly. Ss varied in ability to follow the metronome. A S's constant error might be small, yet his variable error might be large, as if feed-back-based corrections influenced cycle-to-cycle variability. Fast chewers had smaller constant and variable error scores than did slow chewers, suggesting a speed-accuracy relationship. In summary, both temporal and spatial aspects of voluntary chewing were modified compared with those of automatic chewing. During voluntarily controlled chewing, cycle-to-cycle variability was less compared with automatic chewing due to reductions in variability of occlusal phase and the masseter's burst durations, and total jaw excursions were less because gapes and ipsilateral deviations during closing were reduced.


Renal C4d is a potential biomarker of disease activity and severity in pediatric lupus nephritis patients.
Systemic lupus erythematosus (SLE), a multisystemic autoimmune disease, is very aggressive in pediatric-onset patients as they are prone to develop lupus nephritis (LN). Although renal C4d positivity is correlated with the activity of renal disease and SLE in adult-onset LN patients, available information for pediatric-onset patients is limited. To evaluate the potential diagnostic significance of renal C4d staining in pediatric LN patients, we retrospectively detected C4d staining by immunohistochemistry on renal biopsy specimens from 58 pediatric LN patients. The clinical and laboratory data at the time of the kidney biopsy and the renal disease activity of histological injury were analyzed according to the C4d staining status. Glomerular C4d (G-C4d)-positive staining was detected in all 58 cases of LN. Patients with a G-C4d score of 2 displayed more severe proteinuria than those with a G-C4d score of 1 (24-h urinary protein: 3.40 ± 3.55 g vs. 1.36 ± 1.24 g, P < 0.05). Peritubular capillary C4d (PTC-C4d) positivity was found in 34 of 58 LN patients (58.62%). The PTC-C4d-positive patient groups (patients with a PTC-C4d score of 1 or 2) had higher serum creatinine and blood urea nitrogen levels as well as renal pathological activity index (AI) and SLE disease activity index (SLEDAI) scores; however, they had lower serum complement C3 and C4 levels compared to PTC-C4d-negative patients (P < 0.05). In addition, there was positive tubular basement membrane C4d (TBM-C4d) staining in 11 of 58 LN patients (18.96%), and a higher proportion of TBM-C4d-positive patients than TBM-C4d-negative patients (63.63% vs. 21.27%) had hypertension. Our study revealed that G-C4d, PTC-C4d, and TMB-C4d were positively correlated with proteinuria, disease activity and severity, and hypertension, respectively, in pediatric LN patients. These data suggest that renal C4d is a potential biomarker for disease activity and severity in pediatric LN patients, providing insights into the development of novel identification and therapeutic approaches for pediatric-onset SLE with LN.


Improvement in nasal obstruction and quality of life after septorhinoplasty and turbinate surgery.
To evaluate the long-term impact of functional septorhinoplasty (SRP) with and without inferior turbinate reduction (ITR) on disease-specific symptom severity and general health-related quality of life (QOL). Prospective cohort study at a tertiary referral center. Patients undergoing functional SRP with and without ITR were administered the Nasal Obstruction Symptom Evaluation (NOSE) scale to assess severity of nasal obstruction and the EuroQol-5 Dimension Questionnaire Visual Analog Scale (EQ-5D VAS) to assess general health-related QOL preoperatively and at 2, 4, 6, 12, 24, and 36 months postoperatively. Patient demographics, surgical technique, symptom severity, and QOL outcomes were analyzed. A total of 567 patients were included, with 391 patients undergoing functional SRP alone (54.0% female; mean age 36.0 years [standard deviation (SD):16.2]) and 176 patients undergoing functional SRP with ITR (50.0% female; mean age 35.6 years [SD:13.6]). There was a significant decrease in NOSE and increase in EQ-5D VAS scores in both groups through at least 24 months postoperatively. Change in NOSE scores was negatively correlated with change in EQ-5D VAS (r = -0.38, P < 0.01). Compared to patients undergoing SRP, patients also undergoing ITR had a statistically but nonclinically significant improvement in NOSE, with similar trends for EQ-5D VAS that were not significant. SRP results in a sustained, long-term improvement in nasal obstruction based on disease-specific and general health-related QOL measures, with incremental improvement in outcomes with addition of ITR. This study provides the foundation for defining health outcomes and the health utility value of surgical interventions that address nasal obstruction. 2c Laryngoscope, 129:1554-1560, 2019.


Composite Dorsal Augmentation.
Dorsal augmentation is one of the most challenging procedures in rhinoplasty. Solid grafts and diced fascia graft (DC-F) have been employed for this purpose with varying success. Warping, irregularities, and variability of final height are some of the potential pitfalls. The aim of this study was to assess the efficiency of the authors' approach combining multiple grafts for nasal dorsal augmentation. They described a technique employing composite dorsal augmentation that is a combination of a foundation layer utilizing high spreader grafts plus a dorsal gap graft combined with a contour layer of 3 possible types of fascia or DC-F grafts. The combination of the 2 layers for the nasal dorsum can be varied to achieve the required height to correct the patient's deformity and achieve the desired aesthetic goals. Fifty-one patients who underwent dorsal augmentation with composite technique between 2017 and 2020 were retrospectively reviewed. A step-by-step algorithm was applied to achieve the required dorsal height. The patients were divided into 3 groups according to the type of contour graft: double-layer fascia graft, segmental DC-F, or narrow thin full-length DC-F. Smooth continuity and increased projection of the nasal dorsum were achieved in all patients. Composite dorsal augmentation is an effective technique for dorsal augmentations requiring 4 mm or more of height increase. This technique allows to achieve dorsal augmentation employing a combination of grafts from a single donor site together with camouflaging dorsal irregularities and highlighting dorsal aesthetic lines. This algorithm allows optimization of patients' aesthetic profile.


The heparin-glutathione test: an alternative to the hypo-osmotic swelling test to select viable sperm for intracytoplasmic sperm injection.
To evaluate the heparin-glutathione test (HEGLUT) for the selection of viable sperm for intracytoplasmic sperm injection (ICSI). A prospective study. Department of Pediatrics, Obstetrics and Gynecology, University of Valencia and Instituto Valenciano de Infertilidad. Semen samples from healthy donors and patients with infertility. Sperm samples were kept in culture for different periods in Ham's F-10 medium supplemented or not supplemented with heparin, reduced glutathione (GSH), or a heparin-GSH mixture. Control and heparin-GSH-treated spermatozoa were injected into hamster oocytes. The HEGLUT and ICSI were performed. Sperm nuclear decondensation, progressive and nonprogressive motility, and male pronucleus formation. The maximum proportion of sperm nuclear decondensation (28.7%+/-2.1% versus 2.6%+/-0.5% in the control group) was reached after 60 minutes of incubation in the presence of a heparin-GSH mixture. Differences in the percentages of progressive and nonprogressive motility among treatments and times of incubation, although statistically significant, were biologically negligible. No statistically significant differences were observed in the rate of sperm head decondensation (8.2% [4/49] versus 11.1% [6/54]) and male pronucleus formation (18.4% [9/49] versus 22.2% [12/541) after the injection of control and treated spermatozoa into hamster oocytes. The HEGLUT may offer an alternative to the hypo-osmotic swelling test for the selection of viable sperm for ICSI.


Young teenagers' perceptions of their own and others' bodies: a qualitative study of obese, overweight and 'normal' weight young people in Scotland.
The rise in numbers of overweight/obese children in the UK is causing widespread concern. Biomedical constructions of body acceptability and 'good health' mean that overweight/obese young people are frequently seen as deviant. The socio-cultural contexts within which young teenagers become fat, and lay conceptualisations of fatness, have largely been ignored. This qualitative study involved in-depth interviews with teenagers aged 13-14 years (n = 36), drawn from families living in areas classified as socio-economically disadvantaged. Half of the sample had a Body Mass Index (BMI) classifying them as overweight or obese, whilst the remainder were classified as being 'normal' weight. Participants' embodied perceptions of fatness were complex and sometimes contradictory. We discuss what young teenagers perceive the influences on fatness and body size to be; the professed consequences of being fat; participants' experiences of attempting to lose weight; and, their reported interactions with friends and family relating to fatness and dieting. Participants rarely mentioned any health-related consequences of their own and others' fatness, although wearing 'nice' clothes and being slowed down were raised as considerations by girls and boys, respectively. 'Normal' weight teenagers who disliked their bodies or who wanted to lose weight often claimed to be anxious about this. Being very obese also led to anxiety and reported attempts at 'crash dieting'. Acceptance of body size/shape was, however, common amongst the overweight and obese teenagers, although some had attempted weight loss. The teenagers in this study were rarely supportive of friends or family who attempted to lose weight and frequently disagreed with others' perceptions of fatness. These findings are important as they contradict the common perception that being overweight/obese is related to body dissatisfaction and that young people have a fear of fatness.


Initial Clinical Experience of Cherenkov Imaging in External Beam Radiation Therapy Identifies Opportunities to Improve Treatment Delivery.
The value of Cherenkov imaging as an on-patient, real-time, treatment delivery verification system was examined in a 64-patient cohort during routine radiation treatments in a single-center study. Cherenkov cameras were mounted in treatment rooms and used to image patients during their standard radiation therapy regimen for various sites, predominantly for whole breast and total skin electron therapy. For most patients, multiple fractions were imaged, with some involving bolus or scintillators on the skin. Measures of repeatability were calculated with a mean distance to conformity (MDC) for breast irradiation images. In breast treatments, Cherenkov images identified fractions when treatment delivery resulted in dose on the contralateral breast, the arm, or the chin and found nonideal bolus positioning. In sarcoma treatments, safe positioning of the contralateral leg was monitored. For all 199 imaged breast treatment fields, the interfraction MDC was within 7 mm compared with the first day of treatment (with only 7.5% of treatments exceeding 3 mm), and all but 1 fell within 7 mm relative to the treatment plan. The value of imaging dose through clear bolus or quantifying surface dose with scintillator dots was examined. Cherenkov imaging also was able to assess field match lines in cerebral-spinal and breast irradiation with nodes. Treatment imaging of other anatomic sites confirmed the value of surface dose imaging more broadly. Daily radiation therapy can be imaged routinely via Cherenkov emissions. Both the real-time images and the posttreatment, cumulative images provide surrogate maps of surface dose delivery that can be used for incident discovery and/or continuous improvement in many delivery techniques. In this initial 64-patient cohort, we discovered 6 minor incidents using Cherenkov imaging; these otherwise would have gone undetected. In addition, imaging provides automated, quantitative metrics useful for determining the quality of radiation therapy delivery.


A Fight between Plants and Pathogens for the Control of Chloroplasts.
Chloroplasts are the home of innumerable metabolic pathways for plant growth and environmental responses. Recently, in an issue of Cell, Medina-Puche et al. revealed a novel mechanism by which plant pathogens dampened host defense responses, orchestrated from chloroplasts. This mechanism encompassing the plasma membrane and chloroplasts has likely been established via host-pathogen co-evolution.


On the role of NMR spectroscopy for characterization of antimicrobial peptides.
Antimicrobial peptides (AMPs) provide a primordial source of immunity, conferring upon eukaryotic cells resistance against bacteria, protozoa, and viruses. Despite a few examples of anionic peptides, AMPs are usually relatively short positively charged polypeptides, consisting of a dozen to about a hundred amino acids, and exhibiting amphipathic character. Despite significant differences in their primary and secondary structures, all AMPs discovered to date share the ability to interact with cellular membranes, thereby affecting bilayer stability, disrupting membrane organization, and/or forming well-defined pores. AMPs selectively target infectious agents without being susceptible to any of the common pathways by which these acquire resistance, thereby making AMPs prime candidates to provide therapeutic alternatives to conventional drugs. However, the mechanisms of AMP actions are still a matter of intense debate. The structure-function paradigm suggests that a better understanding of how AMPs elicit their biological functions could result from atomic resolution studies of peptide-lipid interactions. In contrast, more strict thermodynamic views preclude any roles for three-dimensional structures. Indeed, the design of selective AMPs based solely on structural parameters has been challenging. In this chapter, we will focus on selected AMPs for which studies on the corresponding AMP-lipid interactions have helped reach an understanding of how AMP effects are mediated. We will emphasize the roles of both liquid- and solid-state NMR spectroscopy for elucidating the mechanisms of action of AMPs.


Diterpenoids from the Whole Plants of Ajuga nipponensis and Their Inhibition of RANKL-Induced Osteoclastogenesis.
Two new diterpenoids, ajudecunoid A (1) and ajudecunoid B (14), along with thirteen known diterpenoids, were isolated from the whole plants of Ajuga nipponensis Makino. Their structures were elucidated by the extensive spectroscopic analysis (UV, IR, MS, and NMR). The absolute configurations of ajudecunoid A (1) and ajudecunoid B (14) were defined through analysis of X-ray crystallography. Fifteen compounds were evaluated for inhibition of the formation of osteoclasts in bone marrow-derived macrophages (BMM) cells. Two neo-clerodane diterpenoids ajuganipponin B (5) and (12S)-6α,19-diacetoxy-18-chloro-4α-hydroxy-12-tigloyloxy-neo-clerod-13-en-15,16-olide (12) showed significant inhibition of osteoclastogenesis with IC50 values of 0.88 and 0.79 μM, respectively. Here we firstly reported diterpenoids with anti-osteoclastogenesis activity from A. nipponensis.


Development of skin aging scale by using dermoscopy.
Some features of skin aging that cannot be detected by the naked eye can be determined more easily by dermoscopy. Therefore, we aimed to measure skin aging with dermoscopy. The study was performed in Istanbul Training and Research Hospital, a tertiary care referral center. A total of 441 participants between the ages of 20-88 (mean 48.4 ± 17.7) were separated into six groups according to their age. All participant's facial sun-exposed areas were examined by dermoscopy in terms of telangiectasia, vascular changes, pigmentation changes, seborrheic keratosis, actinic keratosis, periorbital comedones and cysts, superficial- deep- criss-cross wrinkles as the signs of photoaging and scored with the help of dermoscopic photoaging scale (DPAS). The validity of the scale was assessed with DPAS by the evaluation of both the axillar and the gluteal regions, that were not sun exposed and photoaged, with DPAS. The scale was found to be highly reliable as Cronbach's α coefficient was 0.756. Skin aging of patients from every decade was compared clinically with Glogou photoaging scale and Monheit-Fulton photoaging index and significant correlation was calculated as 0.773 and 0.774, respectively. An increase in photoaging scores from young people toward elders according to their ages was observed and the same linear difference between their mean values was detected. DPAS is a reliable and valid diagnostic tool that can evaluate photoaged skin quantitatively by the help of objective criteria so can be used to evaluate the effect of preventive and therapeutic applications for skin aging.


HPLC-DAD optimization of quantification of vescalagin, gallic and ellagic acid in chestnut tannins.
The quantification of hydrolysable polyphenols such as gallic, ellagic acid and vescalagin by HPLC-DAD is classically run after methanol extraction as a reference solvent. Water extraction is usually discarded because of a lower obtention of total polyphenol content compared to methanol extraction. In our study, methanol was compared to water extraction in both the total polyphenol content method and the HPLC-DAD analysis. Total polyphenol content in water extraction was lower than in methanol extraction, but water extraction gave better results on HPLC-DAD. In conclusion, total polyphenol content cannot be used as reference to choose the solvent of extraction to quantify some polyphenols by HPLC-DAD because of the specific properties of each polyphenol. Indeed, recovery results obtained on hydrolysable polyphenols with water extraction were better and with a lower variability than following methanol extraction.


Analysis of Financial Risk Protection Indicators in Myanmar for Paediatric Surgery.
To estimate proportion of Myanmar paediatric population at risk of impoverishment and catastrophic expenditure due to emergency surgical intervention. Prospective data were collected at two tertiary surgical centres including income, household expenses, expenses related to surgery. Data analysis was performed to estimate out-of-pocket (OOP) direct medical costs and OOP total costs. Catastrophic expenditure: expense exceeded 10% of household income. Risk of impoverishment: net income drops were below an impoverishment threshold (PPP-purchasing power parity): I$ 2.00 PPP/day, I$ 1.25/day PPP, national poverty line. Distribution of income was estimated using a gamma distribution. Comparison to an adult cohort was performed using Chi-square test with a p value of <0.05 being significant. A total of 145 surveys were collected, and 119 (82.1%) contained sufficient data: Paediatric Centre (n = 99) and Adult Centre (n = 20). Overall average per patient direct medical and non-medical OOP costs was I$493: Centre 1: I$540 PPP (range I$41-6,588 PPP) and Centre 2: I$437 PPP (range I$ 36-1,405 PPP). 64% experienced catastrophic expense. There is no significant difference between the centres in the risks of impoverishment or catastrophic expenditure (p = 0.05). Up to 44% are at risk of catastrophic expenditure should surgery be required. Most of the risk (90%) is derived from direct non-medical costs. A high proportion were at the national poverty line threshold (36.1%). Seeking surgical treatment would imperil up to 37% at the national poverty line threshold, and up to 5.7% at the I$2 PPP per day limit. A large proportion of the Myanmar population are at risk of impoverishment or catastrophic expenditure should they require surgery. Financial risk protection mechanisms are needed.


Pain management and spirometry following thoracotomy: a prospective, randomized study of four techniques.
Forty-five patients who underwent anterolateral and posterolateral thoracotomy were studied to compare the relative efficacy of cryoanalgesia, epidural morphine, intrapleural analgesia, and intravenous morphine for relief of postoperative pain and prevention of deterioration in pulmonary function. Spirometry (FEV1, FVC) was performed preoperatively and postoperatively. Patients' pain was assessed using the 0 to 100 mm visual analog scale. Because intravenous morphine was used to supplement pain relief in the patients who received intrapleural analgesia and cryoanalgesia, total morphine use was compared to that administered to patients in the intravenous morphine group. Epidural morphine was found to offer better pain relief than the other treatment modalities. There were no differences in spirometric testing between the groups at any time during the study. Although the number of evaluable patients was insufficient to draw definitive conclusions, 12-week follow-up suggested a difference in the incidence of post-thoracotomy pain syndrome in patients who received cryoanalgesia. It is concluded that post-thoracotomy pain is best relieved with epidural morphine, compared to intrapleural analgesia, cryoanalgesia, and parenteral morphine. There was no change in the deterioration in spirometric tests after thoracotomy, nor was there any advantage offered by cryoanalgesia or intrapleural analgesia over intravenous morphine, with respect to pain relief.


Integrating 3HP-based tuberculosis preventive treatment into Zimbabwe's Fast Track HIV treatment model: experiences from a pilot study.
Tuberculosis (TB) causes one-third of HIV-related deaths worldwide, making TB preventive treatment (TPT) a critical element of HIV programmes. Approximately 16% of people living with HIV (PLHIV) on antiretrovirals in Zimbabwe are enrolled in the Fast Track (FT) differentiated service delivery model, which includes multi-month dispensing of antiretrovirals and quarterly health facility (HF) visits. We assessed the feasibility and acceptability of utilizing FT to deliver 3HP (3 months of once-weekly rifapentine and isoniazid) for TPT by aligning TPT and HIV visits, providing multi-month dispensing of 3HP, and using phone-based monitoring and adherence support. We recruited a purposive sample of 50 PLHIV enrolled in FT at a high-volume HF in urban Zimbabwe. At enrolment, participants provided written informed consent, completed a baseline survey, and received counselling, education and a 3-month supply of 3HP. A study nurse mentor called participants at weeks 2, 4 and 8 to monitor and support adherence and side effects. When participants returned for their routine 3-month FT visit, they completed another survey, and study staff conducted a structured medical record review. In-depth interviews were conducted with providers who participated in the pilot. Participants were enrolled between April and June 2021 and followed through September 2021. Median age = 32 years (IQR 24,41), 50% female, median time in FT 1.8 years (IQR 0.8,2.7). Forty-eight participants (96%) completed 3HP in 13 weeks; one completed in 16 weeks, and one stopped due to jaundice. Most participants (94%) reported "always" or "almost always" taking 3HP correctly. All reported they were very satisfied with the counselling, education, support and quality of care they received from providers and FT service efficiency. Almost all (98%) said they would recommend it to other PLHIV. Challenges reported included pill burden (12%) and tolerability (24%), but none had difficulty with phone-based counselling or wished for additional HF-based visits. Using FT to deliver 3HP was feasible and acceptable. Some reported tolerability challenges but 98% completed 3HP, and all appreciated the efficiency of aligning TPT and HIV HF visits, multi-month dispensing and phone-based counselling. Scaling up this approach could expand TPT coverage in Zimbabwe.


How I do it: tapered rod placement across the cervicothoracic junction for augmented posterior constructs.
Posterior instrumentation techniques are commonly employed for cervicothoracic fixation. The pedicles of the upper thoracic vertebrae can typically accommodate larger diameter screws than the subaxial cervical vertebrae. In many construct systems, this requires the use of a tapered rod, which can be technically challenging to place. Using a three-dimensionally printed biomimetic spine simulator, we illustrate the stepwise process of instrumentation and tapered rod placement across the cervicothoracic junction (CTJ). Tapered rod systems can augment the biomechanical stability of cervicothoracic constructs. Ease of rod placement across the CTJ hinges upon a systematic method of instrumentation.


Oceanic biology: spawning of eels near a seamount.
Discoveries of the larvae of the European and American eels, Anguilla anguilla and A. rostrata, in the Sargasso Sea and of the Japanese eel, A. japonica, in the Philippine Sea indicate that these freshwater eels migrate thousands of kilometres into the open ocean to spawn. Here we pinpoint a spawning location for Japanese eels after genetically identifying newly hatched larvae that we collected from the site. The restricted size of this spawning area ensures that the eel larvae enter a particular current that transports them to the freshwater areas in east Asia where they mature, and it also prevents them from being carried southwards away from their species range by a different local current.


Rehabilitative interventions in patients with persistent post COVID-19 symptoms-a review of recent advances and future perspectives.
The SARS-CoV-2 pandemic has not only caused millions of deaths but left also millions of people with persistent symptoms behind. These long-term COVID-19 sequelae cause a considerable burden on individuals´ health, healthcare systems, and economies worldwide given the high rate of SARS-CoV-2 infections. Therefore, rehabilitative interventions and strategies are needed to counteract the post COVID-19 sequelae. The importance of rehabilitation for patients with persistent COVID-19 symptoms has been recently also highlighted in a Call for Action by the World Health Organisation. Based on previously published research, but also in line with clinical experience, COVID-19 is not one specific disease but rather presents in different phenotypes that vary in their pathophysiological mechanisms, symptomatic manifestations, and potential interventional approaches. This review provides a proposal for differentiating post COVID-19 patients in non-organ-specific phenotypes that may help clinicians to evaluate patients and to plan therapeutic options. Furthermore, we present current unmet needs and suggest a potential pathway for a specific rehabilitation approach in people with persistent post-COVID symptoms.


Dynamics of oogenesis in ghost shrimp Callichirus major (Crustacea: Axiidea): a morphofunctional and histochemical study.
Callichirus major, popularly known as ghost shrimp, is a species of great importance in the fishing industry, because of its use as live bait. This study aimed to describe the different stages of the developing ovaries in C. major. Shrimps were collected along the Corujão beach, Piuma, Brazil (20°50'41.6"S 40°44'15.7"W), and the gonads were dissected for histological and histochemical analysis. The ovary consists of two elongated filaments covered by a connective tissue that divides the organ into lobules, where somatic and germ cells are found. It was possible to classify five types of germ cells: Oogonia (Oog), previtellogenic oocyte (Oc1), early vitellogenic oocyte (Oc2), late vitellogenic oocyte (Oc3) and mature oocyte (Oc4) based on their vitellogenic stage, cytoplasmic, nuclear and morphometric characteristics. The histochemical analysis demonstrated an intense reaction for proteins and polysaccharides in peripheral cytoplasm of Oc3 comparing to others cell types. According to size, volume, color intensity and distribution of oocyte types the gonads were classified into: immature, developing, developed and spent, being in females at this last stage, observed empty follicles and oocytes in reabsorption process. During oogenesis was observed a gradual increase in cytoplasmic acidophilia due to accumulation of yolk granules and the intense histochemical reaction in periphery of Oc3, which indicate the beginning of an extravitellogenic source of nutrients. Based on the microscopic analysis of the vitellogenesis, shrimp C. major showed the initial short phase of oocyte growth following with a fast vitellogenic cycle.


In vitro characterization of EHV-4 gG-deleted mutant.
Equine herpesvirus 4 (EHV-4) is an important pathogen that causes respiratory tract disease in horse populations worldwide. Glycoprotein G (gG) homologs have been identified in several alphaherpesviruses as minor non-essential membrane-anchored glycoproteins. In this study, EHV-4 gG deletion mutant has been generated by using bacterial artificial chromosome technology to investigate the role of gG in viral pathogenesis. Our findings reported here revealed no significant difference between parental EHV-4 and gG-negative strain in their replication cycle in cell culture. Furthermore, virus titers and plaque formation were comparable in both viruses. It is noteworthy that these findings disagree with the previously published study describing gG deletion in another EHV-4 strain.


PbrWRKY70 increases pear (Pyrus bretschneideri Rehd) black spot disease tolerance by negatively regulating ethylene synthesis via PbrERF1B-2.
Various pear plant cultivars exhibit diverse abilities to resist pear black spot disease (BSD), while the precise molecular mechanisms of resistance against pear BSD remain unclear. This study proposed a profound expression of a WRKY gene, namely PbrWRKY70, derived from Pyrus bretschneideri Rehd, within a BSD-resistant pear cultivar. Comparative analysis against the wild-type revealed that the overexpression of PbrWRKY70 engendered augmented BSD resistance of transgenic Arabidopsis thaliana and pear calli. Notably, the transgenic plants exhibited higher activities of superoxide dismutase and peroxidase, along with an elevated capacity to counteract superoxide anions via increased anti-O2-. Additionally, these plants displayed diminished lesion diameter, as well as reduced levels of hydrogen peroxide, malondialdehyde and 1-aminocyclopropane-1-carboxylic acid (ACC) contents. We subsequently demonstrated that PbrWRKY70 selectively bound to the promoter region of ethylene-responsive transcription factor 1B-2 (PbrERF1B-2), a potential negative regulator of ACC, thereby downregulating the expression of ACC synthase gene (PbrACS3). Consequently, we confirmed that PbrWRKY70 could enhance pear resistance against BSD by reducing ethylene production via modulation of the PbrERF1B-2-PbrACS3 pathway. This study established the pivotal relationship among PbrWRKY70, ethylene synthesis and pear BSD resistance, fostering the development of novel BSD-resistant cultivars. Furthermore, this breakthrough holds the potential to enhance pear fruit yield and optimize storage and processing during the later stages of fruit maturation.


Quantitative biology of survival under antibiotic treatments.
The mathematical formulation for the dynamics of growth reduction and/or killing under antibiotic treatments has a long history. Even before the extensive use of antibiotics, attempts to model the killing dynamics of biocides were made [1]. Here, we review relatively simple quantitative formulations of the two main modes of survival under antibiotics, resistance and tolerance, as well as their heterogeneity in bacterial populations. We focus on the two main types of heterogeneity that have been described: heteroresistance and antibiotic persistence, each linked to the variation in a different parameter of the antibiotic response dynamics. Finally, we review the effects on survival of combining resistance and tolerance mutations as well as on the mode and tempo of evolution under antibiotic treatments.


Interleukin-1 enhances pain reflexes. Mediation through increased prostaglandin E2 levels.
Interleukin-1 (IL-1) has been shown to induce inflammatory reactions in part through increased prostaglandin production. Prostaglandins of the E- and I-type sensitize nociceptors in peripheral tissues. We have therefore investigated the effect of IL-1 perfusion in the isolated rabbit ear, a model which allows the assessment of peripheral pain. Natural IL-1 from human monocytes, IL-1 from glioblastoma cells as well as recombinant IL-1 alpha or beta, increased the pain reflex induced by acetylcholine in a concentration dependent manner. The PGE2 levels were measured in the perfusate and were found to be enhanced more than 10-fold after the infusion of IL-1 alpha or IL-1 beta. This effect was paralleled by the enhanced pain reflexes and persisted for at least one hour after cessation of the IL-1 perfusion. Both the increased pain reflexes as well as the enhanced PGE2 levels were abolished by addition of the cyclooxygenase inhibitor diclofenac-Na (Voltaren) to the perfusion fluid. These results show that besides the numerous known physiological functions of IL-1, it may also play a role in peripheral pain sensations.


Fuzheng Huayu recipe alleviates liver fibrosis via inhibiting NLRP3 inflammasome activation in macrophages.
Fuzheng Huayu recipe (FZHY) is a commonly used Traditional Chinese Medicine formula for treating liver fibrosis in clinical settings. Despite its widespread use, the specific curative effects and underlying pharmacological mechanisms of FZHY in treating liver fibrosis are not yet fully understood. This study aims to investigate the antifibrotic mechanism of FZHY treatment by exploring its effects on the activation of NOD-like receptor protein 3 (NLRP3) inflammasome in macrophages. In order to investigate the impact of FZHY on the activation and priming of NLRP3 inflammasome in clinical trials and animal experiments using immunohistochemistry and Western blotting. Twenty-four C57BL/6 mice were used to induce liver fibrosis by feeding a diet that contained 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). To study inflammasome function, Lipopolysaccharide (LPS)/adenine triphosphate (ATP) induced NLRP3 inflammasome activation was induced in bone marrow-derived macrophages (BMDMs) isolated from wild mice. The effects of macrophage NLRP3 inflammasome activation on the function of hepatic stellate cells (HSCs) were explored by treating primary HSCs with preconditioned media from BMDMs culture. FZHY treatment resulted in the downregulation of NLRP3 protein expression and inhibition of its priming and activation in both human fibrotic livers and DDC-induced liver fibrosis. Furthermore, FZHY was observed to block the activation of the NLRP3 inflammasome pathway, which can lead to excessive inflammatory cytokine release in supernatants and cell lysates in response to LPS and ATP. Lastly, treatment with FZHY was able to inhibit the activation of HSCs induced by supernatants from macrophages. FZHY has been shown to potentially prevent NLRP3 inflammasome activation in macrophages which can result in the suppression of HSCs activation. Ultimately, these effects may lead to the improvement of liver fibrosis. The ability of FZHY to act on this novel mechanism represents an important aspect of its therapeutic potential for liver fibrosis.


Lack of change in striatal DARPP-32 levels following nigrostriatal dopaminergic lesions in animals and in parkinsonian syndromes in man.
The present study was performed to determine the effect of a nearly complete nigrostriatal dopaminergic denervation on DARPP-32 levels in the striatum from animals and parkinsonian patients. DARPP-32 levels were estimated by in vitro phosphorylation in the presence of cAMP, or after inactivation of endogenous kinases and phosphatases, in the presence of the catalytic subunit of cAMP-dependent protein kinase. Intranigral 6-hydroxydopamine (6-OHDA) infusion in rats, or peripheral administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets, did not change striatal DARPP-32 levels. Postmortem studies, carried out on brains obtained shortly after death, from patients with Parkinson disease, or from patients with progressive supranuclear palsy, showed that the levels of striatal DARPP-32 were not different from controls. These results indicate that dopaminergic striatal denervation did not modify the amount of DARPP-32 in the striatum, suggesting that the expression of DARPP-32, a protein which mediates some of the effects of dopamine in striatal neurons, is independent from the dopaminergic innervation.


Cross-talk between the HPA axis and addiction-related regions in stressful situations.
Addiction is a worldwide problem that has a negative impact on society by imposing significant costs on health care, public security, and the deactivation of the community economic cycle. Stress is an important risk factor in the development of addiction and relapse vulnerability. Here we review studies that have demonstrated the diverse roles of stress in addiction. Term searches were conducted manually in important reference journals as well as in the Google Scholar and PubMed databases, between 2010 and 2022. In each section of this narrative review, an effort has been made to use pertinent sources. First, we will provide an overview of changes in the Hypothalamus-Pituitary-Adrenal (HPA) axis component following stress, which impact reward-related regions including the ventral tegmental area (VTA) and nucleus accumbens (NAc). Then we will focus on internal factors altered by stress and their effects on drug addiction vulnerability. We conclude that alterations in neuro-inflammatory, neurotrophic, and neurotransmitter factors following stress pathways can impact related mechanisms on craving and relapse susceptibility.


Prognostic impact of fascin-1 expression is more significant in advanced colorectal cancer.
Fascin-1 is not expressed in normal colorectal epithelium, but is up-regulated in colorectal cancer. However, its exact biological mechanism remains unknown. The purpose of this study was to investigate the relationship of fascin-1 expression with the clinicopathologic parameters and its prognostic impact in advanced colorectal cancer. The immunohistochemical stainings for fascin-1, β-catenin, and Ki-67 labeling index were performed with 126 stage III colorectal cancer specimens. Fascin-1 was found to be expressed in 74 (58.7%) of the 126 colorectal cancer specimens. Five-year survival rate was significantly low, whereas the distant recurrence rate was significantly high in patients with fascin-positive stage III colorectal cancer. There was no significant correlation between fascin-1 expression and clinicopathologic factors such as tumor size, nodal metastasis, pathologic stage, β-catenin expression, and Ki-67 labeling index. However, fascin-1 expression was an independent prognostic factor in multivariate analysis. Patients with N1 showed no significant difference in 5-y DFS and OS according to the fascin-1 expression (79.0% versus 60.5%, P = 0.113; 86.5% versus 78.8%, P = 0.566). Patients with N2 showed marginal difference in 5-y DFS and significant difference in 5-y OS according to the fascin-1 expression (59.4% versus 32.4%, P = 0.088; 81.2% versus 39.5%, P = 0.002). This study suggests that fascin-1 expression in colorectal cancer may be clinically useful in predicting distant metastasis and poor survival, and we demonstrated that fascin-1 expression and N stage are significant independent prognostic factors for survival of colorectal cancer patients.


Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling.
Radiation therapy (RT) has a suboptimal effect in patients with pancreatic ductal adenocarcinoma (PDAC) due to intrinsic and acquired radioresistance (RR). Comprehensive bioinformatics and microarray analysis revealed that cholesterol biosynthesis (CBS) is involved in the RR of PDAC. We now tested the inhibition of the CBS pathway enzyme, farnesyl diphosphate synthase (FDPS), by zoledronic acid (Zol) to enhance radiation and activate immune cells. We investigated the role of FDPS in PDAC RR using the following methods: in vitro cell-based assay, immunohistochemistry, immunofluorescence, immunoblot, cell-based cholesterol assay, RNA sequencing, tumouroids (KPC-murine and PDAC patient-derived), orthotopic models, and PDAC patient's clinical study. FDPS overexpression in PDAC tissues and cells (P < 0.01 and P < 0.05) is associated with poor RT response and survival (P = 0.024). CRISPR/Cas9 and pharmacological inhibition (Zol) of FDPS in human and mouse syngeneic PDAC cells in conjunction with RT conferred higher PDAC radiosensitivity in vitro (P < 0.05, P < 0.01, and P < 0.001) and in vivo (P < 0.05). Interestingly, murine (P = 0.01) and human (P = 0.0159) tumouroids treated with Zol+RT showed a significant growth reduction. Mechanistically, RNA-Seq analysis of the PDAC xenografts and patients-PBMCs revealed that Zol exerts radiosensitization by affecting Rac1 and Rho prenylation, thereby modulating DNA damage and radiation response signalling along with improved systemic immune cells activation. An ongoing phase I/II trial (NCT03073785) showed improved failure-free survival (FFS), enhanced immune cell activation, and decreased microenvironment-related genes upon Zol+RT treatment. Our findings suggest that FDPS is a novel radiosensitization target for PDAC therapy. This study also provides a rationale to utilize Zol as a potential radiosensitizer and as an immunomodulator in PDAC and other cancers. National Institutes of Health (P50, P01, and R01).


Down-regulation of astroglial CYP2C, glucocorticoid receptor and constitutive androstane receptor genes in response to cocaine in human U373 MG astrocytoma cells.
Psychostimulant drugs abuse is associated with an increased risk of stroke. Cytochromes P450 (CYP), especially the astrocytic members of the CYP2C subfamily may play an important role in the modulation of cerebrovascular functions, by generating vasodilatator metabolites from arachidonic acid (AA). Our study examined the regulation of CYP2C genes in response to cocaine or amphetamine in the human astrocyte-like U373 MG cells, using reverse transcription-polymerase chain reaction (RT-PCR) and western-blot analysis. A treatment for 48h with increasing concentrations of cocaine caused a significant down-regulation of CYP2C8 and CYP2C9 genes and decreased the protein level. These effects were not observed with amphetamine. One mechanism of the CYP2C mRNA regulation implicates various specific receptors including glucocorticoid receptor (GR) and constitutive androstane receptor (CAR). Effects of cocaine on CYP2C were accompanied by a decrease in the GR and CAR gene expression suggesting that these nuclear receptors could be involved in the CYP2C repression by cocaine in the U373 MG cell line. These findings represent a possible molecular mechanism involved in the cerebrovascular risk associated with cocaine abuse.


Modelling the interactions between C and N farm balances and GHG emissions from confinement dairy farms in northern Spain.
There is world-wide concern for the contribution of dairy farming to global warming. However, there is still a need to improve the quantification of the C-footprint of dairy farming systems under different production systems and locations since most of the studies (e.g. at farm-scale or using LCA) have been carried out using too simplistic and generalised approaches. A modelling approach integrating existing and new sub-models has been developed and used to simulate the C and N flows and to predict the GHG burden of milk production (from the cradle to the farm gate) from 17 commercial confinement dairy farms in the Basque Country (northern Spain). We studied the relationship between their GHG emissions, and their management and economic performance. Additionally, we explored some of the effects on the GHG results of the modelling methodology choice. The GHG burden values resulting from this study (0.84-2.07 kg CO2-eq kg(-l) milk ECM), although variable, were within the range of values of existing studies. It was evidenced, however, that the methodology choice used for prediction had a large effect on the results. Methane from the rumen and manures, and N2O emissions from soils comprised most of the GHG emissions for milk production. Diet was the strongest factor explaining differences in GHG emissions from milk production. Moreover, the proportion of feed from the total cattle diet that could have directly been used to feed humans (e.g. cereals) was a good indicator to predict the C-footprint of milk. Not only were some other indicators, such as those in relation with farm N use efficiency, good proxies to estimate GHG emissions per ha or per kg milk ECM (C-footprint of milk) but they were also positively linked with farm economic performance.


Impact of Virtual Dementia Tour on empathy level of nursing students: A quasi-experimental study.
As a developable ability, empathy is significantly associated with patient-centered care. The authors intended to evaluate the effect of Virtual Dementia Tour (VDT) upon nursing students' empathy level and propose practical rationales for optimizing future dementia care. A total of 45 second-year undergraduate nursing students were organized to watch a theme movie entitled Still Alice and participate in an 8-min VDT. Jefferson Scale of Empathy-Health Professional Students (JSE-HPS) was employed for evaluating the empathy level of nursing students. After VDT, all nursing students participated in a structured interview. Descriptive statistics and paired t-tests were performed using SPSS 24.0. Their empathy levels demonstrated significant overall improvements (106.69 ± 9.49 vs 115.51 ± 10.16, P < 0.01). During the course of VDT, nursing students experienced varying levels of anxiety and frustration. All of them were satisfied with the program since they had gained a deeper understanding of demented patients and the program could change their attitudes toward demented elders. Watching a specially selected movie and participating in VDT may be an effective method for enhancing empathy and caring during nursing student education.


Pharmaco-epidemiology--drugs, arthritis, and neoplasms: industry contribution to the data.
The real possibility that exogenous chemicals, including pharmaceuticals, increase risk of cancer is not a surprise. Epidemiologic systems to monitor exposure, as well as risk with or without such exposure, have been very hard to develop and very expensive to implement, and often have yielded ambiguous or questionably useful findings. The pharmaceutical industry is rising to the challenge of this situation, with attention to epidemiologic responsibilities and potential contributions deriving from them. This paper reviews the overall methodologic and public policy context surrounding pharmaco-epidemiology in the 1980s and then depicts an evolving program in pharmaco-epidemiology at one company, Burroughs Wellcome, as an example of one possible contributor. It discusses the company's epidemiologic approach to the question of association between treatment with disease-modifying antirheumatic drugs, one of which is manufactured by Burroughs Wellcome Company (Imuran brand azathioprine) and a possible increased risk of neoplasms in patients receiving these drugs as treatment for their rheumatoid arthritis. The paper will highlight specific epidemiologic applications of data bases derived from the published literature as well as voluntary reporting to industry. It will describe a proactive program in the development and conduct of epidemiologic studies to address these difficult problems.


Elevated expression in situ of selectin and immunoglobulin superfamily type adhesion molecules in retroocular connective tissues from patients with Graves' ophthalmopathy.
Activation of certain adhesion molecules within vascular endothelium and the surrounding extravascular space is a critical event in the recruitment and targeting of an inflammatory response or autoimmune attack to a particular tissue site. We have recently demonstrated that the adhesion of lymphocytes to cultured retroocular fibroblasts obtained from patients with Graves' ophthalmopathy (GO) is mediated predominantly by the interaction of lymphocyte function-associated antigen-1 (LFA-1), expressed on lymphocytes, with intercellular adhesion molecule-1 (ICAM-1), expressed by these cells following exposure to interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), IL-1 alpha or purified thyroid-stimulating immunoglobulins. We now report the expression and localization in situ of several adhesion molecules, ICAM-1, endothelial leucocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and LFA-3 in retroocular tissues derived from patients with severe GO (n = 4) and normal individuals (n = 3). Serial cryostat sections of tissue specimens were processed for immunoperoxidase staining using various MoAbs against ICAM-1, ELAM-1, VCAM-1 and LFA-3. In addition, consecutive sections were stained with MoAbs against LFA-1, CD45RO (UCHL-1)DR-human leucocyte antigen (HLA-DR), CD11b/CD18 (Mac-1), and CD11c/CD18 (p150,95). In GO-retroocular tissues, strong immunoreactivity for ICAM-1 and LFA-3 was detected in blood vessels (> 90%), in perimysial fibroblasts surrounding extraocular muscle fibres, and in connective tissue distinct from extraocular muscle. No ICAM-1 or LFA-3 immunoreactivity was present in extraocular muscle cells themselves. ICAM-1 and LFA-3 immunoreactivity in normal tissues was minimal or absent both in connective and muscle tissues. Vascular endothelium was strongly positive for ELAM-1 and VCAM-1 in GO-retroocular tissues, while VCAM-1 immunoreactivity was minimal (< 5% of blood vessels) and ELAM-1 immunoreactivity was generally absent in normal retroocular tissue. LFA-1-expressing, activated mononuclear cells and memory T lymphocytes (CD3+/CD45RO+) were only detected in GO-retrocular tissues, and were mainly localized around blood vessels and in areas of ICAM-1-expressing connective and perimysial tissue. HLA-DR expression was restricted to GO-tissue specimens, with strong immunoreactivity detected in blood vessels, macrophages and connective tissue and perimysial fibroblasts. No HLA-DR was detectable in extraocular muscle cells. In conclusion, infiltration of the orbit in GO by mononuclear cells, and their targeting within the orbit, may depend upon the coordinate expression of certain adhesion and MHC molecules.(ABSTRACT TRUNCATED AT 400 WORDS)


Effects of Panax ginseng on blood alcohol clearance in man.
1. Fourteen healthy male volunteers were studied to assess the effects of Panax ginseng on blood alcohol clearance, utilizing each subject as his own control. 2. At 40 min after the last drink, the blood alcohol level in the test group receiving ginseng extract (3 g/65 kg body weight) along with alcohol (72 g/65 kg body weight) was about 35% lower than their control values. 3. When the blood alcohol level was compared on individual bases, alcohol concentrations in 10 out of 14 test subjects ranged from 32 to 51% lower than their control values. 4. These results demonstrate that P. ginseng extract enhances blood alcohol clearance in man.