Investigation of lectinized liposomes as M-cell targeted carrier-adjuvant for mucosal immunization.
In the present investigation hepatitis B surface antigen (HBsAg) encapsulated liposomes were developed and coupled with Ulex europaeus agglutinin 1 (UEA-1) to increase transmucosal uptake by M-cells of the Peyer's patches. The liposomes were characterized for shape, size, polydispersity and encapsulation efficiency. Bovine submaxillary mucin (BSM) was used as a biological model for the in vitro determination of lectin activity and specificity. Dual staining technique was used to investigate targeting of lectinized liposomes to the M-cells. Anti-HBsAg IgG response in serum and anti-HBsAg sIgA level in various mucosal fluids was estimated by using ELISA, following oral immunization with lectinized and non-lectinized liposomes in Balb/c mice. Additionally, interleukin-2 (IL-2) and interferon-γ (IFN-γ) level in the spleen homogenates was determined. The results suggest that lectinized liposomes were successfully developed, exhibited increased activity with BSM as compared to non-lectinized liposomes and α-l-fucose specificity of the lectinized liposomes was also maintained. The lectinized liposomes were predominantly targeted to the M-cells. The serum anti-HBsAg IgG titre obtained after 3 consecutive days oral immunizations with HBsAg encapsulated lectinized liposomes and boosting after third week was comparable with the titre recorded after single intramuscular prime and third week boosting with alum-HBsAg. Moreover, lectinized liposomes induced higher sIgA level in mucosal secretions and cytokines level in the spleen homogenates. The results showed that the developed surface modified liposomes could be a potential module for the development of effective mucosal vaccines.


Prediabetes and insulin resistance in a population of patients with heart failure and reduced or preserved ejection fraction but without diabetes, overweight or hypertension.
The relationships between glucose abnormalities, insulin resistance (IR) and heart failure (HF) are unclear, especially regarding to the HF type, i.e., HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction. Overweight, diabetes and hypertension are potential contributors to IR in persons with HF. This study aimed to evaluate the prevalence of prediabetes and IR in a population of Vietnamese patients with HFrEF or HFpEF but no overweight, diabetes or hypertension, in comparison with healthy controls, and the relation between prediabetes or IR and HF severity. We conducted a prospective cross-sectional observational study in 190 non-overweight normotensive HF patients (114 with HFrEF and 76 with HFpEF, 92.6% were ischemic HF, mean age was 70.1 years, mean BMI 19.7 kg/m2) without diabetes (neither known diabetes nor newly diagnosed by OGTT) and 95 healthy individuals (controls). Prediabetes was defined using 2006 WHO criteria. Glucose and insulin levels were measured fasting and 2 h after glucose challenge. IR was assessed using HOMA-IR and several other indexes. Compared to controls, HF patients had a higher prevalence of prediabetes (63.2% vs 22.1%) and IR (according to HOMA-IR, 55.3% vs 26.3%), higher HOMA-IR, insulin/glucose ratio after glucose and FIRI, and lower ISIT0 and ISIT120 (< 0.0001 for all comparisons), with no difference for body weight, waist circumference, blood pressure and lipid parameters. Prediabetes was more prevalent (69.3% vs 53.9%, p = 0.03) and HOMA-IR was higher (p < 0.0001) in patients with HFrEF than with HFpEF. Among both HFrEF and HFpEF patients, those with prediabetes or IR had a more severe HF (higher NYHA functional class and NT-proBNP levels, lower ejection fraction; p = 0.04-< 0.0001) than their normoglycemic or non-insulinresistant counterparts, with no difference for blood pressure and lipid parameters. In non-diabetic non-overweight normotensive patients with HF, the prevalence of prediabetes is higher with some trend to more severe IR in those with HFrEF than in those with HFpEF. Both prediabetes and IR are associated with a more severe HF. The present data support HF as a culprit for IR. Intervention strategies should be proposed to HF patients with prediabetes aiming to reduce the risk of incident diabetes. Studies should be designed to test whether such strategies may translate into an improvement of further HF-related outcomes.


Total lymphocyte count is a reliable surrogate marker for CD4 cell counts after the first year of antiretroviral therapy: data from an Indonesian cohort study.
Many studies have evaluated the total lymphocyte count (TLC) as a cheap surrogate marker for CD4 cells in HIV-infected patients not receiving antiretroviral therapy (ART). We assessed whether TLC can replace CD4 cell counts in evaluating the immunological response to ART. In a cohort of patients in Indonesia TLC, if measured after at least 1-year ART, correctly identified patients with <200 CD4 cells, and reliably excluded immunological failure, obviating the need for CD4 cell measurement in 43% of patients.


Beyond Arabidopsis: the circadian clock in non-model plant species.
Circadian clocks allow plants to temporally coordinate many aspects of their biology with the diurnal cycle derived from the rotation of Earth on its axis. Although there is a rich history of the study of clocks in many plant species, in recent years much progress in elucidating the architecture and function of the plant clock has emerged from studies of the model plant, Arabidopsis thaliana. There is considerable interest in extending this knowledge of the circadian clock into diverse plant species in order to address its role in topics as varied as agricultural productivity and the responses of individual species and plant communities to global climate change and environmental degradation. The analysis of circadian clocks in the green lineage provides insight into evolutionary processes in plants and throughout the eukaryotes.


Surface manipulation for prevention of migratory viscous crude oil fouling in superhydrophilic membranes.
Here, we present a proactive fouling prevention mechanism that endows superhydrophilic membranes with antifouling capability against migratory viscous crude oil fouling. By simulating the hierarchical architecture/chemical composition of a dahlia leaf, a membrane surface is decorated with wrinkled-pattern microparticles, exhibiting a unique proactive fouling prevention mechanism based on a synergistic hydration layer/steric hindrance. The density functional theory and physicochemical characterizations demonstrate that the main chains of the microparticles are bent towards Fe3+ through coordination interactions to create nanoscale wrinkled patterns on smooth microparticle surfaces. Nanoscale wrinkled patterns reduce the surface roughness and increase the contact area between the membrane surface and water molecules, expanding the steric hindrance between the oil molecules and membrane surface. Molecular dynamic simulations reveal that the water-molecule densities and strengths of the hydrogen bonds are higher near the resultant membrane surface. With this concept, we can successfully inhibit the initial adhesion, migration, and deposition of oil, regardless of the viscosity, on the membrane surface and achieve migratory viscous crude oil antifouling. This research on the PFP mechanism opens pathways to realize superwettable materials for diverse applications in fields related to the environment, energy, health, and beyond.


Utilization of Near-Infrared Fluorescent Imaging for Pharmaceutically Relevant Applications.
Optical imaging can be utilized for several pharmaceutical applications involving near-infrared fluorescent (NIRF) dyes or NIRF moiety-containing products. Especially during the early phases of product development, NIRF dyes can be used as surrogates for drugs and optical imaging methods can be utilized to optimize the pharmaceutical product properties based on dye entrapment efficiency, in vitro dye release, cellular uptake, and in vivo biodistribution. Based on in vivo accumulation, product efficacy and toxicity can be evaluated in the early development stage. Compared to visible fluorescent dyes, NIRF offers advantages such as low background from formulation excipients as well as biological components.In this chapter, the utility of NIRF imaging methods for in vitro characterization (in vitro release and cellular uptake) and in vivo/ex vivo applicability of pharmaceutically relevant products is presented in detail. Specifically, the application of fluorescence imaging to characterize perfluorocarbon-based formulations for dye loading, in vitro release, cellular uptake, and in vivo imaging to assess target accumulation and biodistribution is discussed. These methods are widely applicable to other nanoparticle-based products involved in inflammation/cancer imaging and therapy. Overall, NIRF-based techniques are indispensible because they are relatively easy, fast, and cost effective to characterize and optimize pharmaceutical products at different stages of product development.


The Validation of a Novel Robot-Assisted Radical Prostatectomy Virtual Reality Module.
To perform the first validation of a full procedural virtual reality robotic training module and analysis of novice surgeon's learning curves. Participants completed the bladder neck dissection task and urethrovesical anastomosis task (UVA) as part of the prostatectomy module. Surgeons completed feedback questionnaires assessing the realism, content, acceptability and feasibility of the module. Novice surgeons completed a 5.5-hour training programme using both tasks. King's College London, London. 13 novice, 24 intermediate and 8 expert surgeons completed the validation study. Realism was scored highly for BDN (mean 3.4/5) and UVA (3.74/5), as was importance of BDN (4.32/5) and UVA (4.6/5) for training. It was rated as a feasible (3.95/5) and acceptable (4/5) tool for training. Experts performed significantly better than novice group in 6 metrics in the UVA including time (p = 0.0005), distance by camera (p = 0.0010) and instrument collisions (p = 0.0033), as well as task-specific metrics such as number of unnecessary needle piercing points (p = 0.0463). In novice surgeons, a significant improvement in performance after training was seen in many metrics for both tasks. For bladder neck dissection task, this included time (p < 0.0001), instrument collisions (p = 0.0013) and total time instruments are out of view (p = 0.0251). For UVA, this included time (p = 0.0135), instrument collisions (p = 0.0066) and task-specific metrics such as injury to the urethra (p = 0.0032) and bladder (p = 0.0189). Surgeons found this full procedural VR training module to be a realistic, feasible and acceptable component for a robotic surgical training programme. Construct validity was proven between expert and novice surgeons. Novice surgeons have shown a significant learning curve over 5.5 hours of training, suggesting this module could be used in a surgical curriculum for acquisition of technical skills. Further implementation of this module into the curriculum and continued analysis would be beneficial to gauge how it can be fully utilised.


Pyrenocine A induces monopolar spindle formation and suppresses proliferation of cancer cells.
Pyrenocine A, a phytotoxin, was found to exhibit cytotoxicity against cancer cells with an IC50 value of 2.6-12.9 μM. Live cell imaging analysis revealed that pyrenocine A arrested HeLa cells at the M phase with characteristic ring-shaped chromosomes. Furthermore, as a result of immunofluorescence staining analysis, we found that pyrenocine A resulted in the formation of monopolar spindles in HeLa cells. Monopolar spindles are known to be induced by inhibitors of the kinesin motor protein Eg5 such as monastrol and STLC. Monastrol and STLC induce monopolar spindle formation and M phase arrest via inhibition of the ATPase activity of Eg5. Interestingly, our data revealed that pyrenocine A had no effect on the ATPase activity of Eg5 in vitro, which suggested the compound induces a monopolar spindle by an unknown mechanism. Structure-activity relationship analysis indicates that the enone structure of pyrenocine A is likely to be important for its cytotoxicity. An alkyne-tagged analog of pyrenocine A was synthesized and suppressed proliferation of HeLa cells with an IC50 value of 2.3 μM. We concluded that pyrenocine A induced monopolar spindle formation by a novel mechanism other than direct inhibition of Eg5 motor activity, and the activity of pyrenocine A may suggest a new anticancer mechanism.


Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas.
The effects of the LDH-A depletion via shRNA knockdown on three murine glioma cell lines and corresponding intracranial (i.c.) tumors were studied and compared to pharmacologic (GNE-R-140) inhibition of the LDH enzyme complex, and to shRNA scrambled control (NC) cell lines. The effects of genetic-shRNA LDH-A knockdown and LDH drug-targeted inhibition (GNE-R-140) on tumor-cell metabolism, tumor growth, and animal survival were similar. LDH-A KD and GNE-R-140 unexpectedly increased the aggressiveness of GL261 intracranial gliomas, but not CT2A and ALTS1C1 i.c. gliomas. Furthermore, the bioenergetic profiles (ECAR and OCR) of GL261 NC and LDH-A KD cells under different nutrient limitations showed that (a) exogenous pyruvate is not a major carbon source for metabolism through the TCA cycle of native GL261 cells; and (b) the unique upregulation of LDH-B that occurs in GL261 LDH-A KD cells results in these cells being better able to: (i) metabolize lactate as a primary carbon source through the TCA cycle, (ii) be a net consumer of lactate, and (iii) showed a significant increase in the proliferation rate following the addition of 10 mM lactate to the glucose-free media (only seen in GL261 KD cells). Our study suggests that inhibition of LDH-A/glycolysis may not be a general strategy to inhibit the i.c. growth of all gliomas, since the level of LDH-A expression and its interplay with LDH-B can lead to complex metabolic interactions between tumor cells and their environment. Metabolic-inhibition treatment strategies need to be carefully assessed, since the inhibition of glycolysis (e.g., inhibition of LDH-A) may lead to the unexpected development and activation of alternative metabolic pathways (e.g., upregulation of lipid metabolism and fatty-acid oxidation pathways), resulting in enhanced tumor-cell survival in a nutrient-limited environment and leading to increased tumor aggressiveness.


Research on Acute Toxicity and Pharmacodynamics of Jinyulian Oral Solution.
A research on Jinyulian Oral Solution was conducted and the objectives were to discover its possible acute toxicity and antibacterial effects when used in vitro and in vivo. Regarding the acute toxicity test, Kunming mice were fed a maximum amount of the solution as their stomachs could hold, i.e., 40 mL kg(-1). To ascertain the minimum inhibitory concentration (MIC) of the solution, two types of germs, i.e., Staphylococcus aureus and Escherichia coli, were selected and tube dilution method was adopted. An antibacterial experimental model relying on animals' body was developed for the researchers to observe the solution's antibacterial effects. Test results showed that no abnormalities were discovered within 14 days after the initial date of testing and the mice grew as normal when fed with an amount of the solution 250 times of a normal clinical doze (In this case a man was assumed to weigh 60 kg.) and that the solution demonstrated obvious antibacterial effects on the two types of selected germs. The respective measured MIC50 and MIC90 values of the two germs were 3.2, 12.8, 6.4, and 25.6 mg L(-1). Therefore, it is reasonable to conclude that Jinyulian Oral Solution possesses no acute toxicity but obvious antibacterial effects on the two before-mentioned germs.


The Effects of Chronic Consumption of Lipid-Rich and Delipidated Bovine Dairy Milk on Brown Adipose Tissue Volume in Wild-Type Mice.
Brown adipose tissue (BAT) activation is associated with increased energy expenditure by inducing non-shivering thermogenesis. The ingestion of a milk fat globule membrane (MFGM) supplement and a high calorie diet are reported gateways into BAT activation. However, little is known about the effect of the MFGM and high calorie diets on BAT volume. To gain insight into this, mice were maintained on a high-fat (HF) or low-fat (LF) diet in conjunction with either full-cream (FC) or skim bovine dairy milk (BDM). After being maintained on their respective diets for 13 weeks, their body composition, including BAT volume, was measured using X-ray microtomography. A high calorie diet resulted in an increase in the BAT volume and mice consuming an HF diet in conjunction with FC BDM had a significantly greater BAT volume than all the other groups. Conversely, mice consuming an HF diet in addition to skim milk had a lower BAT volume compared to the HF control. The data presented suggest that the consumption of a high calorie diet in conjunction with FC BDM increases the BAT volume in wild-type mice. This study may provide valuable insight into future studies investigating BAT volume and BAT activity in relation to environmental factors, including diet.


Comparison of two different levels of physical training in patients with moderate to severe COPD.
Our objective was to compare the effect of a 4-week homebased low and middle intensity and frequency training program in patients with moderate to severe chronic obstructive pulmonary disease. From 124 patients hospitalized with chronic obstructive lung disease (COPD) in an 18-month period 65 fulfilled the inclusion criteria and were invited to participate. Only 31 (48%) accepted and among these only 20 patients (31% of invited) completed the 4-week study period. The walking time in seconds in a standardized treadmill walking test was unchanged after 4 weeks of low intensity training 60 minutes per week for two weekly training sessions. In contrast, the walking time in seconds increased 55% (p < 0.001) from 321 seconds to 499 seconds in 9 patients who completed 4 weeks of middle intensity training which comprised 2 1/2 hours of training per week for 5 weekly training sessions. There was no change in lung function over the 4 weeks but the combined score for physical quality of life (physical component summary) measured by SF-36 increased (p < 0.05) with both low intensity and middle intensity physical training. In conclusion, homebased physical training, which aims at improvements in patient performance and quality of life as part of pulmonary rehabilitation programs, is only accepted by about one-third of unselected patients with moderate to severe COPD. The minimum training time necessary to improve physical performance is 2-3 hours per week of middle intensity training.


5'-AMP activated protein kinase α2 controls substrate metabolism during post-exercise recovery via regulation of pyruvate dehydrogenase kinase 4.
It is well known that exercise has a major impact on substrate metabolism for many hours after exercise. However, the regulatory mechanisms increasing lipid oxidation and facilitating glycogen resynthesis in the post-exercise period are unknown. To address this, substrate oxidation was measured after prolonged exercise and during the following 6 h post-exercise in 5´-AMP activated protein kinase (AMPK) α2 and α1 knock-out (KO) and wild-type (WT) mice with free access to food. Substrate oxidation was similar during exercise at the same relative intensity between genotypes. During post-exercise recovery, a lower lipid oxidation (P < 0.05) and higher glucose oxidation were observed in AMPKα2 KO (respiratory exchange ratio (RER) = 0.84 ± 0.02) than in WT and AMPKα1 KO (average RER = 0.80 ± 0.01) without genotype differences in muscle malonyl-CoA or free-carnitine concentrations. A similar increase in muscle pyruvate dehydrogenase kinase 4 (PDK4) mRNA expression in WT and AMPKα2 KO was observed following exercise, which is consistent with AMPKα2 deficiency not affecting the exercise-induced activation of the PDK4 transcriptional regulators HDAC4 and SIRT1. Interestingly, PDK4 protein content increased (63%, P < 0.001) in WT but remained unchanged in AMPKα2 KO. In accordance with the lack of increase in PDK4 protein content, lower (P < 0.01) inhibitory pyruvate dehydrogenase (PDH)-E1α Ser(293) phosphorylation was observed in AMPKα2 KO muscle compared to WT. These findings indicate that AMPKα2 regulates muscle metabolism post-exercise through inhibition of the PDH complex and hence glucose oxidation, subsequently creating conditions for increased fatty acid oxidation.


RIFLE classification in geriatric patients with acute kidney injury in the intensive care unit.
The RIFLE classification is widely used to assess the severity of acute kidney injury (AKI), but its application to geriatric AKI patients complicated by medical problems has not been reported. We investigated 256 geriatric patients (≥65 years old; mean age, 74.4 ± 6.3 years) who developed AKI in the intensive care unit (ICU) according to the RIFLE classification. Etiologic, clinical, and prognostic variables were analyzed. They were categorized into RIFLE-R (n = 53), RIFLE-I (n = 102), and RIFLE-F (n = 101) groups. The overall in-hospital mortality was 39.8 %. There were no significant differences in RIFLE category between survivors and non-survivors. Survivors had significantly less needs for a ventilator and vasopressor, and lower number of failing organs. Survivors had higher systolic blood pressure, hemoglobin level, and serum albumin levels. We performed a logistic regression analysis to identify the independent predictors of in-hospital mortality. In a univariate analysis, hypertension, chronic kidney disease, RIFLE classification, number of failing organs, need for a ventilator and vasopressor, systolic blood pressure, hemoglobin level, and serum albumin levels were identified as prognostic factors of in-hospital mortality. However, in a multivariate analysis, hypertension, chronic kidney disease, number of failing organs, and serum albumin levels were independent risk factors, with no significant difference for in-hospital mortality with the RIFLE classification. The RIFLE classification might not be associated with mortality in geriatric AKI patients in the ICU. In geriatric patients with AKI, various factors besides severity of AKI should be considered to predict mortality.


Antifibrillatory efficacy of ersentilide, a novel beta-adrenergic and Ikr blocker, in conscious dogs with a healed myocardial infarction.
IKr blockade is ineffective in preventing ventricular fibrillation elicited by the interaction between acute myocardial ischemia and elevated sympathetic activity. This depends in part on the fact that adrenergic activation offsets more than 50% of the action potential prolonging effect of IKr blockade, and thus impairs its primary mechanism of action. This study examined the antifibrillatory effect of ersentilide (CK-3579), a novel antiarrhythmic agent which combines blockade of the rapid component of the delayed rectifier potassium channel (IKr) with relatively weak beta-adrenergic blockade, in a conscious canine model of lethal arrhythmias. Ersentilide was tested in 19 dogs with a healed myocardial infarction (MI) undergoing two minutes of circumflex artery occlusion (CAO) during sub-maximal treadmill exercise. Epicardial monophasic action potential duration was measured before and after ersentilide in 8 anesthetized open chest dogs at baseline and during stimulation of the left stellate ganglion at constant paced heart rate. In the control tests 13 of the 19 dogs had ventricular fibrillation (VF) during the exercise and ischemia test, 6 did not. During a subsequent exercise test, ersentilide prevented VF in 85% (11 of 13) of the high risk animals and showed no proarrhythmic effects in the 6 dogs without arrhythmias in the initial test. Ersentilide lowered heart rate at all levels of exercise and during acute myocardial ischemia. The antifibrillatory effect was maintained in 3 of 4 dogs in which heart rate was kept at control levels by atrial pacing. Ersentilide prolonged left ventricular monophasic action potential duration by 30% (from 179 +/- 6 ms to 233 +/- 5 ms, p < 0.001) at a 360 ms cycle length and completely prevented its shortening during sympathetic stimulation. The combination of IKr and weak beta-adrenergic blockade, using ersentilide, represents a very effective and safe antiarrhythmic intervention able to overcome the limitations present in drugs devoid of any antiadrenergic effect. Such a combination may be very useful in the management of post-myocardial infarction patients at high arrhythmic risk.


Temporally informed random forests for suicide risk prediction.
Suicide is one of the leading causes of death worldwide, yet clinicians find it difficult to reliably identify individuals at high risk for suicide. Algorithmic approaches for suicide risk detection have been developed in recent years, mostly based on data from electronic health records (EHRs). Significant room for improvement remains in the way these models take advantage of temporal information to improve predictions. We propose a temporally enhanced variant of the random forest (RF) model-Omni-Temporal Balanced Random Forests (OT-BRFs)-that incorporates temporal information in every tree within the forest. We develop and validate this model using longitudinal EHRs and clinician notes from the Mass General Brigham Health System recorded between 1998 and 2018, and compare its performance to a baseline Naive Bayes Classifier and 2 standard versions of balanced RFs. Temporal variables were found to be associated with suicide risk: Elevated suicide risk was observed in individuals with a higher total number of visits as well as those with a low rate of visits over time, while lower suicide risk was observed in individuals with a longer period of EHR coverage. RF models were more accurate than Naive Bayesian classifiers at predicting suicide risk in advance (area under the receiver operating curve = 0.824 vs. 0.754, respectively). The proposed OT-BRF model performed best among all RF approaches, yielding a sensitivity of 0.339 at 95% specificity, compared to 0.290 and 0.286 for the other 2 RF models. Temporal variables were assigned high importance by the models that incorporated them. We demonstrate that temporal variables have an important role to play in suicide risk detection and that requiring their inclusion in all RF trees leads to increased predictive performance. Integrating temporal information into risk prediction models helps the models interpret patient data in temporal context, improving predictive performance.


Development of a test strip for rapid detection of Gymnodinium catenatum.
Harmful algal blooms (HABs) are major ecological and environmental problems in China's coastal waters and seriously threaten the stability of the marine ecosystem and human health. Gymnodinium catenatum is a toxic red tide dinoflagellate. It can produce paralytic shellfish toxins (PSP), which cause serious hazards to marine organisms, public health, and safety. In this paper, a test strip based on colloidal gold immunochromatography (GICG) was developed for the rapid detection of Gymnodinium catenatum. The experimental results showed that the test strip has good specificity and sensitivity. It not only detects the different components of Gymnodinium catenatum but also may detect algal toxins. The lowest density of Gymnodinium catenatum that can be detected by this test strip is approximately 120 cells/mL. Cross-reaction indicated that the test strip had a high specificity for Gymnodinium catenatum. This test strip provides a rapid method for in situ detection of Gymnodinium catenatum and a reference method for the monitoring of other harmful algae to serve as an early warning of upcoming red tides. It also provides a new way to prepare more detection methods for toxic algal toxins.


Induction of fetal haemoglobin expression in erythroid cells--a model based on iron availability signalling.
The K562 cell line has erythroid origin and is used for the study of fetal haemoglobin (HbF) production after treatment with several drugs, such as hydroxyurea, cisplatin and cytosine arabinoside (Ara C). It represents an important tool for the study of cancer differentiation therapy and treatment of thalassaemia and sickle cell disease. Although subject to intense research, the mechanisms involved in the induction of HbF are not fully established, and the regulation of several genes and signalling pathways has been proposed. Using the methodology of differential display, we investigated the changes in gene expression in K562 cells treated with doxorubicin and aclarubicin, which induce HbF expression and cell cycle arrest. Several genes were shown to present differential expression patterns, many of them related to the iron signalling pathway. Particular attention was given to Ndrg1, expressed as early as 24 h after treatment, which can be regulated by iron and is involved with blocking of the cell cycle. A review of the literature shows that, similar to doxorubicin and aclarubicin, most of the drugs used to induce HbF present some kind of effect on the iron signalling pathway, activating in the cells the machinery necessary for the incorporation of extracellular iron. Considering these results, as well as the fact that in erythroid cells the synthesis of haemoglobin is of vital importance, we propose that the production of fetal haemoglobin in erythroid cells is highly dependent on the iron signalling pathway.


Medullary thyroid carcinoma in ethnic Chinese with MEN2A: a case report and literature review.
Medullary Thyroid Carcinoma (MTC) is the most common cause of death in MEN patients. It is curative by prophylactic total thyroidectomy, but controversies remain as to the optimal timing for prophylactic thyroidectomy. The current recommendation is for prophylactic total thyroidectomy before age 5, but a recent study suggested that in the ethnic Chinese, even "high risk" mutations did not result in early malignant change, and it was suggested that prophylactic thyroidectomy may be performed at a later age. We report a case of an ethnic Chinese girl with MEN2A codon 634 (C634R) mutation, whose operative specimen at prophylactic thyroidectomy at 4 years 8 months showed MTC. We advocate that management of MEN2A patients should be codon-directed, regardless of ethnicity.


Trends in nosocomial infections and multidrug-resistant microorganisms in Spanish pediatric intensive care units.
Nosocomial infections (NI) are a major healthcare problem. National surveillance systems enable data to be compared and to implement new measures to improve our practice. A multicentre, prospective, descriptive and observational study was conducted using the data from surveillance system for nosocomial infections created in 2007 for Spanish pediatric intensive care units. Data were collected for one month, between 01 and 31 March, for every study year (2008-2012). The objective was to report 5-years of NI surveillance data, as well as trends in infections by multidrug resistant organisms in Spanish pediatric intensive care units. A total of 3667 patients were admitted to the units during the study period. There were 90 (2.45%) patients with nosocomial infections. The mean rates during the 5 years study were: central line-associated bloodstream infection, 3.8/1000 central venous catheter-days, Ventilator-associated pneumonia 7.5/1000 endotracheal tube-days, and catheter-associated urinary tract infections 4.1/1000 urinary catheter-days. The comparison between the 2008 and 2009 rates for nosocomial infections did not show statistically significant differences. All rates homogeneously decreased from 2009 to 2012: central line-associated bloodstream infection 5.83 (95% CI 2.67-11.07) to 0.49 (95% CI 0.0125-2.76), P=0.0029; ventilator-associated pneumonia 10.44 (95% CI 5.21-18.67) to 4.04 (95% CI 1.48-8.80), P=0.0525; and Catheter-associated urinary tract infections 7.10 (95% CI 3.067-13.999) to 2.56 (95% CI 0.697-6.553), P=0.0817; respectively. The microorganism analysis: 63 of the 99 isolated bacteria (63.6%) were Gram-negative bacteria (36.5% were resistant), 19 (19.2%) Gram-positive bacteria, and 17 (17.2%) were Candida spp. infections. The local surveillance systems provide information for dealing with nosocomial infections rates.


Racial-ethnic, gender identity, and sexual orientation disparities in COVID-19-related social and health outcomes: A decomposition analysis.
Despite the growing literature on racial-ethnic disparities during the pandemic, less is known about the explanatory mechanisms of these disparities and inequalities across other axes, such as gender and sexual identities. We studied the levels and sources of racial-ethnic, gender identity, and sexual minority disparities in social (i.e., unmet resource needs) and health (i.e., hospitalization) outcomes among individuals diagnosed with COVID-19, hypothesizing differential age structure, underlying health, and work and living arrangements as contributors to inequalities. Using large-scale administrative data from Chicago and adjusting for covariates, we found substantial racial-ethnic and gender identity disparities in both outcomes, and weak evidence of sexual minority disparities in unmet needs. Subsequent decomposition analyses revealed that living in larger households, having a higher share of non-adult cases, and facing higher burdens of chronic illness, obesity, and unemployment each statistically significantly drove racial-ethnic disparities in unmet needs, but these together explained less than 15% of the disparities. Similarly, about 20% of the Black-White gap in hospitalization resulted from disparities in underlying health and unemployment, whereas a higher proportion of non-adult cases or higher unemployment rates respectively proved the only significant pathways to partially explain transgender individuals' disadvantages in unmet needs (12%) or hospitalization (6%). These findings highlight the importance of considering multiple dimensions of social differences in studying health disparities, the vulnerabilities of transgender and non-adult communities during the pandemic, and the valid yet quite limited roles of previously suggested sociodemographic factors in accounting for COVID-19-related categorical inequalities.


Proton T2 relaxation study of water, N-acetylaspartate, and creatine in human brain using Hahn and Carr-Purcell spin echoes at 4T and 7T.
Carr-Purcell and Hahn spin-echo (SE) measurements were used to estimate the apparent transverse relaxation time constant (T2) of water and metabolites in human brain at 4T and 7T. A significant reduction in the T2 values of proton resonances (water, N-acetylaspartate, and creatine/phosphocreatine) was observed with increasing magnetic field strength and was attributed mainly to increased dynamic dephasing due to increased local susceptibility gradients. At high field, signal loss resulting from T2 decay can be substantially reduced using a Carr-Purcell-type SE sequence.


The scintigraphic visualization of a lingual thyroid after excision of associated ectopic thyroid tissue.
The scintigraphic findings in a 2-year-old boy with both a lingual thyroid and ectopic thyroid tissue in the neck are presented. One day following excision of the neck mass, no functioning thyroid tissue was seen. However, one month later, the lingual gland was well visualized. The possible reason for this is discussed.


Evaluation of a new radiographic technique: outcome following removal of mandibular third molars.
To compare the effect on outcome of third molar removal of pre-operative radiographic assessment by two different techniques. Two hundred and sixty three patients were allocated prior to surgery to one of two diagnostic groups. One hundred and thirty-seven were examined by the Scanora and 126 by a panoramic plus three intra-oral radiographs. Ten oral surgeons recorded their operating time in minutes. Postoperative pain was recorded 4 h after the operation by the patients on a Visual Analog Scale (VAS). The following clinical parameters were recorded at the 1-week postoperative examination: alveolitis, bleeding, and swelling related to the operation area, and any other complications such as paresthesia, nausea and trismus. There was no significant difference in operation time between the two groups of patients (t-test; P > 0.82) nor in the frequency of immediate postoperative pain (chi 2-test; P > 0.5). There were no statistically significant differences in pain score between patients who experienced pain in the two groups (P = 0.10). Sixty-four patients experienced one or more postoperative complications, but the differences between the two groups were not statistically significant (chi 2-test; P > 0.05). There were no significant differences between the surgeons in the number of patients they operated on who experienced pain (chi 2-test; P = 0.18) or who developed complications (chi 2-test; P = 0.27). There are no adverse effects on the rate of postoperative complications when surgeons with little experience with it base their diagnosis and treatment plan on Scanora compared with conventional radiography.


Population cytogenetics of rare fragile sites in Japan.
A population cytogenetic study of three groups of rare fragile sites defined in Human Gene Mapping 8 (HGM8, Berger et al. 1985) has been conducted using peripheral blood lymphocytes of healthy Japanese subjects. We have examined 1,022 blood donors for folate-sensitive and bromodeoxyuridine (BrdU)-requiring, and 845 for distamycin A-inducible fragile sites. Out of 17 rare autosomal fragile sites defined in HGM8, the following six were identified in Japan; folate-sensitive fra(2)(q11), fra(11)(q13) and fra(11)(q23), distamycin A-inducible fra(16)(q22) and fra(17)(p12), and BrdU-requiring fra(10)(q25). The incidences of distamycin A-inducible fra(16)(q22) (1.42%) and fra(17)(p12) (3.08%) were considerably higher than those of the other sites in Japan. Furthermore, a folate-sensitive fra(17)(p12) and a distamycin A-inducible fra(8)(q24.1) have been newly found in the present study. Their incidences were 0.10% (1/1,022) and 0.71% (6/845), respectively. Since the expression of this fra(17)(p12) was induced by fluorodeoxyuridine, suppressed by thymidine, but not induced by distamycin A, it can be classified as a folate-sensitive site. The expression of the new distamycin A-inducible fra(8)(q24.1) was also enhanced by treatment with Hoechst 33258, berenil and 4',6-diamidino-2-phenylindole (DAPI). This fragile site fulfils all four classical criteria suggested by Sutherland (1979) and also new criteria for a rare fragile site defined in HGM8 (Berger et al. 1985).


A new chemical synthesis of 2-amino-(N-D-ribofuranosyl)acetamide 5'-phosphate.
2-Amino-(N-D-ribosyl)acetamide 5'-phosphate (GAR,10) has been prepared in a readily scaled-up synthesis from 2,3-O-isopropylidene-D-ribofuranosylamine p-toluenesulfonate (3) by condensation with the mixed anhydride of N-)benzyloxy-carbonyl)glycine, followed by phosphorylation with 2-cyanoethyl phosphate and removal of the protecting groups. By varying the conditions, the alpha-4 and the beta-5 anomers could be obtained and separated from each other. Anomerization occurs upon removing the O-isopropylidene group from either 7 or 8, so that the final compound (10) is an equimolar mixture of both anomers, of which only one is active toward GAR-transformylase.


Laparoendoscopic single-site and natural orifice surgery in gynecology.
To evaluate the current literature on the use of single port and natural orifice surgery in gynecology. Appraisal of articles published on the use of this technology in gynecology. Most reports on single port and natural orifice surgery are case reports or case series. However, most have reported successful outcomes such as diagnostic or extirpative gynecologic procedures. The main limitation is the availability of instrumentation to successfully accomplish the task. Single port and natural orifice surgery offers the potential for advancing the minimally invasive approach to gynecologic surgery.


Fundamental concepts of protein therapeutics and spacing in oncology: an updated comprehensive review.
Current treatment regimens in cancer cases cause significant side effects and cannot effectively eradicate the advanced disease. Hence, much effort has been expended over the past years to understand how cancer grows and responds to therapies. Meanwhile, proteins as a type of biopolymers have been under commercial development for over three decades and have been proven to improve the healthcare system as effective medicines for treating many types of progressive disease, such as cancer. Following approving the first recombinant protein therapeutics by FDA (Humulin), there have been a revolution for drawing attention toward protein-based therapeutics (PTs). Since then, the ability to tailor proteins with ideal pharmacokinetics has provided the pharmaceutical industry with an important noble path to discuss the clinical potential of proteins in oncology research. Unlike traditional chemotherapy molecules, PTs actively target cancerous cells by binding to their surface receptors and the other biomarkers particularly associated with tumorous or healthy tissue. This review analyzes the potential and limitations of protein therapeutics (PTs) in the treatment of cancer as well as highlighting the evolving strategies by addressing all possible factors, including pharmacology profile and targeted therapy approaches. This review provides a comprehensive overview of the current state of PTs in oncology, including their pharmacology profile, targeted therapy approaches, and prospects. The reviewed data show that several current and future challenges remain to make PTs a promising and effective anticancer drug, such as safety, immunogenicity, protein stability/degradation, and protein-adjuvant interactions.


Improving glandular coverage during prostate biopsy using a long-core needle: technical performance of an end-cutting needle.
To compare the technical performance of a 33-mm core-length biopsy needle with that of the standard 18 mm needle, as many prostate cancers are isoechoic and in large prostates the tissue coverage with the 18 mm needle is inadequate. A 33-mm core length BioPince VSL disposable needle (Amedic, Sweden) and a standard TruCut 18 mm needle (Medical Device Technology Inc., FL, USA) were used to take prostatic biopsies in two groups of 15 patients. The following variables were assessed for each group: mean core length, core quality, capsular coverage (one or both capsules within the specimen), and side-effects in the first week after biopsy (for the BioPince group, surveyed using a self-completed questionnaire). The results were compared with historical data from a group of 30 patients biopsied using the standard needle. For the BioPince and standard groups the mean (sd) core length was 19.4 (8.9) and 14.9 (5.1) mm, respectively. Four needles in the BioPince group failed to capture a sample, requiring needle replacement. The samples were fragmented in 15 of 90 (17%) and 41 of 90 (46%) biopsies in the BioPince and standard groups, respectively (P < 0.05). Specimens had both capsules present in five of 90 (6%) and four of 90 (4%), respectively. Within 7 days minor bleeding was the most common side-effect. Pain after biopsy was the only symptom showing a significant difference between the groups, at six of 15 and none (P = 0.001), respectively. The incidence of haematuria, haematospermia and rectal bleeding was similar in the two groups (P > 0.05), but fever more common (three vs none) in the BioPince group (P = 0.06). When set at a 33-mm stroke length, the BioPince needle increases the mean core length by 30%, with less fragmentation than a standard 18 mm needle. However, it has a significant failure rate for capture (27% needle replacement rate), slightly greater morbidity (pain and possibly fever) and shows no advantage in capsular coverage. Therefore, there are shortcomings with this end-cutting needle when used at 33 mm core length.


The role of renewable and non-renewable energy consumption in CO2 emissions: a disaggregate analysis of Pakistan.
The energy sector has become the largest contributor to greenhouse gas (GHG) emissions. Among these GHG emissions, most threatening is CO2 emission which comes from the consumption of fossil fuels. This empirical work analyzes the roles of renewable energy consumption and non-renewable energy consumption in CO2 emissions in Pakistan. The empirical evidence is based on an auto-regressive distributive lag (ARDL) model of data from 1970 to 2016. The disaggregate analysis reveals that renewable energy consumption has an insignificant impact on CO2 emission in Pakistan and that, in the non-renewable energy model, natural gas and coal are the main contributors to the level of pollution in Pakistan. Economic growth positively contributes to CO2 emission in the renewable energy model but not in the non-renewable energy model. Policies that emphasize the contribution of renewable energy to economic growth and that add more clean energy into the energy mix are suggested.


Anaesthetic outcomes in obese parturients: the effect of assessment in the high-risk clinic.
Obese parturients are at high risk of complications during anaesthesia and early use of epidural analgesia in labour has been recommended for obese patients during labour. To assess the outcome of anaesthesia outpatient consultation for obese parturients. We retrospectively compared outcomes of obese patients antenatally and an obese and non-obese control group over a 1-year period. Outcomes included potential airway problems, anaesthetic for caesarean section, use and success of epidural analgesia and cervical dilation at epidural placement. The proportion of obese patients who had predictable intubation difficulty was low (5%). Epidural use analgesia in labour (69 vs 36 vs 66%, P = 0.148) was similar between groups (obese, obese controls and non-obese controls, respectively). Cervical dilation at the time of epidural insertion in the obese group (2.0, 1.0-3.0 cm) was not different from obese controls (3.0, 1.75-5.75 cm). There was no difference in the number of attempts required to site the epidural between groups or the number of patients that required resiting of the epidural catheter. General anaesthesia was not required in any emergency case in this group. The outcomes of obese patients attending the anaesthetic clinic were mixed. Not all patients who were to advised have epidurals did so but those who did requested them in early labour and there was no requirement for general anaesthesia during emergency caesarean section and adverse airway events were avoided in this group.


Synthesis and function of (2'-5')An: inhibition of (2'-5')An synthetase by heparin and the use of heparin-agarose for partial purification of (2'-5')An synthetase from rabbit reticulocyte lysates.
Heparin, but not a number of other acid mucopolysaccharides, inhibits (2'-5')An synthetase partially purified from rabbit reticulocytes. The effect of heparin was apparent at 10 micrograms/ml (21%). Maximum inhibition was observed at 200 micrograms/ml (80%). At the latter concentration, the dsRNA-dependent (2'-5')An synthetase activity was inhibited 80% whereas the dsRNA-independent enzyme activity was inhibited only 30%. The formation of the dimer, trimer, tetramer and high oligomers of (2'-5')An was inhibited to the same extent with the addition of heparin. Heparin covalently bound to agarose beads was shown to be a useful affinity resin for the purification of (2'-5')An synthetase from rabbit reticulocyte lysates.


Thalidomide for the treatment of patients with myelodysplastic syndromes.
We examined the efficacy of thalidomide in 34 patients with myelodysplastic syndromes (MDS): five RAEB-T, four RAEB, three CMML, six RARS, and 16 RA. Patients belonged to the following cytogenetic groups: 15 complex abnormal karyotypes, 12 normal karyotypes, four cases with 5q- as sole anomaly and three single aberrations. The median thalidomide dose was 400 mg/day (25/34 patients). Four patients discontinued the study after less than 5 weeks, because of fatigue (three) or skin rash (one). One patient died of heart failure after 4 weeks. In the remaining 29 patients (median follow-up: 13 months), treatment responses were classified according to the IWG criteria. Six patients (four RA, two CMML) showed progressive disease (five with transformation into AML) and four patients showed stable disease. Hematological improvement (HI) was observed in 19 patients. Nine of the responders (three RA, one RARS, two RAEB, three RAEB-T) achieved partial remission with granulocytes > or = 1500/microl, Hb > 11 g/dl and platelets > or =100,000/microl. Four patients (one RARS, one CMML, one RAEB, one RAEB-T) had a major response, with platelet and RBC transfusion independence. Six patients (five RA, one RARS) showed minor responses (three HI-E, two HI-E+HI-P, one HI-E+HI-N). Hematological improvement occurred after a median of 2 months of thalidomide treatment. Two patients (RAEB-T) relapsed after a partial remission lasting 8 and 16 months, respectively. In summary, a therapeutic benefit was achieved in 19 of 34 study patients (56%).


Non-invasive prenatal paternity testing from maternal blood.
Prenatal paternity analysis can be performed only after invasive sampling of chorionic villi or amnionic fluid. Aiming to enable noninvasive paternity testing, we attempted to amplify fetal alleles from maternal plasma. Cell-free DNA was isolated from plasma of 20 pregnant women and amplified with ampFLSTR Identifiler and ampFLSTR Yfiler kits. Unfortunately, autosomal fetal alleles were heavily suppressed by maternal DNA, and the only locus that was reliably amplified with AmpFLSTR Identifiler kit was amelogenin, which revealed only fetal gender. Much better success was obtained with AmpFLSTR Yfiler kit, which, in the case of male fetuses, successfully amplified between six and 16 fetal loci. All amplified fetal alleles matched the alleles of their putative fathers, confirming the tested paternity. To the best of our knowledge, this is a first report of noninvasive prenatal paternity testing.


Enhanced ultrafine nanofibril biosynthesis of bacterial nanocellulose using a low-cost material by the adapted strain of Komagataeibacter xylinus MSKU 12.
Bacterial nanocellulose (BNC) is a renewable and biodegradable biopolymer which has currently received considerable attention due to the rapid increase in environmental issues. In this study, a cost-effective strategy for BNC production was successfully improved in the adapted strain, C30, which was obtained from Komagataeibacter xylinus MSKU 12 by a repetitive cultivation in a low-cost coconut water containing acetic acid and ethanol (CW-AE medium) at 37 °C. The adaptive procedure allowed the strain C30 to be adapted to grow and produce BNC with a higher yield in a limiting nutrient CW-AE medium, than that in a standard HS-AE medium. This strain could produce a high yield of BNC (9.69 g/L dry weight) in a low-cost medium, a modified CW-AE medium supplemented with sucrose and ammonium sulfate. Moreover, SEM images showed that BNC pellicle produced by the strain C30 in the modified CW-AE medium exhibited finer nanofibrils with a narrower range of width compared with those of MSKU 12 while no significant differences in their physicochemical characteristics were detected among these BNCs produced. Therefore, this finding demonstrates, not only the potential strain for the cost-effective BNC production at high temperature, but also the superior ultrafine nanofibrils production useful for further applications.


Lumbar MRI Reporting Efficiency for Trainees Over the Academic Year: An Opportunity for Improving Clinical Workflows in Academic Medical Centers.
Reporting efficiency is commonly used to measure performance and quality in diagnostic imaging. For academic centers, balancing the clinical demand for efficient reporting and educational obligation to trainees remains a major challenge. The objective of this study was to quantify the effect of trainee education on reporting efficiency over the academic year (July to June) for a single diagnostic imaging examination type. The authors reviewed a 10-year data set of lumbar spinal MRI reports and time-stamp data and compared change in mean reporting time for trainee versus attending radiologist-only reports. Odds ratios, linear regression, and correlation analysis were performed to evaluate relationships of mean and cumulative reporting times, volume, and study month. Mean reporting time for the trainee group peaked in July (287.2 ± 4.9 min). The largest month-to-month increase was from June to July (+46.3 min, P < .01) for the trainees, and July showed the largest deviation from annualized mean reporting time (odds ratio, 1.31; 95% confidence interval, 1.16-1.47; P < .001). Mean reporting time improved linearly over the course of the academic year from July to June for trainees (R2 = 0.59, P = .002), but this effect was absent in the attending radiologist-only group (P = .52). This study quantifies the effect of trainee education on reporting efficiency and models the operational "learning curve" of improved performance over the academic year. These data may inform staffing and workflow improvement efforts in academic radiology departments.


Purification and thermal analysis of perfluoro-n-alkanoic acids.
Purification of perfluoro-n-alkanoic acids (C(n)F(2n+1)COOH, n=7, 9, 11, 13, 15 and 17) was made by repeated recrystallizations from n-hexane/acetone mixed solvent, and their purity was found to be more than 99.5% by GC-MS, NMR, and elemental analysis. The thermal behaviors such as melting point and enthalpy change of fusion were investigated using differential scanning calorimetry (DSC). The melting point monotonously increased with increasing carbon number (n) of the acids, while the enthalpy change showed irregularity at n=14. The crystal structure of these acids was found to be dependent upon solvent used for recrystallization; that is, the acids recrystallized from the above solvent becomes more stable energetically, indicating their higher enthalpy change of fusion than that of the solidified acids from fused ones. The solid state was also found to vary depending upon the thermal history, indicating that a few crystal structures of the solid state are quite similar energetically. The melting points (T(m)) of perfluoro-n-alkanoic acids are higher than those of corresponding n-alkanoic acids, and the difference in T(m) increases with increasing carbon number in the acids.


Usefulness of the CONUT index upon hospital admission as a potential prognostic indicator of COVID-19 health outcomes.
In-hospital mortality in patients with coronavirus disease 2019 (COVID-19) is high. Simple prognostic indices are needed to identify patients at high-risk of COVID-19 health outcomes. We aimed to determine the usefulness of the CONtrolling NUTritional status (CONUT) index as a potential prognostic indicator of mortality in COVID-19 patients upon hospital admission. Our study design is of a retrospective observational study in a large cohort of COVID-19 patients. In addition to descriptive statistics, a Kaplan-Meier mortality analysis and a Cox regression were performed, as well as receiver operating curve (ROC). From February 5, 2020 to January 21, 2021, there was a total of 2969 admissions for COVID-19 at our hospital, corresponding to 2844 patients. Overall, baseline (within 4 days of admission) CONUT index could be scored for 1627 (57.2%) patients. Patients' age was 67.3 ± 16.5 years and 44.9% were women. The CONUT severity distribution was: 194 (11.9%) normal (0-1); 769 (47.2%) light (2-4); 585 (35.9%) moderate (5-8); and 79 (4.9%) severe (9-12). Mortality of 30 days after admission was 3.1% in patients with normal risk CONUT, 9.0% light, 22.7% moderate, and 40.5% in those with severe CONUT (P < 0.05). An increased risk of death associated with a greater baseline CONUT stage was sustained in a multivariable Cox regression model (P < 0.05). An increasing baseline CONUT stage was associated with a longer duration of admission, a greater requirement for the use of non-invasive and invasive mechanical ventilation, and other clinical outcomes (all P < 0.05). The ROC of CONUT for mortality had an area under the curve (AUC) and 95% confidence interval of 0.711 (0.676-0746). The CONUT index upon admission is potentially a reliable and independent prognostic indicator of mortality and length of hospitalization in COVID-19 patients.


Lymphangioma-like variant of AIDS-associated Kaposi's sarcoma with pronounced edema formation.
An HIV-positive black man developed subcutaneous noduli in the framework of a lymphangioma-like variant of Kaposi's sarcoma. Extensive lymphedema formation also occurred on the legs, face and hands. Treatment with alpha-interferon led to partial regression of Kaposi's sarcoma and the lymphedema.


[Relaparotomy in the early period after appendectomy in children with acute appendicitis].
The experience with 102 relaparotomies in children for complications following the operations for acute appendicitis is analyzed. The repeated operation should be a minimal one, as to its volume, and sparing in character.


Seroconversion to human-cytomegalovirus-specific pre-early nuclear antigens in renal transplant recipients.
Seroconversion to human cytomegalovirus (H-CMV)-specific antigens was observed in 8 out of 9 renal transplant recipients. In 7 of the 8 recipients antibody to "pre-early nuclear antigens" (PENA), which are detectable in human embryonic lung cells within 1 hr of H-CMV infection by anti-complement immunofluorescence staining, developed concomitantly with the increase in other antibodies including anti-early antigens (EA), anti-nuclear inclusions (NI), and complement-fixing (CF) antibody in 1--2 months after transplantation. About 1 year later, anti-PENA and anti-EA titers were concomitantly decreased in 2 recipients, whereas anti-NI and CF antibody titers were maintained at elevated levels in all the seroconverted recipients. These results support the idea that the development of antibody to PENA, like antibody to EA, may represent a current or recent infection with (or reactivation of) H-CMV. In one patient, antibody to PENA did not develop through the observation period despite increases in antibody to EA and other antibodies; this lends support to immunological distinctness of PENA from EA.


Cauda equina syndrome secondary to lumbar disc herniation: Surgical delay and its relationship with prognosis.
To determine whether surgical treatment delayed for more than 48 hours in patients with cauda equina syndrome (CES) influenced the clinical outcome. A retrospective study of 18 patients treated in our hospital from March 2000 to January 2012, after presenting with CES. The pre- and post-operative clinical status was determined: existence of back pain and/or sciatica, sensory disturbance in the perineum, sensory and motor deficits in the lower extremities, and the degree of sphincter incontinence (complete or incomplete CES). A clinical assessment was performed using the Oswestry disability index. As regards the onset of symptoms, 44% (8 of 18) of patients were treated at an early stage (within 48 hours). None of the patients with complete CES operated in the early stage had urinary incontinence, and also had greater motor recovery. Of the 5 patients with complete CES who underwent delayed surgery, 3 showed residual urinary incontinence. A mean of 12.55 was obtained on the Oswestry disability index scale at the end of follow-up. Although no statistically significant difference was found in our study, we observed greater motor and sphincter recovery in patients who were operated on within 48 hours.


Syscan3, a kit for detection of anti-Candida antibodies for diagnosis of invasive candidiasis.
Sera from 76 immunocompetent and 293 immunocompromised subjects were assayed for anti-Candida antibodies. The sensitivity, specificity, positive predictive value, and negative predictive value for invasive candidiasis were 74%, 75%, 62%, and 84% in the immunocompetent group and 15%, 60%, 1.7%, and 93% in the immunocompromised group, respectively. Syscan3 has high negative predictive value.


Pharmacist and Physician Interpretation of Abbreviations for Acetaminophen Intended for Use in a Consumer Icon.
Concomitant use of multiple acetaminophen medications is associated with overdose. To help patients identify acetaminophen medications and thus avoid concomitant use, an icon with an abbreviation for "acetaminophen" has been proposed for all acetaminophen medications. This study assessed pharmacists' and physicians' use and interpretation of abbreviations for "acetaminophen", to identify abbreviations with other meanings that might cause confusion. Physicians (n = 150) reported use and interpretation of candidate abbreviations Ac and Acm. Pharmacists (n = 150) interpretations of prescription orders using the candidate abbreviations APAP, Ac, Ace and Acm in typed, handwritten or spoken form, were judged for critical confusions likely to cause patient harm. Critical confusion was rare, except for omission by pharmacists of the acetaminophen dose for Hydrocodone/APAP prescriptions (10%). Ac was in common use to indicate "before meals", and was interpreted as such, but some physicians (8%) said they use Ac to indicate anticoagulant drugs. Most pharmacists (54%) interpreted Ace as acetaminophen, and none interpreted it as referring to ACE-inhibitors. Acm was rarely used in prescriptions, had no common interfering meanings, and was often (63%) interpreted as acetaminophen, especially when prescribed in combination with an opiate (85%). The data validated concerns about abbreviations in prescribing: all abbreviations resulted in some misinterpretations. However, Acm was rarely misinterpreted, was readily associated with "acetaminophen", and seemed appropriate for use in a graphic icon to help consumers/patients identify acetaminophen medications.


Latina Adolescents Health Risk Behaviors and Suicidal Ideation and Suicide Attempts: Results from the National Youth Risk Behavior Survey 2001-2013.
Suicidal ideation and suicide attempts are more common in Latina adolescents than White or African-American adolescents. Several health risk behaviors have been identified as being associated with Latina adolescent suicides. However, to date, no study has identified the consistency and stability of these risk behaviors over time. This study utilized the national Youth Risk Behaviors Survey from 2001 to 2013 to estimate the prevalence of suicidal ideation, suicide attempts, and health risk behaviors associated with suicidal behaviors in Latina adolescents. Our analysis found the prevalence of suicidal ideation and suicide attempts varied significantly over the 13-year study span, decreasing from 2001 to 2009 and increased from 2011 to 2013. The analyses found 11 health risk behaviors that were significantly associated with both suicidal ideation and suicide attempts that did not vary over time. The stability of these 11 health risk behaviors associated with suicidal behaviors could be useful to school personnel to identify early at risk Latina adolescents who may benefit from school and community mental health resources.


Impact of artificial intelligence on human loss in decision making, laziness and safety in education.
This study examines the impact of artificial intelligence (AI) on loss in decision-making, laziness, and privacy concerns among university students in Pakistan and China. Like other sectors, education also adopts AI technologies to address modern-day challenges. AI investment will grow to USD 253.82 million from 2021 to 2025. However, worryingly, researchers and institutions across the globe are praising the positive role of AI but ignoring its concerns. This study is based on qualitative methodology using PLS-Smart for the data analysis. Primary data was collected from 285 students from different universities in Pakistan and China. The purposive Sampling technique was used to draw the sample from the population. The data analysis findings show that AI significantly impacts the loss of human decision-making and makes humans lazy. It also impacts security and privacy. The findings show that 68.9% of laziness in humans, 68.6% in personal privacy and security issues, and 27.7% in the loss of decision-making are due to the impact of artificial intelligence in Pakistani and Chinese society. From this, it was observed that human laziness is the most affected area due to AI. However, this study argues that significant preventive measures are necessary before implementing AI technology in education. Accepting AI without addressing the major human concerns would be like summoning the devils. Concentrating on justified designing and deploying and using AI for education is recommended to address the issue.


Reactive oxygen species generation is independent of de novo sphingolipids in apoptotic photosensitized cells.
Our recent studies have shown that the de novo sphingolipids play a role in apoptosis of photosensitized cells. To elucidate the involvement of the de novo sphingolipids in reactive oxygen species (ROS) production and mitochondrial depolarization during apoptosis, the stress inducer photodynamic therapy (PDT) with the photosensitizer Pc 4 was used. In Jurkat cells PDT-triggered ROS production or mitochondrial membrane potential (deltapsi(m)) loss was not prevented by the de novo sphingolipid synthesis inhibitor ISP-1. However, PDT + C16-ceramide led to enhanced mitochondrial depolarization and DEVDase activation. The superoxide dismutase mimic manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) protected Jurkat cells from ROS generation and apoptosis, but not from deltapsi(m) reduction. Sphinganine or C16-ceramide counteracted MnTBAP-induced protection from apoptosis in Jurkat, as well as CHO cells. In LY-B cells, CHO-derived mutants deficient in serine palmitoyltransferase (SPT) activity and the de novo sphingolipid synthesis, mitochondrial depolarization, but not ROS generation, was suppressed post-PDT. In LY-B cells transfected with the SPT component LCB1, deltapsi(m) collapse post-PDT was restored. The data support the following hypotheses: MnTBAP protects against apoptosis via steps downstream of deltapsi(m) loss; de novo sphingolipids are not required for ROS generation, but can play a role in deltapsi(m) dissipation in photosensitized apoptotic cells.


Use of Bacillus-siamensis-inoculated biochar to decrease uptake of dibutyl phthalate in leafy vegetables.
Dibutyl phthalate (DBP) is a frequently detected farmland contaminant that is harmful to the environment and human health. In this study, a DBP-degrading endophytic Bacillus siamensis strain T7 was immobilized in rice husk-derived biochar for bioremediation of DBP-polluted agricultural soils. The effects of this microbe-biochar composite on the soil prokaryotic community and the mechanism by which it regulates DBP degradation, were also investigated. A supplement of T7-biochar composite not only significantly boosted DBP biodegradation in soil by raising the DBP degradation rate constant and half-life from 0.1979 d-1 and 2.3131 d to 0.2434 d-1 and 2.1062 d, respectively, but also impeded DBP uptake by leafy vegetables. The general bioremediation effect of T7-biochar alliance excelled pure T7 suspensions and biochar, by trapping more DBP and boosting its complete degradation in soil. Besides, the combination of strain T7 and biochar can increase the proportion of some beneficial bacteria and boost the functional diversity of soil prokaryotic community, then to a certain extent may reverse the negative effect of DBP pollution on the agricultural soils. These results indicate that the rice-husk-derived biochar is a proper media when utilizing functional microbes into environmental treatment. Overall, T7-biochar composite is a promising soil modifier for soil bioremediation and the production of DBP-free crops.


Extracellular Vesicles in the Tumor Microenvironment: Various Implications in Tumor Progression.
Extracellular vesicle (EV) shedding is a biologically conserved cellular process across virtually every cell type. In cancer, EVs shed from tumor and stromal cells to the tumor microenvironment play a major role in determining tumor fate, which to a large extent is dictated by the biologically active cargo contained in EVs. Current understanding of various cancer-associated EVs has enabled the outlining of mechanistic connections between cargo and tumor-promoting functions. In this chapter, we describe examples of EV-mediated communication between tumor cells and stromal cells, highlighting the molecular constituents responsible for pro-tumorigenic effects. Furthermore, we discuss the roles of matrix-degrading EVs in cell invasion. Finally, we summarize research on the potential use of EVs as a novel approach to cancer therapeutics.


The Chemical Use, Abuse, and Dependence Scale (CUAD). Rationale, reliability, and validity.
This article describes the rationale for the development of the Chemical Use, Abuse, and Dependence Scale (CUAD). The instrument is in a semistructured interview format; it derives both substance use severity scores and DSM-III-R substance use disorder diagnoses and can be administered in a short period with minimal training. The reliability and validity of the CUAD are reported and appear satisfactory. The CUAD is recommended for use as a detection, diagnostic, and treatment selection index in clinical, research, and program evaluation contexts.


The use of psychostimulants in the pediatric patient.
The psychostimulant drugs have a long history of safe and effective usage in the treatment of ADHD. They remain the drugs of first choice in this condition. Children with ADHD should be aggressively treated with at least two different classes of psychostimulants before moving to nonpsychostimulant agents. As long as side effects are not troublesome, higher dosages may be used to adequately control the ADHD symptoms, and such high dosages do not impair learning. No evidence shows long-term effects of psychostimulants on growth. Effective use of the psychostimulants is essential for any clinician involved in the treatment of children with ADHD.


High concentrations of cellulosic ethanol achieved by fed batch semi simultaneous saccharification and fermentation of waste-paper.
A fundamental goal of second generation ethanol production is to increase the ethanol concentration to 10% (v/v) or more to optimise distillation costs. Semi simultaneous saccharification and fermentations (SSSF) were conducted at small pilot scale (5L) utilising fed-batch additions of solid shredded copier paper substrate. Early addition of Accellerase® 1500 at 16 FPU/g substrate and 30 U/g β-glucosidase followed by substrate only batch addition allowed low final equivalent enzyme concentrations to be achieved (3.7 FPU/g substrate) whilst maintaining digestion. Batch addition resulted in a cumulative substrate concentration equivalent to 65% (w/v). This in turn resulted in the production of high concentrations of ethanol (11.6% v/v). The success of this strategy relied on the capacity of the bioreactor to perform high shear mixing as required. Further research into the timing and number of substrate additions could lead to further improvement in overall yields from the 65.5% attained.


Modification of the activity and surface topography of peritoneal macrophages by cytophilic antibody.
Cytophilic antibody (Cab) attached to the macrophage surface substantially changes the cell surface relief as tested in the scanning electron microscope. Diffuse loss of surface structure is accompanied by diminished ability to interiorize opsonized sheep erythrocytes and to damage non-specifically bystanding target cells (chicken erythrocytes). Cross-linking of Cab on the macrophage surface by antigen or antibody partially restores macrophage membrane activity.


[Complex evaluation of the healing of intestinal anastomoses in the early postoperative period].
Eighty-six patients were subjected to complex examination in the immediate postoperative period to check the condition of intestinal anastomoses. In 58 (67.4%) patients inflammation in the zone of the anastomosis was found to be negligible and produced no specific clinical manifestations; 28 (32.6%) patients had marked inflammatory changes in the region of the anastomosis. This condition, interpreted as anastomositis, is favourable for the development of incompetence of the sutures of the anastomosis, which was diagnosed in 4.7% of patients. Timely diagnosis of anastomositis and application of a complex of nonoperative measures is conducive to reduction of the frequency of postoperative complications and mortality.


Novel H3 receptor antagonists. Sulfonamide homologs of histamine.
Sulfonamides derived from 4(5)-(omega-aminoalkyl)-1H-imidazoles containing chain lengths of three- to five-carbons were synthesized. Good to moderate H3 receptor binding affinities were observed for several butyl and pentyl homologs, whereas binding affinities were considerably weaker in the propyl series. Separation of the imidazole ring and the sulfonamide unit by a four- or five-carbon tether afforded potent H3 receptor antagonists.


Evaluation of balance and executive function relationships in older individuals.
Executive function is an important cognitive factor in gait and balance control. Weakening of balance system components and executive functions due to aging may affect walking and balance and increase the risk of falling. The present study aimed to investigate the relationship between balance and executive function in older individuals and the contributions of physical activity and depression to this relationship. A total of 84 healthy individuals aged 60 and over were included in the study. In the study, the Timed Up and Go Test (TUG), Mini Balance Evaluation Systems Test (Mini-BESTest), Digit Symbol Substitution Test (DSST), Trail Making Test A and B (TMT A and TMT B), Physical Activity Scale for the Elderly (PASE), and Geriatric Depression Scale (GDS) were applied. The Mini-BESTest and TUG correlated with DSST, TMT A, and TMT B. GDS was correlated with TUG. PASE was correlated with Mini-BESTest and TUG. Executive functions differed according to education level; DSST, TMT B, and GDS were effective in fall history. There was a significant relationship between balance and executive function. It was found that balance and walking speed increased as executive function skills increased. Depression and physical activity are associated with balance and gait speed. Balance and executive functions are related to each other, and physical activity and depression contribute to this relationship. In order to protect against the negative effects of aging, cognitive and physical training can be performed to prevent balance and executive function declines.


The Spanish contribution to the European Randomized Study of Screening for Prostate Cancer.
To summarize the experience of the Spanish participation in the European Randomized Study of Screening for Prostate Cancer (ERSPC). In this study men aged 45-70 years were randomized (1:1) and allocated to one of two arms: screening, with an indication for transrectal ultrasonography (TRUS) and sextant prostate biopsy when the serum prostate-specific antigen (PSA) level was >4 ng/mL (until May 1998) and from then when the PSA was >2.9 ng/mL; and a control group (no diagnostic tests). The findings from a digital rectal examination were not considered as a criterion for biopsy. When the serum PSA was above the threshold levels, biopsy-negative men were invited again after a year ('early recall'). The next (second) screening round was programmed for the rest of participants after a 4-year interval. Cancer-specific mortality was recorded and compared in both groups. In all, 4278 men were recruited (2416 in the screening group and 1862 in the control group). The recruitment phase was closed in June 1999. During the first screening round 40 cancers were detected; the detection rate was then 1.7% and 4.15 biopsies were needed to detect each cancer. The clinical stage was localized in 88.6% and regional or metastatic in 11.4%. Within the first round, 17 more cancers were detected at early recall attendance. During the second screening round 14 cancers were found, giving a detection rate of 1.9%; 17 more cancers were also diagnosed outside the screening programme (contamination), seven in the screening group and 10 in the control group. Until February 2003, 85 participants had died (53 screened and 32 control) but none from prostate cancer. Cancer detection rates can be increased with further early recalls; the clinical stage was localized in an important proportion of cancers detected.


[The organization of a post-intensive care rehabilitation unit].
When a patient is admitted to a post-intensive care rehabilitation unit, the functional outcome is the main objective of the care. The motivation of the team relies on strong cohesion between professionals. Personalised support provides a heightened observation of the patient's progress. Listening and sharing favour a relationship of trust between the patient, the team and the families.


Efficacy of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide (P32/98) in fatty Zucker rats with incipient and manifest impaired glucose tolerance.
Incretin enhancers are a new class of antidiabetic drugs with promising therapeutic potential for type 2 diabetes. Therapeutic intervention in prediabetes is an attractive strategy for preventing or delaying diabetes onset. The aim of the present study was to investigate the therapeutic effects of incretin enhancement on incipient impaired glucose tolerance (iIGT) and manifest IGT (mIGT) using the dipeptidyl peptidase IV (DPP-4) inhibitor P32/98- and fatty Zucker rat (ZR, fa/fa) as a model. ZRs were classified into groups with iIGT and mIGT (n = 10 per group). P32/98 (21.61 mg/kg body weight) was administered orally to ZR with iIGT and mIGT once daily for 6 and 3 weeks respectively. Assessments included body weight, morning blood glucose and insulin, oral glucose tolerance test (oGTT; 2 g glucose/kg), plasma parameters and blood glucose day-night profile (DNP). In addition, glucose responsiveness of isolated islets and islet morphology were analysed. P32/98 decreased non-fasting morning blood glucose more effectively in ZR with iIGT than in ZR with mIGT. Compared with study entry, P32/98 improved DNP of blood glucose in ZR with mIGT and nearly normalized DNP in ZR with iIGT. An acute bolus of inhibitor reduced glucose load during oGTT in rats chronically treated with placebo or P32/98. In contrast to placebo-treated rats, rats receiving long-term treatment with P32/98 required less insulin during oGTT. This effect was larger in rats with iIGT vs. rats with mIGT. In isolated pancreatic islets of ZR with mIGT, treatment with P32/98 decreased pancreatic insulin content and increased glucose responsiveness, while the beta-cell volume density was unaffected. P32/98 significantly reduced triglycerides and non-esterified fatty acids. Intestinal growth was comparable between inhibitor- and placebo-treated fatty rats. Enhancement of incretin with the DPP-4 inhibitor P32/98 has therapeutic effects in hyperinsulinaemia, hyperglycaemia and IGT in ZR with iIGT and mIGT. Apparently, administration of P32/98 in ZR with iIGT results in more efficient beta-cell function, which is associated with less need for insulin to cope with deterioration of glucose tolerance. Importantly, P32/98 has a strong effect on dyslipidaemia in mIGT. P32/98 has no side effect on intestinal growth. Daily intake of P32/98 is a promising strategy for treatment of glucose intolerance and has the potential to prevent type 2 diabetes.


Numerical simulation of air age in dental offices.
Dental professionals are at high risk of exposure to communicable diseases during clinical practice, but many dental clinics provide clinical care in closed spaces. Therefore, it is essential to develop efficient ventilation methods in dental clinics that do not rely on natural ventilation. In this study, to clarify the factors that cause air retention in dental offices, we conducted computational flow dynamics simulations focusing on (1) the flow path from the entrance to the exhaust port and (2) the presence of partitions. A three-dimensional model of a dental clinic with three dental chairs was created, and simulations were conducted for scenarios with and without partitions with different entrance and exhaust port positions. Evaluation of these simulations on the basis of the age of air, an indicator of ventilation efficiency, showed that the value of the air age near the partition was locally high in the scenarios with partitions. In the scenarios where the exhaust port was located close to the entrance, the air age near the exhaust port was high, regardless of the presence of a partition. In addition to wearing protective clothing and sterilizing instruments, it is important to consider air quality improvement as a countermeasure against airborne and droplet infections, such as virus infections, in dental clinics.


β-Lactoglobulin as nanotransporter--Part II: Characterization of the covalent protein modification by allicin and diallyl disulfide.
The whey protein β-lactoglobulin has been proposed as a transporter for covalent bound bioactive compounds in order to enhance their stability and reduce their sensory perception. The garlic derived compounds allicin and diallyl disulfide were bound covalently to the native and heat denatured protein. The binding site and the influence of the modification on the digestibility were determined by mass spectrometric analysis of the modified β-lactoglobulin. Further, the conformation of the modified protein was assessed by circular dichroism and dynamic light scattering. The free thiol group of Cys(121) turned out to be the major binding site. After proteolysis with trypsin at pH 7 but not with pepsin at pH 2, a limited transfer to other cysteinyl residues was observed. The covalently bound ligands did not mask any proteolytic cleavage sites of pepsin, trypsin or chymotrypsin. The modified β-lactoglobulin showed a native like conformation, besides a moderate loosening of protein folding. The covalent binding of organosulfur compounds to β-lactoglobulin provides a bioactive ingredient without impairing the digestibility and functional properties of the protein.


A novel sensor based on electropolymerization of β-cyclodextrin and L-arginine on carbon paste electrode for determination of fluoroquinolones.
An electrochemical sensor for fluoroquinolones (FQs) based on polymerization of β-cyclodextrin (β-CD) and L-arginine (L-arg) modified carbon paste electrode (CPE) (P-β-CD-L-arg/CPE) was built for the first time. Synergistic effect of L-arg and β-CD was used to construct this sensor for quantification of these important antibiotics. Scanning electron microscope (SEM) image shows that polymer of β-CD and L-arg has been successfully modified on electrode. Electrochemical impedance spectroscopy (EIS) and cyclic voltammograms (CV) further indicate that polymer of β-CD and L-arg efficiently decreased the charge transfer resistance value of electrode and improved the electron transfer kinetic between analyte and electrode. Under the optimized conditions, this modified electrode was utilized to determine the concentrations of ciprofloxacin, ofloxacin, norfloxacin and gatifloxacin. The differential pulse voltammogram (DPV) exhibits the oxidation peak currents were linearly proportional to their concentration in the range of 0.05-100 μM for ciprofloxacin, 0.1-100 μM for ofloxacin, 0.1-40 μM for norfloxacin and 0.06-100 μM for gatifloxacin, respectively. This method was also successfully used to detect the concentrations of each drug in pharmaceutical formulations and human serum samples. In addition, this proposed fluoroquinolones sensor exhibited good reproducibility, long-term stability and fast current response.


How to trace stem cells for MRI evaluation?
Applications of imaging techniques to visualize stem cells for monitoring, control and treatment of biological systems, in particular the brain, is at the forefront of investigations. These approaches involve the identification of stem and precursor cells that may be of various origins, but are related to specific clinical conditions, and the choice of the appropriate markers to achieve the required imaging while minimizing the side effects. This article will review examples of the contrast agent design for rational approaches in stem cell imaging. Potential pitfalls or side effects associated with contrast agents, in particular iron oxide nanoparticles, for cell labelling are also discussed.


Polyhydroxylated sterols from the Indonesian soft coral Sinularia sp. and their effect on farnesoid X-activated receptor.
Chemical investigation of the Indonesian soft coral Sinularia sp. resulted in the isolation of three known (1, 2 and 7) and five new (3-6 and 8) sterols, characterized by either 24-methylcholestane or gorgostane skeletons. The stereostructures of the new compounds have been elucidated by application of HR-MS and 2D NMR techniques. The isolated steroids have been evaluated for their interaction with the farnesoid X-activated receptor (FXR) and some of them, including the new compound 3 and gorgosterol (7), showed a consistent antagonistic activity, potentially useful for the treatment of cholestasis. The FXR antagonistic activity of gorgosterol (7) was also supported by gene expression experiments. Our results represent the first evaluation of soft coral steroids for interaction with nuclear receptors and qualify gorgosterol (7) as a new chemotype of FXR antagonist.


[Salmonella enteritidis splenic abscess complicating a Plasmodium falciparum malaria attack].
Salmonella splenic abscesses are rare and usually occur on pre-existing lesions. A Moorish 16 year-old woman from Senegal presented with a S. enteritidis abscess without any factor other than an attack of P. falciparum malaria. Treatment associated quinine salts, antibiotherapy and splenectomy. P. falciparum malaria attacks not only induce humoral and then cellular immunodepression but are also at the origin of infarction or splenic hematoma that may enhance bacterial infection and the development of abscesses. Splenectomy or percutaneous drainage associated with antibiotherapy is the usual treatment for splenic abscesses. Prognosis remains severe (13 to 16% mortality).


Mitochondrial deficits in human iPSC-derived neurons from patients with 22q11.2 deletion syndrome and schizophrenia.
Schizophrenia (SZ) is a highly heterogeneous disorder in both its symptoms and risk factors. One of the most prevalent genetic risk factors for SZ is the hemizygous microdeletion at chromosome 22q11.2 (22q11DS) that confers a 25-fold increased risk. Six of the genes directly disrupted in 22qDS encode for mitochondrial-localizing proteins. Here, we test the hypothesis that stem cell-derived neurons from subjects with the 22q11DS and SZ have mitochondrial deficits relative to typically developing controls. Human iPSCs from four lines of affected subjects and five lines of controls were differentiated into forebrain-like excitatory neurons. In the patient group, we find significant reductions of ATP levels that appear to be secondary to reduced activity in oxidative phosphorylation complexes I and IV. Protein products of mitochondrial-encoded genes are also reduced. As one of the genes deleted in the 22q11.2 region is MRPL40, a component of the mitochondrial ribosome, we generated a heterozygous mutation of MRPL40 in a healthy control iPSC line. Relative to its isogenic control, this line shows similar deficits in mitochondrial DNA-encoded proteins, ATP level, and complex I and IV activity. These results suggest that in the 22q11DS MRPL40 heterozygosity leads to reduced mitochondria ATP production secondary to altered mitochondrial protein levels. Such defects could have profound effects on neuronal function in vivo.


A novel miRNA inhibits metastasis of prostate cancer via decreasing CREBBP-mediated histone acetylation.
To identify novel miRNAs implicated in prostate cancer metastasis. Sixty-five prostate cancer tissues and paired pan-cancer tissues were sequenced. Novel miRNAs were re-analyzed by MIREAP program. Biological functions of miR-N5 were transwell experiment and colony formation. Target genes of miR-N5 were analyzed by bioinformatic analysis. Downstream of target gene was analyzed by The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) databases and confirmed by CHIP experiment. We identified a novel miRNA-miR-N5, which was downregulated in PCa cells, PCa tissue, and in the serum of patients with PCa. Knockout of miR-N5 enhanced migration and invasiveness in vitro. miR-N5 specified targeted CREBBP 3'-UTR and inhibited CREBBP expression, which mediated H3K56 acetylation at the promoter of EGFR, β-catenin and CDH1. This study may shed the light on miR-N5 which influences metastasis via histone acetylation.


Focal adhesion kinase mediates the interferon-gamma-inducible GTPase-induced phosphatidylinositol 3-kinase/Akt survival pathway and further initiates a positive feedback loop of NF-kappaB activation.
Interferon-gamma-inducible GTPase (IGTP) expression is upregulated in coxsackievirus B3 (CVB3)-infected murine heart and inhibits CVB3-induced apoptosis through activation of the PI3 kinase/Akt pathway. However, the mechanism of this pathway activation is unknown. In this study, using doxcycycline-inducible Tet-On HeLa cells that overexpress IGTP, we have demonstrated that focal adhesion kinase (FAK) is phosphorylated in response to IGTP expression and that transfection of the Tet-On HeLa cells with a dominant negative FAK (FRNK) blocks Akt activation. Furthermore, induction of IGTP also promoted the NF-kappaB activation as evidenced by its enhanced nuclear translocation, binding to transcriptional promoters and increased transcriptional activity. However, FRNK transfection and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 both blocked the IGTP-induced translocation and NF-kappaB activation. Furthermore, silencing NF-kappaB with siRNAs significantly inhibited the phosphorylation of FAK and Akt, but not their total expression levels, indicating that NF-kappaB activation is required for the IGTP-induced activation of FAK and PI3K/Akt. Finally, blocking this survival pathway by transfection of FRNK or silencing of NF-kappaB reduced CVB3 replication and enhanced cell death during CVB3 infection. Taken together, these results suggest that FAK is a mediator upstream of PI3K/Akt and NF-kappaB functions as a downstream effector and also positively regulates the activity of upstream kinases.


Birth of plant proteomics in India: a new horizon.
In the post-genomic era, proteomics is acknowledged as the next frontier for biological research. Although India has a long and distinguished tradition in protein research, the initiation of proteomics studies was a new horizon. Protein research witnessed enormous progress in protein separation, high-resolution refinements, biochemical identification of the proteins, protein-protein interaction, and structure-function analysis. Plant proteomics research, in India, began its journey on investigation of the proteome profiling, complexity analysis, protein trafficking, and biochemical modeling. The research article by Bhushan et al. in 2006 marked the birth of the plant proteomics research in India. Since then plant proteomics studies expanded progressively and are now being carried out in various institutions spread across the country. The compilation presented here seeks to trace the history of development in the area during the past decade based on publications till date. In this review, we emphasize on outcomes of the field providing prospects on proteomic pathway analyses. Finally, we discuss the connotation of strategies and the potential that would provide the framework of plant proteome research. The past decades have seen rapidly growing number of sequenced plant genomes and associated genomic resources. To keep pace with this increasing body of data, India is in the provisional phase of proteomics research to develop a comparative hub for plant proteomes and protein families, but it requires a strong impetus from intellectuals, entrepreneurs, and government agencies. Here, we aim to provide an overview of past, present and future of Indian plant proteomics, which would serve as an evaluation platform for those seeking to incorporate proteomics into their research programs. This article is part of a Special Issue entitled: Proteomics in India.


The role of potassium in atherosclerosis.
Atherosclerosis (AS) is a chronic progressive inflammatory condition with a leading prevalence worldwide. Endothelial dysfunction leads to low-density lipoprotein trafficking into subendothelial space and the subsequent form of oxidized LDL (ox-LDL) within intimal layer, perpetuating the vicious cycle of endothelial dysfunction. K+ exerts beneficial effects in vascular wall by reducing LDL oxidization, vascular smooth muscle cells (VSMCs) proliferation, and free radical generation. K+ also modulates vascular tone through a regulatory effect on cell membrane potential. The most relevant papers on the association between 'potassium channels' and 'atherosclerosis' were selected among those deposited on PubMed from 1990 to 2020. Here, we provide a short narrative review that elaborates on the role of K+ in atherosclerosis. This review also update the current knowledge about potential pharmacological agents targeting K+ channels with a special focus on pleiotropic activities of agents such as statins, sulfonylureas and dihydropyridines. In this review, the mechanism of different K+ channels on vascular endothelium will be summarized, mainly focusing on their pathophysiological role in atherosclerosis and potential therapeutic application.


Maps of heavy metals in the soils of the European Union and proposed priority areas for detailed assessment.
Soil contamination is one of the greatest concerns among the threats to soil resources in Europe and globally. Despite of its importance there was only very course scale (1/5000km(2)) data available on soil heavy metal concentrations prior to the LUCAS topsoil survey, which had a sampling density of 200km(2). Based on the results of the LUCAS sampling and auxiliary information detailed and up-to-date maps of heavy metals (As, Cd, Cr, Cu, Hg, Pb, Zn, Sb, Co and Ni) in the topsoil of the European Union were produced. Using the maps of heavy metal concentration in topsoil we made a spatial prediction of areas where local assessment is suggested to monitor and eventually control the potential threat from heavy metals. Most of the examined elements remain under the corresponding threshold values in the majority of the land of the EU. However, one or more of the elements exceed the applied threshold concentration on 1.2Mkm(2), which is 28.3% of the total surface area of the EU. While natural backgrounds might be the reason for high concentrations on large proportion of the affected soils, historical and recent industrial and mining areas show elevated concentrations (predominantly of As, Cd, Pb and Hg) too, indicating the magnitude of anthropogenic effect on soil quality in Europe.


The value of placental vascularization indices for predicting preeclampsia and fetal growth restriction in different stages of gestation: A prospective and longitudinal study.
To assess value of placental vascularization indices (PVIs) for predicting preeclampsia (PE) and fetal growth restriction (FGR) in different stages of pregnancy in high-risk women. PVIs derived from 3-dimensional power doppler(3DPD) imaging were measured at seven stages of pregnancy: 11-13+6w, 15-19+6w, 20-23+6w, 24-27+6w, 28-31+6w, 32-36+6w, and ≥37w. PE and FGR were used as outcomes in logistic regression models. Area under the receiver operating characteristic (ROC) curve (AUC) of each PVI was calculated, cut-off points were determined to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR). Finally, AUCs combined with baseline characteristics, uterine artery pulsatility index (UTPI) and PVIs were used to determine whether PVIs could increase the predictive value. Adverse outcomes occurred in 10.9% of pregnancies. Statistical differences appeared in 32-36+6w only. AUCs of vascularization index (VI) and vascularization flow index (VFI) for 32-36+6w were 0.79 (0.70-0.87, p: 0.000), and 0.78 (0.69-0.88, p: 0.000). Sensitivity, specificity, PPV, NPV, PLR, and NLR for VI were 0.91, 0.63, 20%, 98%, 2.39, and 0.15, and those for VFI were 0.62, 0.84, 29%, 95%, 3.75, and 0.45. AUC increased from 0.79 to 0.85 by adding PVIs to baseline characteristics and UTPI model. No statistical significance was found before 32w. VI and VFI were valuable for predicting PE and FGR at the 32-36+6w stage, while their values before 32w were poor.


CXCR3 polymorphisms associated with risk of asthma.
The chemokine (C-X-C motif) receptor 3 (CXCR3) gene, on chromosome Xq13, is known to have critical roles in inflammatory and immune responses. In an effort to discover polymorphisms have been implicated in asthma, we investigated the genetic polymorphisms in CXCR3 to evaluate it as a potential candidate gene for a host genetic study of asthma. Statistical analysis revealed that one SNP in intron 1, c.12+234G > A, showed significant association with the risk of asthma development (P = 0.007, OR = 0.81). By subgroup analyses stratified by gender and atopic status, the genetic effect of c.12+234G > A on asthma was more apparent among male atopic subjects (P = 0.0009, OR = 0.61). Our findings suggest that polymorphisms in CXCR3 might be one of the genetic factors for the risk of asthma development, especially in male atopic subjects. CXCR3 variation/haplotype information identified in this study will provide valuable information and insight into strategies for the control of asthma and its subgroup, atopy.