Defining intrinsic hydrophobicity of amino acids' side chains in random coil conformation. Reversed-phase liquid chromatography of designed synthetic peptides vs. random peptide data sets.
The two leading RP-HPLC approaches for deriving hydrophobicity values of amino acids utilize either sets of designed synthetic peptides or extended random datasets often extracted from proteomics experiments. We find that the best examples of these two methods provide virtually identical results--with exception of Lys, Arg, and His. The intrinsic hydrophobicity values of the remaining residues as determined by Kovacs et al. (Biopolymers 84 (2006) 283) correlates with an R(2)-value of 0.995+ against amino acid retention coefficients from our Sequence Specific Retention Calculator model (Anal. Chem. 78 (2006) 7785). This novel finding lays the foundation for establishing consensus amino acids hydrophobicity scales as determined by RP-HPLC. Simultaneously, we find the assignment of hydrophobicity values for charged residues (Lys, Arg and His at pH 2) is ambiguous; their retention contribution is strongly affected by the overall peptide hydrophobicity. The unique behavior of the basic residues is related to the dualistic character of the RP peptide retention mechanism, where both hydrophobic and ion-pairing interactions are involved. We envision the introduction of "sliding" hydrophobicity scales for charged residues as a new element in peptide retention prediction models. We also show that when using a simple additive retention prediction model, the "correct" coefficient value optimization (0.98+ correlation against values determined by synthetic peptide approach) requires a training set of at least 100 randomly selected peptides.


Chemical carcinogen induction of DNA-repair synthesis in human peripheral blood monocytes.
Fresh ex vivo cultures of normal human peripheral blood monocytes, which are nonreplicative and known to possess cytochrome P-450 associated mixed-function oxidase activity, were used to assay DNA-excision repair manifested as augmented [3H]thymidine (dThd) incorporation following treatment in culture with diverse mutagenic carcinogens. Untreated monocyte cultures established from pools of 3-6 normal donors incorporated a low level of cytoplasmic [3H]dThd throughout a majority of the cells during an 18-h incubation. This background incorporation into whole cells was 80-90% inhibited by hydroxyurea (HU) at concentrations greater than 5 mM. Dose-related increases in the cumulative 18-h [3H]dThd incorporation in monocytes were observed following treatment with UV, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methyl methanesulfonate (MMS), mitomycin C (MMC), N-acetoxy-acetylaminofluorene (NA-AAF), aflatoxin B1 (AFB1), benzo[a]pyrene (BaP), and dimethylnitrosamine (DMN). The presence of HU during chemical treatment and throughout this 18 h of incubation with [3H]dThd did not influence the dose-response curves obtained with UV, MMS, NA-AAF and BaP but it increased the input dose of MNNG, MMC, DMN and AFB1 required to give peak repair incorporation. When HU was added to cultures following MNNG damage no interference with repair response was observed. HU apparently influences the extent of DNA damage by direct reactivity with these chemicals or their endogenously generated metabolites rather than inhibiting DNA-repair processes. These results provide evidence that monocytes are enzymatically proficient in base and nucleotide excision pathways and have endogenous capacity to metabolize BaP, AFB1 and DMN to DNA-damaging metabolites. As such, the monocyte is a potentially useful human cell type for detecting genotoxic chemicals and studying individuality in chemical-biological interactions.


Serum chemistry and gut morphology of two strains of broiler chickens to varying interval of post hatch feeding.
This trial was carried out to determine the responses of two broiler strains of chicken to different post-hatch access to feed. 180-day old chicks (Arbor acre and Marshal strains) with initial weight range of 39.36-42.24 g were used for this study. Each strain was divided on weight equalization into three treatment groups consisting of three time-periods with access to feeds (4 h, 24 h, 48 h) post hatch in a 2 × 3 factorial experiment after which they were fed ad-libitum. Thirty (30) birds were assigned to each treatment which comprised of three replicates of ten birds. Data collected on serum biochemical constituents and gut morphology were measured and subjected to analysis of variance in a randomized design. The Marshal strain recorded a higher (p < 0.05) final live weight (2420.00 g/bird) than the Arbor acre strain (2218.30 g/bird). Birds fed at 4 h and 24 h post-hatch recorded higher (p < 0.05) final live weights (2402.00 and 2391.00 g/bird) than those fed at 48 h post-hatch (2133.00 g/bird). Interaction effects showed that the Marshal strain fed at 4 h post-hatch had the highest (p < 0.05) final live weight (2594.00 g/bird). Highest (p < 0.05) serum total protein and albumin (37.3 and 22.8 g/l) were recorded in birds fed at 4 h post-hatch when assessed at 4 weeks of age. Furthermore, birds fed at 4 h and 24 h post-hatch recorded higher (p < 0.05) serum total protein and albumin than those fed at 48 h post-hatch. Birds fed at 4 h post-hatch recorded the highest (p < 0.05) duodenal villus height at 4th and 8th week of age and highest (P < 0.05) jejunal villus height when assessed in the 2nd week of age. It was concluded that Marshal strain fed at 4 h post-hatch elicited the highest growth performance and the most developed gut morphological features.


Development of a system of indicators for sustainable port management.
The 1998 project ECOPORT, "Towards A Sustainable Transport Network", developed by the Valencia Port Authority (VPA), established the bases for implementing an Environmental Management System (EMS) in industrial harbours. The use of data and information shall always be required to develop an efficient EMS. The objective of the present research (INDAPORT) study is to propose a system of sustainable environmental management indicators to be used by any port authorities. All activities performed within a port area are analysed for any potential environmental impacts and risks. An environmental analysis of port activities has been carried out with the objective of designing the indicators system. Twenty-one corresponding activities have been identified for large industrial ports. Subsequently, the same methodology developed to date will be later applied to other Spanish and European ports. The study has been developed by using an original system and a methodology, which simultaneously use stage diagrams and systemic models (material and energy flow charts). Multi-criteria analysis techniques were used to evaluate potential impacts (identification of factors and evaluation of impacts).


Early Predictors of Gestational Diabetes Mellitus in IVF-Conceived Pregnancies.
Gestational diabetes mellitus (GDM) is associated with adverse maternal and fetal outcomes. This study aimed to identify early and reliable GDM predictors that would enable implementation of preventive and management measures. The participants were a 28-week prospective cohort of in vitro fertilization (IVF)-conceived pregnant women (≤39 years, body mass index [BMI] 18.5-38 kg/m2) without a known history of diabetes mellitus. Fasting blood samples were analyzed at baseline (pre-IVF) and 12 weeks' gestation for reproductive hormones, glucose, serum insulin, lipids, thyroid function, adiponectin, and lipopolysaccharide-binding protein. At 28 weeks, a 75-g oral glucose tolerance test was used to screen for GDM. For the overall group at baseline, 22% had BMI ≥30 kg/m2, 45% had polycystic ovary syndrome, 16% had hemoglobin A1C of 5.7% to 6.1%, and 14% had a past history of GDM. At 28 weeks of gestation (n = 158), 34 women had developed GDM and 124 had not. Significant baseline predictors of GDM onset included greater BMI (29.0 vs 25.8 kg/m2), older age (34 vs 32 years), higher levels of follicle-stimulating hormone/luteinizing hormone ratio (1.2 vs 1.0), hemoglobin A1C (5.5 vs 5.2%), insulin (10.6 vs 7.1 μIU/mL), homeostatic model assessment of insulin resistance (2.2 vs 1.7), total cholesterol (199 vs 171 mg/dL), and low-density lipoprotein cholesterol (123 vs 105 mg/dL), and lower triglyceride levels (74 vs 76 mg/dL). Significant 12-week GDM predictors included greater maternal weight gain (delta: 3.4 vs 1.5 kg) and higher levels of insulin (11.3 vs 7.6 μIU/mL), triglycerides (178 vs 120 mg/dL), and homeostatic model assessment of insulin resistance (2.3 vs 1.5). Twelve-week BMI is a predictor of GDM following adjustment for polycystic ovary syndrome status and maternal age. While preconception maternal BMI, age, and follicle-stimulating hormone/luteinizing hormone ratio are predictors of subsequent development of GDM, early IVF-conceived gestational weight gain is the best predictor of GDM onset.


Ten years of training community urologists and general surgeons to do cadaver kidney retrievals.
We trained 82 community hospital cadaver kidney retrieval teams during a 10-year period ending June 30, 1987. During the last 5 years of that period the concept of multiple organ retrieval was introduced into the training sessions and 429 cadaver kidney grafts were retrieved. Of those kidneys 292 were transplanted at our hospital, and the function of 220 cadaver kidney grafts retrieved by the community hospital teams was compared to that of 72 retrieved by the transplant center retrieval team. Of the cadaver kidney transplants 114 were from multiple organ donors. There was no significant difference in 1-month serum creatinine nadir of surviving grafts (2.1 +/- 1.8 versus 1.9 +/- 1.7 mg. per dl.), 6-month serum creatinine level (1.7 +/- 0.8 versus 1.6 +/- 0.6 mg. per dl.), 12-month serum creatinine level (1.8 +/- 0.9 versus 1.6 +/- 0.6 mg. per dl.) and 5-year actuarial graft survival (44.8 +/- 4.1 versus 52.4 +/- 7.5%), with the community hospital data presented first. The delayed graft function rate was significantly higher in the recipients of cadaver kidney grafts retrieved by community hospital teams (54 versus 35%), which was reduced by the in situ flush technique. There was no significant difference in delayed graft function rate (48 versus 40%) for the 114 cadaver kidney transplants retrieved from multiple organ donors by either community hospital or transplant center teams. With continuing education and quality control, community hospital retrieval teams can provide kidneys satisfactory for transplantation, even when working with multiple organ retrieval teams.


TGR5 expression in benign, preneoplastic and neoplastic lesions of Barrett's esophagus: Case series and findings.
To examined the bile acid receptor TGR5 expression in squamous mucosa, Barrett's mucosa, dysplasia and esophageal adenocarcinoma (EA). Slides were stained with TGR5 antibody. The staining intensity was scored as 1+, 2+ and 3+. The extent of staining (percentage of cells staining) was scored as follows: 1+, 1%-10%, 2+, 11%-50%, 3+, 51%-100%. A combined score of intensity and extent was calculated and categorized as negative, weak, moderate and strong staining. TGR5 mRNA was measured by real time PCR. We found that levels of TGR5 mRNA were significantly increased in Barrett's dysplastic cell line CP-D and EA cell line SK-GT-4, when compared with Barrett's cell line CP-A. Moderate to strong TGR5 staining was significantly higher in high-grade dysplasia and EA cases than in Barrett's esophagus (BE) or in low-grade dysplasia. Moderate to strong staining was slightly higher in low-grade dysplasia than in BE mucosa, but there is no statistical significance. TGR5 staining had no significant difference between high-grade dysplasia and EA. In addition, TGR5 staining intensity was not associated with the clinical stage, the pathological stage and the status of lymph node metastasis. We conclude that TGR5 immunostaining was much stronger in high-grade dysplasia and EA than in BE mucosa or low-grade dysplasia and that its staining intensity was not associated with the clinical stage, the pathological stage and the status of lymph node metastasis. TGR5 might be a potential marker for the progression from BE to high-grade dysplasia and EA.


Amylase activity and stability at high and low temperature depending on calcium and other divalent cations.
Since the extracellular amylase from B. caldolyticus had been characterized as a Ca-dependent enzyme, we wanted to determine the function and specificity of this ion, and it's possible significance for the thermophilic properties of the enzyme. The first question concerned the substitution of Ca with regard to the activity at 70 C. Our data show that Sr or other divalent cations can only to a limited extent replace Ca, and that only in presence of Ca full activity can be achieved. When the majority of the binding sites of the subunits are occupied by cations other than Ca, an almost total loss of activity results. The reason for this kind of inactivation was found in the responsibility of Ca for the stability of the enzyme at high temperature. The omission of Ca then leads to an irreversible denaturation of the enzyme, so that after this kind of treatment no activity is detectable at either high or low temperature, which means that the amylase is not a thermostable enzyme in the classical sense. The stabilizing effect of Ca could not be substituted by any other of the cations tested. Experiments concerning the stability of the enzyme at various temperatures in absence of presence of Ca revealed that the enzyme is stable up to 55 C as long as trace amounts of Ca are available. If these are omitted by a chelator, the enzyme becomes unstable between 40 and 45 C. Experiments in which a certain protein concentration range was tested at 40 and 70 C with given concentrations of Ca showed that the stability, and with it the activity, at high temperature is directly related to the amount of Ca available: The more the Ca supply is limited, the less enzyme protein can be kept in the right configuration, and irreversibly denatures as a result. At low temperature, however, the enzyme becomes almost independent of Ca, and the small amounts necessary to obtain full activity can be replaced by other divalent cations. The main conclusions concerning the role of Ca are that at high temperatures it participates in achieving the correct configuration of the thermostable form of the enzyme, and that in this function it is irreplacable. At low temperature it acts as an unspecific cofactor. The other conclusion is that the amylase can exist either as a caldo-active, thermostable, Ca-dependent enzyme, or in a Ca-independent thermostable state with a lower activity.


Steroid Sensitive Nephrotic Syndrome: Revised Guidelines.
Steroid sensitive nephrotic syndrome (SSNS) is one of the most common chronic kidney diseases in children. These guidelines update the existing Indian Society of Pediatric Nephrology recommendations on its management. To frame revised guidelines on diagnosis, evaluation, management and supportive care of patients with the illness. The guidelines combine evidence-based recommendations and expert opinion. Formulation of key questions was followed by review of literature and evaluation of evidence by experts in two face-to-face meetings. The initial statements provide advice for evaluation at onset and follow up and indications for kidney biopsy. Subsequent statements provide recommendations for management of the first episode of illness and of disease relapses. Recommendations on the use of immunosuppressive strategies in patients with frequent relapses and steroid dependence are accompanied by suggestions for step-wise approach and plan of monitoring. Guidance is also provided regarding the management of common complications including edema, hypovolemia and serious infections. Advice on immunization and transition of care is given. The revised guideline is intended to improve the management and outcomes of patients with SSNS, and provide directions for future research.


Self-examination low-cost full-field OCT (SELFF-OCT) for patients with various macular diseases.
The treatment guidelines for many macular diseases rely on frequent monitoring with optical coherence tomography (OCT). However, the burden of frequent disease control leads to low therapy adherence in real life. OCT home monitoring would address this issue but requires an inexpensive and self-operable device. With self-examination low-cost full-field OCT (SELFF-OCT), our group has introduced a novel technology that may fulfill both requirements. In this pilot study, we report the initial experiences with a clinical prototype. Fifty-one patients with different macular diseases were recruited in a cross-sectional study. The most common diseases were age-related macular degeneration (AMD; 39/51), diabetic macular edema (DME; 6/51), and retinal vein occlusion (RVO; 3/51). Patients received a short training in device usage and then performed multiple self-scans with the SELFF-OCT device. For comparison, scans with a standard clinical spectral domain (SD-)OCT were taken. After a brief training, 77% of the patients were able to successfully acquire images that were clinically gradable. No significant influence on success could be found for age (p = 0.08) or BCVA (p = 0.97). Relevant disease biomarkers in the most common retinal diseases could be detected. SELFF-OCT was used successfully for retinal self-examination and in the future could be used for retinal home monitoring. Future improvements in technology are expected to improve success rates and image quality. The Trial was registered in the German Trial Register under the number DRKS00013755 on 14.03.2018.


The effect of a food addiction explanatory model of eating behaviours on weight-based stigma: An experimental investigation.
Weight stigmatization and discrimination are pervasive issues that have numerous adverse consequences for those with excess weight. It has been proposed that some individuals may be addicted to hyperpalatable processed foods, resulting in weight promoting eating behaviours. The current study replicated and extended a study examining the effect of a food addiction explanation for eating behaviours on weight-based stigma and weight-controllability beliefs. Undergraduate students (N = 757) were randomly assigned to one of four conditions where they read a newspaper article accompanied by a photo of a woman 1) who was either of a higher body mass index (BMI) or a lower BMI, and 2) that attributed her eating behaviours to either food addiction or poor dietary and lifestyle choices. Stigma towards the woman and individuals with a higher BMI in general were assessed. Results indicated that the woman with a higher BMI elicited greater weight stigma. Attributing weight to food addiction increased perceptions of psychopathology towards the woman, whereas attributing weight to poor dietary and lifestyle choices elicited judgment towards the woman. Neither explanation about eating behaviours elicited stigma towards individuals with a higher BMI in general. Findings suggest that a food addiction explanation alone may not be sufficient to reduce weight stigma.


The African swine fever virus lectin EP153R modulates the surface membrane expression of MHC class I antigens.
We have modeled a 3D structure for the C-type lectin domain of the African swine fever virus protein EP153R, based on the structure of CD69, CD94 and Ly49A cell receptors, and this model predicts that a dimer of EP153R may establish an asymmetric interaction with one MHC-I molecule. A functional consequence of this interaction could be the modulation of MHC-I expression. By using both transfection and virus infection experiments, we demonstrate here that EP153R inhibits MHC-I membrane expression, most probably by impairing the exocytosis process, without affecting the synthesis or glycosylation of MHC antigens. Interestingly, the EP153-mediated control of MHC requires the intact configuration of the lectin domain of the viral protein, and specifically the R133 residue. Interference of EP153R gene expression during virus infection and studies using virus recombinants with the EP153R gene deleted further support the inhibitory role of the viral lectin on the expression of MHC-I antigens.


How to determine kidney function in cancer patients?
A precise and efficient method for estimating kidney function in cancer patients is important to determine their eligibility for clinical trials and surgery and to allow for appropriate dose adjustment of anti-cancer drugs, especially toxic drugs with a narrow therapeutic index. Since direct measurement of glomerular filtration rate (GFR) is cumbersome, several formulae have been developed to estimate kidney function. Most of these are based on serum creatinine concentration. Though the CKD-EPI formula is recognised as being the most accurate, there is an ongoing debate on which is the optimal formula for cancer patients. In this review, we provide an overview of different GFR estimating equations for kidney function and the advantages and disadvantages of each method and compare their performance in cancer patients. We discuss the importance of body surface area-indexing and propose a framework for evaluating kidney function in cancer patients.


Synthesis of a phosphorano-stabilized U(IV)-carbene via one-electron oxidation of a U(III)-ylide adduct.
Addition of the Wittig reagent Ph(3)P═CH(2) to the U(III) tris(amide) U(NR(2))(3) (R = SiMe(3)) generates a mixture of products from which the U(IV) complex U═CHPPh(3)(NR(2))(3) (2) can be obtained. Complex 2 features a short U═C bond and represents a rare example of a uranium carbene. In solution, 2 exists in equilibrium with the U(IV) metallacycle U(CH(2)SiMe(2)NR)(NR(2))(2) and free Ph(3)P═CH(2). Measurement of this equilibrium as a function of temperature provides ΔH(rxn) = 11 kcal/mol and ΔS(rxn) = 31 eu. Additionally, the electronic structure of the U═C bond was investigated using DFT analysis.


Associations between a history of sexual abuse and dental anxiety, caries experience and oral hygiene status among adolescents in sub-urban South West Nigeria.
Sexual and oral health are important areas of focus for adolescent wellbeing. We assessed for the prevalence of sexual abuse among adolescents, oral health factors associated with this history, and investigated whether sexual abuse was a risk indicator for dental anxiety, caries experience and poor oral hygiene. This was a cross-sectional study conducted between December 2018 and January 2019 among adolescents 10-19 years old in Ile-Ife, Nigeria. Survey data collected included respondents' age, sex, and socioeconomic status, oral health risk factors (dental anxiety, frequency of tooth brushing intake of refined carbohydrates in-between-meals, flossing, dental visits, smoking, alcohol intake, use of psychoactive substances), caries experience, oral hygiene status, history of sexual abuse, and sexual risk behaviors (age of sexual debut, history of transactional sex, last sexual act with or without condom, multiple sex partners). Regression models were constructed to determine the association between outcome variables (dental anxiety, presence of caries experience and poor oral hygiene) and explanatory variables (oral health risk factors and history of sexual abuse). The prevalence of sexual abuse in our cohort was 5.9%: 4.3% among males and 7.9% among females. A history of sexual abuse was associated with alcohol consumption (p = 0.009), cigarette smoking (p = 0.001), and a history of transactional sex (p = 0.01). High/severe dental anxiety was significantly associated with increased odds of a history of sexual abuse (AOR = 1.81; 95% CI 1.10, 2.98), but not with caries experience (AOR = 0.66; 95% CI 0.15, 2.97) nor poor oral hygiene (AOR = 1.68; 95% CI 0.95, 2.96). Dental anxiety was associated with increased odds of alcohol intake (AOR = 1.74; 95% CI 1.19, 2.56), twice daily tooth brushing (AOR = 1.48; 95% CI 1.01, 2.17) and daily consumption of refined carbohydrates in-between-meals (AOR = 2.01; 95% CI 1.60, 2.54). Caries experience was associated with increased odds of using psychoactive substances (AOR = 4.83; 95% CI 1.49, 15.62) and having low socioeconomic status (AOR = 0.40; 95% CI 0.18, 0.92). Poor oral hygiene was associated with increased odds of having middle socioeconomic status (AOR = 1.43; 95% CI 1.05, 1.93) and daily consumption of refined carbohydrates in-between-meals (AOR = 1.38; 95% CI 1.08, 1.78). Adolescents who are highly dentally anxious need to be screened for a history of sexual abuse to facilitate access to professional care and support.


Deciphering the messages carried by extracellular vesicles in hematological malignancies.
Extracellular vesicles (EVs) are nanosized membrane-bound particles released from all living cells examined thus far. EVs can transfer information in the form of proteins, nucleic acids, and lipids from donor cells to recipient cells. Here we summarize recent advances in understanding the role(s) EVs play in hematological malignancies (HM) and outline potential prognostic and diagnostic strategies using EVs. EVs have been shown to promote proliferation and angiogenesis, and alter the bone marrow microenvironment to favour the growth and survival of diverse HM. They also promote evasion of anti-cancer immune responses and increase multi-drug resistance. Using knowledge of EV biology, including HM-specific packaging of cargo, EV based diagnostics and therapeutic approaches show substantial clinical promise. However, while EVs may represent a new paradigm to solve many of the challenges in treating and/or diagnosing HM, much work is needed before they can be used clinically to improve patient outcomes.


Naturally occurring nonneoplastic histopathological lesions in the female SENCAR mouse.
Lesions that were considered naturally occurring were surveyed in female SENCAR mice used in short-term bioassays. These lesions were encountered in selected target organs and in organs and tissues with gross lesions encountered at necropsy. The genitourinary system was the most frequent site for lesions; cystic ovaries, cystic endometrial hyperplasia, and glomerulonephritis were commonly encountered in this system.


Restructuring health care financing in Chile.
The current Chilean government adopted a neoclassical model of development and subsequently introduced various incentives for the privatization of medical care. This paper analyzes health care financing in Chile during the last decade and evaluates government efforts to minimize state-financed medical care. In so doing, this paper provides a framework for analyzing private vs public medical care delivery systems in developing countries. For this reason, the first section discusses the major attributes and issues of public and private delivery systems followed by a case study examining the origins, effectiveness and impact of the restructured health system in Chile.


Soil cadmium and lead affecting biochemical properties of Matricaria chamomilla L. at different growth stages in the greenhouse and field.
Heavy metals bioremediation by medicinal plants is an important research issue, which has yet to be investigated. Matricaria chamomilla accumulation of soil cadmium (Cd, 0, 10 and 40 mg/kg) and lead (Pb, 0, 60 and 180 mg/kg) affecting plant biochemical properties L. at different growth stages in the greenhouse and field was investigated. The 10-kg experimental pots (located in the greenhouse and field with 80% of field capacity moisture) were filled with the treated soils, and were planted with M. chamomilla L. seeds (three replicates). Plants were sampled to determine their biochemical properties including Cd and Pb contents, pigments, proline (Pro), leaf relative water (LRW), lipid peroxidation (LX), and superoxide dismutase (SOD, EC 1.15. 1.1), and catalase (CAT, EC 126.96.36.199) activities. Soil final concentration of Cd and Pb was also determined. Heavy metal stress significantly decreased plant pigment contents; however, it significantly increased plant PRO, LRW, LX and SOD, and not CAT. Heavy metal, growth stage, growth location, and their interactions significantly affected plant heavy metal concentrations. Interestingly, although significantly higher concentration of Cd was observed in plant aerial part under greenhouse conditions, plant roots had significantly higher concentrations of Cd under field conditions, and it was reverse for Pb. Increased concentration of Cd and Pb significantly enhanced plant Pro content and the highest one was resulted by Pb3 (913.46 mg/g fresh weight) significantly higher than other treatments including Cd3 (595.34 mg/g fresh weight). M. chamomilla is a suitable species for the bioremediation of soils polluted with Cd and Pb.


Functional activity level reported by an informant is an early predictor of Alzheimer's disease.
Loss of autonomy in day-to-day functioning is one of the feared outcomes of Alzheimer's disease (AD), and relatives may have been worried by subtle behavioral changes in ordinary life situations long before these changes are given medical attention. In the present study, we ask if such subtle changes should be given weight as an early predictor of a future AD diagnosis. Longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to define a group of adults with a mild cognitive impairment (MCI) diagnosis remaining stable across several visits (sMCI, n=360; 55-91 years at baseline), and a group of adults who over time converted from having an MCI diagnosis to an AD diagnosis (cAD, n=320; 55-88 years at baseline). Eleven features were used as input in a Random Forest (RF) binary classifier (sMCI vs. cAD) model. This model was tested on an unseen holdout part of the dataset, and further explored by three different permutation-driven importance estimates and a comprehensive post hoc machine learning exploration. The results consistently showed that measures of daily life functioning, verbal memory function, and a volume measure of hippocampus were the most important predictors of conversion from an MCI to an AD diagnosis. Results from the RF classification model showed a prediction accuracy of around 70% in the test set. Importantly, the post hoc analyses showed that even subtle changes in everyday functioning noticed by a close informant put MCI patients at increased risk for being on a path toward the major cognitive impairment of an AD diagnosis. The results showed that even subtle changes in everyday functioning should be noticed when reported by relatives in a clinical evaluation of patients with MCI. Information of these changes should also be included in future longitudinal studies to investigate different pathways from normal cognitive aging to the cognitive decline characterizing different stages of AD and other neurodegenerative disorders.


Effect of land-use and land-cover change on mangrove soil carbon fraction and metal pollution risk in Zhangjiang Estuary, China.
Land-use and land-cover change (LULCC) is the main cause of mangrove deforestation and degradation. However, the effect of LULCC on mangrove soil organic carbon (SOC) fractions and metal pollution risks, and the difference between the effects of those two soil evolutions are largely unknown. Here, we collected soil samples from natural systems (mangroves and mudflat), land-cover changes (Spartina alterniflora invasion), and anthropogenic land-use changes (cropland and culture pond) in Zhangjiang Estuary. We determined the soil aggregate fractions (macro-aggregate, micro-aggregate, and silt-clay fraction) and the associated carbon, and heavy metal dynamics. Our findings suggested that LULCC did not remarkably affect SOC contents, but changed the soil aggregate structures. LULCC significantly increased aggregate-associated carbon fractions, especially macro-aggregate carbon fraction. The large proportion of silt-clay fraction in natural systems was corresponding to a high percentage of mineral organic carbon, indicating that LULCC decreases the mangrove SOC stability. Land-cover change promoted the accumulation of SOC, nitrogen, and heavy metals compared with uninvaded mudflat. The heavy metal contents in mangrove soil were highest among all studied soils, expect for Cd, which suggested that mangrove soil had high metal accumulation. However, land-use changes could stimulate the mobility and dynamics of metals enriched in mangrove soils; these changes, especially in cropland, will also cause a large amount of exogenous Cd being exported into the adjacent aquatic environment. Thus, mangrove shifts metal pollutant from sink to source when affected by land-use changes. The contamination index demonstrated that heavy metals have posed ecological risks, especially for Cd in cropland. Compared with mangrove, land-use change was dominated by single-element pollution, but land-cover change showed low multiple-element complex pollution. These findings elucidate the effects of LULCC on mangrove SOC fraction and metal pollution risk, and are of great significance for designing the long-term management and conservation policies for mangrove managers.


Early afferent activity from the facet joint after painful trauma to its capsule potentiates neuronal excitability and glutamate signaling in the spinal cord.
Cervical facet joint injury induces persistent pain and central sensitization. Preventing the peripheral neuronal signals that initiate sensitization attenuates neuropathic pain. Yet, there is no clear relationship among facet joint afferent activity, development of central sensitization, and pain, which may be hindering effective treatments for this pain syndrome. This study investigates how afferent activity from the injured cervical facet joint affects induction of behavioral sensitivity and central sensitization. Intra-articular bupivacaine was administered to transiently suppress afferent activity immediately or 4 days after facet injury. Mechanical hyperalgesia was monitored after injury, and spinal neuronal hyperexcitability and spinal expression of proteins that promote neuronal excitability were measured on day 7. Facet injury with saline vehicle treatment induced significant mechanical hyperalgesia (P<.027), dorsal horn neuronal hyperexcitability (P<.026), upregulation of pERK1/2, pNR1, mGluR5, GLAST, and GFAP, and downregulation of GLT1 (P<.032). However, intra-articular bupivacaine immediately after injury significantly attenuated hyperalgesia (P<.0001), neuronal hyperexcitability (P<.004), and dysregulation of excitatory signaling proteins (P<.049). In contrast, intra-articular bupivacaine at day 4 had no effect on these outcomes. Silencing afferent activity during the development of neuronal hyperexcitability (4 hours, 8 hours, 1 day) attenuated hyperalgesia and neuronal hyperexcitability (P<.045) only for the treatment given 4 hours after injury. This study suggests that early afferent activity from the injured facet induces development of spinal sensitization via spinal excitatory glutamatergic signaling. Peripheral intervention blocking afferent activity is effective only over a short period of time early after injury and before spinal modifications develop, and is independent of modulating spinal glial activation.


Vim thalamotomy in a patient with Holmes' tremor and palatal tremor - Pathophysiological considerations.
We peformed a ventral intermediate nucleus (Vim) thalamotomy in a patient with Holmes' tremor and palatal tremor. The frequencies of these movement disorders were 4 Hz and 3 Hz, respectively. Vim thalamotomy stopped the Holmes' tremor but not the palatal tremor. Our observations suggest different mechanisms for these two involuntary movements. A 57-arm 11 months after a pontine hemorrhage. Transoral carotid ultrasonography revealed periodic motion of her posterior pharyngeal wall with a frequency of 3 Hz. Recording of neuronal activities in the thalamus revealed a 4Hz rhythmic discharge time that was associated with her tremor in the contralateral arm. A left Vim thalamotomy was performed. The resting tremor of the upper limb stopped, but the kinetic tremor recurred 6 months after the thalamotomy. No effect was observed on her palatal tremor. The different effects of Vim thalamotomy on the Holmes' tremor and palatal tremor suggest different oscillation sources for these two involuntary movements.


Mechanism of enhanced production of triterpenoids in algal-fungal consortium.
Chlorella pyrenoidosa-Ganoderma lucidum symbiotic systems were constructed. The mechanism of enhanced production of triterpenoids in algal-fungal consortium by comparing the contents of triterpenoids in individual fungal systems and algal-fungal consortium systems was investigated. The production of triterpenoids in C. pyrenoidosa-G. lucidum consortium increased significantly (P < 0.05). The categories and relative abundances of metabolites in the individual systems and algal-fungal systems were measured and analyzed by metabonomic tests. There were 57 significant different metabolites (VIP > 1 and P < 0.05) including 12 downregulated metabolites and 45 upregulated metabolites were obtained. The significant enriched metabolic pathways (VIP > 1 and P < 0.05) of citrate cycle (TCA cycle), tyrosine metabolism, glycolysis, and terpenoid backbone biosynthesis in algal-fungal consortium were obtained. The relative abundances of important precursors of triterpenoids including mevalonic acid, lanosterol, and hydroquinone were 1.4 times, 1.7 times, and 2 times, respectively, in algal-fungal consortium than that in the individual fungal systems. The presence of C. pyrenoidosa in algal-fungal consortium promoted the biosynthesis of triterpenoids in G. lucidum.


Inner retinal layers' alterations and microvasculature changes after vitrectomy for rhegmatogenous retinal detachment.
To examine the retinal layers' changes and alterations in retinal microvasculature in patients with rhegmatogenous retinal detachment (RRD) treated with pars plana vitrectomy (PPV). Participants in this study were 103 patients with RRD, 85 macula off and 18 macula on, who were treated with PPV and gas tamponade without internal limiting membrane peeling, in two centers. All participants underwent best corrected visual acuity measurement, slit-lamp examination, fundoscopy, spectral domain-optical coherence tomography and optical coherence tomography angiography at week 5 and at month 6 postoperatively. The fellow untreated eyes were also examined and served as control data. A statistically significant enlargement in foveal avascular zone (FAZ) in both superficial capillary plexus (SCP) and deep capillary plexus (DCP) was noticed 5 weeks postoperatively in patients with RRD treated with PPV compared to the fellow eyes and remained 6 months after surgery. The FAZ enlargement in the operated eyes was accompanied with a statistically significant thinning of the inner retinal layer. In addition, there was a significant decrease in foveal and parafoveal vessel density (VD) in both SCP and DCP in the operated eyes compared to control eyes at week 5 postoperatively, which also remained at postoperative month 6. The study demonstrated that patients with RRD treated with PPV presented changes in the retinal microvasculature in both SCP and DCP, including enlargement of FAZ and decrease in VD. These changes seemed to be associated with inner retinal layer thinning.


COVID-19: Current Challenges and Future Perspectives.
This Special Issue focuses on recent global research on the current coronavirus (COVID-19) pandemic [...].


A kinetic model of cooperativity in aspartate transcarbamylase.
A relatively simple kinetic model is proposed to account simultaneously for data on the binding of carbamyl phosphate and succinate to aspartate trans carbamylase (ATCase), and for the relaxation spectrum associated with this binding. The model also accounts for measurements of the initial velocity of the reaction of ATCase with respect to aspartate and carbamyl phosphate. The principal assumption made is that ATCase consists of three identical noninteracting cooperative dimers. Ordered binding and both sequential and concerted conformational changes in the dimers are needed to account for the properties of ATCase. The values of the parameters of this model can be determined by fitting to existing experimental evidence. Various new quantitative predictions are made that can serve as additional tests of the proposed theory.


Air pollution and tourism growth relationship: exploring regional dynamics in five European countries through an EKC model.
The present study intends to explore the relationship between tourism growth and air pollution at a regional level for five important tourism European destinations: France, Spain, Greece, Portugal, and Italy. Most of the studies found in the literature examine this relationship on a national scale and focus only on the CO2 pollutant, which is a greenhouse gas but not a critical pollutant in terms of air quality and human exposure. This research focuses on a regional basis (NUTS 2 classification) and takes into account the main critical pollutants in terms of urban air pollution (namely: NOx, PM10, and PM2.5), and considers 10 years, from 2009 until 2018. This work aims to investigate evidence of a tourism-induced Environmental Kuznets Curve (EKC) for the countries through the construction of five panels, one for each country, including different variables: the Gross Domestic Product, the energy consumption, and the number of nights spent at tourist accommodation establishments from both domestic and foreign tourists. The Levin-Lin-Chu unit root test proves the variables to be stationary, while the Pedroni cointegration test shows that they are integrated. The pooled OLS estimator is employed throughout the countries to check the relationship among the variables. Results reveal that the tourism-induced EKC hypothesis is not validated for any of the countries. The findings also show that in Portugal, Italy, and Greece, there is a negative relationship between economic growth and environmental pollution, while mixed evidence is found for France and Spain. Moreover, differences in the impacts of international and domestic tourists on air pollution are found: foreign tourists negatively impact emissions, while domestic ones increase them. This result is clear for Spain, Greece, and Italy. The Granger panel causality test is then conducted to see the causality among the variables.


Underweight rather than adiposity is an important predictor of death in rural Chinese adults: a cohort study.
To assess the associations of body mass index (BMI) with all-cause and cause-specific mortalities among rural Chinese. A prospective study of 28 895 individuals was conducted from 2006 to 2014 in rural Deqing, China. Height and weight were measured. The association of BMI with mortality was assessed by using Cox proportional hazards model and restricted cubic spline regression. There were a total of 2062 deaths during an average follow-up of 7 years. As compared with those with BMI of 22.0-24.9 kg/m2, an increased risk of all-cause mortality was found for both underweight men (BMI <18.5 kg/m2) (adjusted HR (aHR): 1.45, 95% CI: 1.18 to 1.79) and low normal weight men (BMI of 18.5-21.9 kg/m2) (aHR: 1.20, 95% CI: 1.03 to 1.38). A J-shaped association was observed between BMI and all-cause mortality in men. Underweight also had an increased risk of cardiovascular disease and cancer mortalities in men. The association of underweight with all-cause mortality was more pronounced in ever smokers and older men (60+ years). The results remained after excluding participants who were followed up less than 1 year. The present study suggests that underweight is an important predictor of mortality, especially for elderly men in the rural community of China.


High-fat diet induces systemic B-cell repertoire changes associated with insulin resistance.
The development of obesity-associated insulin resistance is associated with B-lymphocyte accumulation in visceral adipose tissue (VAT) and is prevented by B-cell ablation. To characterize potentially pathogenic B-cell repertoires in this disorder, we performed high-throughput immunoglobulin (Ig) sequencing from multiple tissues of mice fed high-fat diet (HFD) and regular diet (RD). HFD significantly changed the biochemical properties of Ig heavy-chain complementarity-determining region-3 (CDRH3) sequences, selecting for IgA antibodies with shorter and more hydrophobic CDRH3 in multiple tissues. A set of convergent antibodies of highly similar sequences found in the VAT of HFD mice but not RD mice showed significant somatic mutation, suggesting a response shared between mice to a common antigen or antigens. These findings indicate that a simple high-fat dietary intervention has a major impact on mouse B-cell repertoires, particularly in adipose tissues.


Systematic review and meta-analysis: the incidence and prevalence of paediatric coeliac disease across Europe.
Coeliac disease is one of the most prevalent immune-mediated gastrointestinal disorders in children. To review the incidence and prevalence of paediatric coeliac disease, and their trends, regionally across Europe, overall and according to age at diagnosis. Systematic review and meta-analysis from January 1, 1950 to December 31, 2019, based on PubMed, CINAHL and the Cochrane Library, searches of grey literature and websites and hand searching of reference lists. A total of 127 eligible studies were included. The prevalence of previously undiagnosed coeliac disease from screening surveys (histology based) ranged from 0.10% to 3.03% (median = 0.70%), with a significantly increasing annual trend (P = 0.029). Prevalence since 2000 was significantly higher in northern Europe (1.60%) than in eastern (0.98%), southern (0.69%) and western (0.60%) Europe. Large increases in the incidence of diagnosed coeliac disease across Europe have reached 50 per 100 000 person-years in Scandinavia, Finland and Spain. The median age at diagnosis increased from 1.9 years before 1990 to 7.6 since 2000. Larger increases in incidence were found in older age groups than in infants and ages <5 years. Paediatric coeliac disease incidence and prevalence have risen across Europe and appear highest in Scandinavia, Finland and Spain. The most recent evidence shows large increases in incidence in most regions, but stabilisation in some (notably Sweden and Finland). Sharp increases in the age at diagnosis may reflect increases in milder and asymptomatic cases diagnosed since reliable serology testing became widely used, through endomysial antibodies after 1990 and tissue transglutaminase antibodies around 2000.


Identification of Factors Influencing Out-of-county Hospitalizations in the New Cooperative Medical Scheme.
Throughout the duration of the New Cooperative Medical Scheme (NCMS), it was found that an increasing number of rural patients were seeking out-of-county medical treatment, which posed a great burden on the NCMS fund. Our study was conducted to examine the prevalence of out-of-county hospitalizations and its related factors, and to provide a scientific basis for follow-up health insurance policies. A total of 215 counties in central and western China from 2008 to 2016 were selected. The total out-of-county hospitalization rate in nine years was 16.95%, which increased from 12.37% in 2008 to 19.21% in 2016 with an average annual growth rate of 5.66%. Its related expenses and compensations were shown to increase each year, with those in the central region being higher than those in the western region. Stepwise logistic regression reveals that the increase in out-of-county hospitalization rate was associated with region (X1), rural population (X2), per capita per year net income (X3), per capita gross domestic product (GDP) (X4), per capita funding amount of NCMS (X5), compensation ratio of out-of-county hospitalization cost (X6), per time average in-county (X7) and out-of-county hospitalization cost (X8). According to Bayesian network (BN), the marginal probability of high out-of-county hospitalization rate was as high as 81.7%. Out-of-county hospitalizations were directly related to X8, X3, X4 and X6. The probability of high out-of-county hospitalization obtained based on hospitalization expenses factors, economy factors, regional characteristics and NCMS policy factors was 95.7%, 91.1%, 93.0% and 88.8%, respectively. And how these factors affect out-of-county hospitalization and their interrelationships were found out. Our findings suggest that more attention should be paid to the influence mechanism of these factors on out-of-county hospitalizations, and the increase of hospitalizations outside the county should be reasonably supervised and controlled and our results will be used to help guide the formulation of proper intervention policies.


Molecular detection and corelation of Helicobacter pylori in dental plaque and gastric biopsies of dyspeptic patients.
Helicobacter pylori is a microaerophilic organism, which colonizes in the gastric mucosa. Its role in etiology and development of acute and chronic gastritis and peptic ulcer diseases is scientifically proved. Oral cavity especially supragingival, subgingival plaque and so forth simulate the same microaerophilic environment favorable for the growth of this bacterium. Detection of H. pylori simultaneously in the oral cavity and gastric mucosa of patients suffering from gastric pathologies. To detect H. pylori in the oral cavity and gastric mucosa using endoscopy, urease test and real-time polymerase chain reaction (PCR) (urease A gene). Determining its association and corelation with patient demographics, oral hygiene maintenance and periodontal disease status. Endoscopic examination, oral findings oral hygiene index-simplified (OHI-S) and community periodontal index and treatment needs (CPITN) indices were recorded. Antral biopsies and supragingival plaque samples were taken from 56 dyspeptic adult patients. The collected samples were subjected to histological examination, urease broth test and urease A gene amplification using real-time PCR. H. pylori was detected in the supragingival plaque of individuals with H. pylori-induced gastric diseases using rapid urease test and real-time PCR analysis. Occurrence of same strain of H. pylori simultaneously in plaque and gastric mucosa was observed. Positive correlation was obtained between the collected indices and quantity of H. pylori colonization.


Surface-Initiated Atom Transfer Radical Polymerization for the Preparation of Well-Defined Organic-Inorganic Hybrid Nanomaterials.
Surface-initiated atom transfer radical polymerization (SI-ATRP) is a powerful tool that allows for the synthesis of organic-inorganic hybrid nanomaterials with high potential applications in many disciplines. This review presents synthetic achievements and modifications of nanoparticles via SI-ATRP described in literature last decade. The work mainly focuses on the research development of silica, gold and iron polymer-grafted nanoparticles as well as nature-based materials like nanocellulose. Moreover, typical single examples of nanoparticles modification, i.e., ZnO, are presented. The organic-inorganic hybrid systems received according to the reversible deactivation radical polymerization (RDRP) approach with drastically reduced catalyst complex concentration indicate a wide range of applications of materials including biomedicine and microelectronic devices.


[The use of leukocyte interferon in the combined therapy of condylomata acuminata of the genitals].
A new method for the treatment of condyloma acuminatum is described: leukocytic interferon combined with liquid nitrogen cryotherapy. This treatment has resulted in a stable therapeutic effect.


Impact of obesity and diabetes mellitus in critically ill patients with SARS-CoV-2.
Evaluate the associations of obesity and diabetes with the risk of mortality in critically ill patients infected with SARS-CoV-2. This cohort study included 115 adult patients admitted to the ICU with SARS-CoV-2 pneumonia. Anthropometric variables and biochemical (C-reactive protein, ferritin, leukocyte, neutrophils, and fibrinogen) were measured. Multivariate logistic regression analyses were used to investigate the associations. Mean age was 50.6±11.2 years, 68.7% were male. Median BMI was 30.9kg/m2. All patients had invasive mechanical ventilation. Patients with diabetes had increased risk of mortality with OR of 2.86 (CI 95% 1.1-7.4, p=0.026); among those patients who, in addition to diabetes had obesity, the risk was de 3.17 (CI 95% 1.9-10.2, p=0.038). Patients with obesity had 1.25 times greater risk of developing a severe SARS-CoV-2 infection (95% CI 1.09-1.46, p=0.025). Negative correlation was observed between BMI and the PaO2/FiO2 ratio (r=-0.023, p<0.05). Obese patients required more days of mechanical ventilation and longer hospital stay compared to non-obese patients. Diabetes and obesity are risk factors for increasing severity of SARS-CoV-2 infection, and they are both associated with an increase in mortality.


Determining the effect of selected mental factors on turnover intention through two modulators - stress and resilience over COVID-19 period.
Turnover intention among nurses has risen in an alarming rate since the onset of the pandemic. There are various underlying factors to turnover intention. The present study aims to determine the effect of a number of mental factors on nurses' professional-turnover intention through two modulators of stress and resilience over COVID-19 period. The current cross-sectional study was conducted at three hospitals in Khuzestan Province, southern Iran, during the winter of 2021. To collect the data, given the restrictions in place during COVID-19 period, the web link of electronic self-reported questionnaires (including general health, mental workload, work-family conflict, resilience, job stress, corona fear, and turnover intention) were sent to 350 nurses through e-mail and other social media (WhatsApp and Telegram). Accordingly, they were asked to complete the questionnaire during rest periods within two weeks. Totally, 300 people (85% participation) filled out the questionnaires. Finally, a model was constructed in the Amos software. The results showed that the four independent parameters of decreasing general health, increasing mental workload, increasing WFCs and fear of COVID-19 can indirectly increase nurses' turnover intention by increasing job stress. Among these variables, the highest indirect effect coefficient on turnover intention was related to the general health parameter (-0.141). The results also demonstrated a negative correlation between job stress and resilience, with lower resilience raising job stress and, consequently, increasing intention to quit the job. Mental factors affecting turnover intension were identified in this study through path analysis. Therefore, it is recommended that the required resilience-enhancing measures to be taken by hospitals and nursing administrations to reduce psychological pressures caused by mentioned variables with the aim of minimizing job-related stress and fostering nurse retention.


How I Diagnose and Treat Thrombocytopenia in the Geriatric Patient.
Thrombocytopenia in the elderly is a common but diagnostically challenging condition that has variable clinical impact to those affected. Diagnostic approach requires evaluation of pre-existing clinical conditions, detailed review of medications, and assessment for disorders that warrant urgent treatment. We describe a systematic approach to diagnosis of thrombocytopenia and present a schematic review for management strategies. Three clinical scenarios are presented that are relevant for their prevalence and management challenges in an elderly population. The first addresses primary immune thrombocytopenia (ITP) and reviews different treatment options. The second addresses complications of thrombocytopenia in management of the myelodysplastic syndrome (MDS). The last reviews diagnostic challenges of drug induced immune thrombocytopenia (DITP).


[Reference values for the peak expiratory flow].
Peak expiratory flow (PEF) is an important screening method for investigation and follow-up of the pulmonary function. Since reading the obtained PEF results requires reference values, the aim of this study was to establish normal values for PEF in our adolescent population. The investigation included 1154 healthy teenagers aged from 15 to 19 years using a peak flow meter Harlow, Essex CM 2ED. Detailed explanations, purpose of investigation and function demonstrations were done prior to testing. Results were statistically analyzed. Obtained results showed an increase of PEF values with age and body height in both sexes. Elevation of PEF was more significant in boys; high correlation was found in regard to age and height in boys and moderate correlation in girls. Regression equations for sex, age and height were made after measurements and data analysis. PEF values can be easily calculated knowing one's age and height.


Protocols for endothelial cell isolation from mouse tissues: brain, choroid, lung, and muscle.
Endothelial cells (ECs) harbor distinct phenotypical and functional characteristics depending on their tissue localization and contribute to brain, eye, lung, and muscle diseases such as dementia, macular degeneration, pulmonary hypertension, and sarcopenia. To study their function, isolation of pure ECs in high quantities is crucial. Here, we describe protocols for rapid and reproducible blood vessel EC purification established for scRNA sequencing from murine tissues using mechanical and enzymatic digestion followed by magnetic and fluorescence-activated cell sorting. For complete details on the use and execution of these protocol, please refer to Kalucka et al. (2020), Rohlenova et al. (2020), and Goveia et al. (2020).


Incorporating the entity of under-transfusion into hemovigilance monitoring: Documenting cases due to lack of inventory.
Under-transfusion is an underreported entity within most hospitals and hemovigilance systems. While critical blood shortages are being reported more frequently, without incident codes to document instances of under-transfusion due to lack of inventory, estimating its impact on patient care as it relates to hemotherapy (HT) has hampered our ability to assess and inform strategic initiatives to combat inventory issues as well as prepare for future blood supply threats. An 11-member working group of the AABB (Association for the Advancement of Blood and Biotherapies) Hemovigilance Committee was formed in October 2020 to study the topic of under-transfusion including its potential causes and clinical expressions. The group was also charged with proposing simple definition/incident codes to be used by hemovigilance systems to document such instances. The working group proposed four simple incident codes under the new process code-No Blood (NB)-that can be used by hemovigilance systems to appropriately document instances of under-transfusion due to lack of inventory. The codes were described as: (1) NB 01-Inventory less than usual level due to supplier shortage; (2) NB 02-Demand for blood product exceeding usual inventory levels; (3) NB 03-Substitution with incompatible/inappropriate units; and (4) NB 04-Suboptimal dose/no transfusion given. The adoption of these codes within hemovigilance systems globally would assist in recognition and reporting instances of under-transfusion due to inventory, thus supporting development of better collection strategies, inventory management techniques as well as effective policies to improve blood safety and availability.


Symptomatology differences of major depression in psychiatric versus general hospitals: A machine learning approach.
Symptomatology differences of major depressive disorder (MDD) in psychiatric and general hospitals in China leads to possible misdiagnosis. Looking at the symptomatology of first-visit patients with MDD in different mental health services, and identifying predictors of health-seeking behavior using machine learning may help to improve diagnostic accuracy. 1500 patients first diagnosed with MDD were recruited from 16 psychiatric hospitals and 16 general hospitals across China. Socio-demographic characteristics, causal attribution, symptoms of depression within and outside Diagnostic and Statistical Manual of Mental Disorders (DSM) framework were collected using a self-made questionnaire. A predictive model of 62 variables was established using Random forest, symptom frequencies of patients in general hospitals and psychiatric hospitals were compared. The machine learning approach revealed that symptoms were strong predictors of health-seeking behavior among patients with MDD. General hospitals patients had higher frequencies of suicidal ideation (χ2=15.230, p<0.001), psychosis (χ2=14.264, p<0.001), weight change (all p<0.001), hypersomnia (χ2=25.940, p<0.001), and a tendency of denying emotional/cognitive symptoms compared with psychiatric hospitals patients. Stigma and preference bias were not measured. Severity of current depressive episodes was not assessed. Data of previous episode(s) was not presented. Symptom evaluation targeting specific patient population in different hospitals is crucial for diagnostic accuracy. Suicide prevention reliant on collaboration between general hospitals and psychiatric hospitals is required in the future construction of Chinese mental health system.


Fast proton and water transport in ceramic membrane-based magic-angle graphene.
Ceramic membranes for energy conversion and storage devices are essential for becoming carbon neutral due to low cost and high stability, but limited by slow proton and water transport. Meanwhile magic-angle graphene with unconventional superconductivity ushers in a new era, properties research of which are in infant stage, urgently longing for specific applications. Herein, we investigate the ionic-conductivity and water-transport properties of ceramic membrane-based magic-angle graphene by choosing proton and water as a proof-of-concept for the first time, discover the twist-angle tuned proton conduction and water transport in ceramic membrane-based magic-angle graphene, demonstrate the faster proton and water transport in magic-angle graphene than that in graphene, and construct an efficient device of protonic ceramic membrane fuel cell based upon the new fast proton-conducting materials of magic-angle graphene. The proton conduction and water transport in magic-angle graphene can be easily tuned by the twist angle, explained by the corresponding potential energy surface. The smaller the twist angle is, and the faster the proton transport is. The protonic migration energy barrier in magic-angle graphene is lower by about 50% than that in graphene. Additionally, the water transport properties in magic-angle graphene can be improved by tuning twist angles. The electrode with magic-angle graphene can provide higher performance of protonic ceramic membrane fuel cells. The present work opens the specific application of ceramic membrane-based magic-angle graphene as new proton-conducting and water-transport materials in energy and environment.


Evolutionarily conserved hierarchical gene regulatory networks for plant salt stress response.
Plant cells constantly alter their gene expression profiles to respond to environmental fluctuations. These continuous adjustments are regulated by multi-hierarchical networks of transcription factors. To understand how such gene regulatory networks (GRNs) have stabilized evolutionarily while allowing for species-specific responses, we compare the GRNs underlying salt response in the early-diverging and late-diverging plants Marchantia polymorpha and Arabidopsis thaliana. Salt-responsive GRNs, constructed on the basis of the temporal transcriptional patterns in the two species, share common trans-regulators but exhibit an evolutionary divergence in cis-regulatory sequences and in the overall network sizes. In both species, WRKY-family transcription factors and their feedback loops serve as central nodes in salt-responsive GRNs. The divergent cis-regulatory sequences of WRKY-target genes are probably associated with the expansion in network size, linking salt stress to tissue-specific developmental and physiological responses. The WRKY modules and highly linked WRKY feedback loops have been preserved widely in other plants, including rice, while keeping their binding-motif sequences mutable. Together, the conserved trans-regulators and the quickly evolving cis-regulatory sequences allow salt-responsive GRNs to adapt over a long evolutionary timescale while maintaining some consistent regulatory structure. This strategy may benefit plants as they adapt to changing environments.


Quantifying the Economic Impact of Bovine Tuberculosis on Livestock Farms in South-Western Spain.
Pasture-based livestock farming generates income in regions with limited resources and is key to biodiversity conservation. However, costs derived from fighting disease can make the difference between profit and loss, eventually compromising farm survival. Animal TB (TB), a chronic infection of cattle and other domestic and wild hosts, is one of the primary limitations of beef cattle farming in some parts of Europe. When an animal tests positive for TB, a loss of profit is caused in the farm, which is due mainly to the animal's slaughter, replacement of the slaughtered animal and the need to immobilize the rest of the herd. We estimated the economic impact in terms of loss of profit as a result of incremental costs and forgone incomes. We show that farms with a larger number of heads are more capable of dealing with the loss of profit caused by the disease. The quantification of the loss of profit contributes to the ongoing debate on the co-sharing of TB costs between government and farmers. The compensation farmers receive from the public administration to mitigate the economic effects of the disease control interventions is only intended to balance the loss due to slaughter of the infected cattle, being the loss of profit a more global concept.


Onychoscopic evaluation of onychomycosis in a tertiary care teaching hospital: a cross-sectional study from South India.
Onychoscopy is the dermoscopic evaluation of nail and associated structures. It is useful in identifying the various onychoscopic patterns which act as a link between naked eye examination and nail histopathology and may help in avoiding nail biopsy in unnecessary cases. To evaluate the onychoscopic patterns in confirmed cases of onychomycosis. An observational, prospective, cross-sectional study was performed in 500 patients with symptoms related to the nails and nail folds. Onychomycosis was confirmed in 234 patients by KOH mount/fungal culture/biopsy. These patients underwent dermoscopy with a handheld 20× polarized contact dermoscope (Heine's delta 20 T). The dermoscopic patterns were identified, and their correlation with the clinical subtype of onychomycosis was analyzed. The study included 234 confirmed cases of onychomycosis. The common dermoscopic patterns observed were spikes (43.16%), jagged (29.9%), longitudinal striae (49.1%), linear edge (3.4%), and distal irregular termination (34.6%). The statistically significant findings of distal and lateral subungual onychomycosis (DLSO) were longitudinal striae, spikes, and jagged patterns. The new patterns observed in our study are bluish streaks and globules (8.9%) and bluish gray globules (7.6%) in cases of DLSO which were not statistically significant. Onychoscopy, being handy, inexpensive, and noninvasive, has the potential to reduce the invasive procedures. Statistically significant patterns in DLSO and total dystrophic onychomycosis (TDO) are described in our study. Few new patterns have been described whose significance has to be tested by conducting larger sample size studies.


Effect of dipolar ions on the entropy-driven polymerization of tobacco mosaic virus protein.
The effect of the dipolar ions, glycine, glycylglycine, and glycylglycylglycine on the polymerization of tobacco mosaic virus (TMV) protein has been studied by the methods of light scattering and ultracentrifugation. All three dipolar ions promote polymerization. The major reaction in the early stage is transition from the 4 S to the 20 S state. As in the absence of dipolar ions, the polymerization is enhanced by an increase in temperature; it is endothermic and therefore entropy-driven. The effect of the dipolar ions can be understood in terms of their action as salting-out agents; they increase the activity coefficient of TMV A protein, the 4 S material, and thus shift the equilibrium toward the 20 S state. The salting-out constants, K, for the reaction in 0.10 ionic strength phosphate buffer at pH 6.7 was found by the light scattering method to be 1.6 for glycine, 2.5 for glycylglycine, and 2.5 for glycylglycylglycine. A value of 2.7 was obtained by the ultracentrifugation method for glycylglycine in phosphate buffer at 0.1 ionic strength and pH 6.8 at 10 degrees C. For both glycine and glycylglycine, K increases when the ionic strength of the phosphate buffer is decreased. This result suggests that electrolytes decrease the activity coefficient of the dipolar ions, a salting-in phenomenon. However, the salting-in constants evaluated from these results are substantially higher than those previously determined by solubility measurements. The effect of glycine and glycylglycine on polymerization was studied at pH values between 6.2 and 6.8. The effectiveness of both dipolar ions is approximately 50% greater at pH 6.8 than at pH 6.2. The variation of the extent of polymerization with pH in the presence of the dipolar ions is consistent with the interpretation that approximately one hydrogen ion is bound for half of the polypeptide units in the polymerized A protein.


A plant-specific RNA-binding domain revealed through analysis of chloroplast group II intron splicing.
Comparative genomics has provided evidence for numerous conserved protein domains whose functions remain unknown. We identified a protein harboring "domain of unknown function 860" (DUF860) as a component of group II intron ribonucleoprotein particles in maize chloroplasts. This protein, assigned the name WTF1 ("what's this factor?"), coimmunoprecipitates from chloroplast extract with group II intron RNAs, is required for the splicing of the introns with which it associates, and promotes splicing in the context of a heterodimer with the RNase III-domain protein RNC1. Both WTF1 and its resident DUF860 bind RNA in vitro, demonstrating that DUF860 is a previously unrecognized RNA-binding domain. DUF860 is found only in plants, where it is represented in a protein family comprising 14 orthologous groups in angiosperms. Most members of the DUF860 family are predicted to localize to chloroplasts or mitochondria, suggesting that proteins with this domain have multiple roles in RNA metabolism in both organelles. These findings add to emerging evidence that the coevolution of nuclear and organellar genomes spurred the evolution of diverse noncanonical RNA-binding motifs that perform organelle-specific functions.


[Pancytopenia in disseminated tuberculosis: Think of macrophage activation syndrome].
The macrophage activation syndrome (MAS), also known as haemophagacytosis, is a non-specific clinical syndrome, which includes, among other things general debility, fever and hepatospleneomegaly. The most frequent pathological abnormalities are pancytopenia, hypertryglyceraemia, and hyperferrititinaemia. These clinical and biological criteria, which determine the severity of MAS, must be associated with a histological criterion - haemophagocytosis (with histiocytosis), which is usually medullary but can more rarely be splenic, hepatic or ganglionic. MAS can be primary or secondary. In the latter case, it is frequently associated with an infection of which tuberculosis is the most common. We describe the case of a young immunocompetent patient who had disseminated tuberculosis complicated by MAS. It is important to be aware of MAS, because its occurrence is associated with a poor prognosis and its optimal treatment, which requires a multidisciplinary approach, has not been fully defined. The optimum strategy in relation to specific aetiologies remains to be clarified.


No association of the dopamine D2 receptor genetic bilocus score (rs1800497/rs1799732) on food addiction and food reinforcement in Chilean adults.
Purpose: Different systems regulate food intake. In the reward system, dopamine (DA) is the main neurotransmitter, and a variety of genetic variants (rs1799732 and rs1800497) are associated with addiction. Addiction is a highly polygenic disease, where each allelic variant adds a small amount of vulnerability. Polymorphisms rs1799732 and rs1800497 are associated with eating behavior and hedonic hunger, but links to food addiction remain unclear. Aim: To evaluate the association between the bilocus profile (rs1799732-rs1800497) of the dopaminergic pathway with food reinforcement and food addiction in Chilean adults. Methods: A cross-sectional study recruited a convenience sample of 97 obese, 25 overweight, and 99 normal-weight adults (18-35 years). Anthropometric measurements were performed by standard procedures and eating behavior was assessed using the: Food Reinforcement Value Questionnaire (FRVQ) and Yale Food Addiction scale (YFAS). The DRD2 genotypes were determined by TaqMan assays (rs1800497 and rs1799732). A bilocus composite score was calculated. Results: In the normal weight group, individuals who were heterozygous for the rs1977932 variant (G/del) showed higher body weight (p-value 0.01) and abdominal circumference (p-value 0.01) compared to those who were homozygous (G/G). When analyzing rs1800497, a significant difference in BMI was observed for the normal weight group (p-value 0.02) where heterozygous showed higher BMI. In the obese group, homozygous A1/A1 showed higher BMI in comparison to A1/A2 and A2/A2 (p-value 0.03). Also, a significant difference in food reinforcement was observed in the rs1800497, where homozygous for the variant (A1A1) show less reinforcement (p-value 0.01).In relation to the bilocus score in the total sample, 11% showed "very low dopaminergic signaling", 24.4% were "under", 49.7% showed "intermediate signaling", 12.7% showed "high" and 1.4% showed "very high". No significant genotypic differences were observed in food reinforcement and food addiction by bilocus score. Conclusions: The results indicate that the genetic variants rs1799732 and rs1800497 (Taq1A) were associated with anthropometric measurements but not with food addiction or food reinforcement in Chilean university students. These results suggest that other genotypes, such as rs4680 and rs6277, which affect DA signaling capacity through a multilocus composite score, should be studied. Level V: Evidence obtained from a cross-sectional descriptive study.


Cholesterol and breast cancer risk: a cohort study using health insurance claims and health checkup databases.
This study aimed to investigate the association between serum cholesterol and triglyceride levels and breast cancer risk in Japanese women. We retrospectively evaluated the association between the levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) and the incidence of breast cancer in a cohort study by using the health insurance claims and health checkup data from a database provided by JMDC Inc. We included 956,390 women who were insured between April 2008 and June 2019, identified breast cancer cases by using validated definitions, and estimated the risk of breast cancer by using multivariable Cox proportional hazards regression models adjusted for potential confounders. During the 2,832,277 person-years observation period (median 2.4 years), 6284 participants were diagnosed with breast cancer. There was marginally significant association between LDL-C and breast cancer risk when comparing the highest and lowest quintiles and at the clinical cutoff values for diagnosing hyperlipidemia. HDL-C was not associated with breast cancer. However, when stratified by age groups (< 50 and ≥ 50), HDL-C was inversely associated with breast cancer risk in women over 50 years old. TG was not associated with breast cancer risk. In this population, there was a modest association of LDL-C at the clinical cutoff values for diagnosing hyperlipidemia (140 mg/mL), and there were no associations of HDL-C and TG with breast cancer risk.


20-year survival of seminoma after repeated radiation treatment at 200 kV for abdominal metastases of seminoma: renal and vertebral sequelae.
A 25-year-old man with a seminoma is irradiated several times until the age of 33 for multiple and relapsing metastases. The recovery is maintained for 20 years. The very high total irradiation doses have caused osteonecrotic lesions of the lumbar spine and some functional, but discreet renal problems.


Factors that affect outcomes of prolapse repair using single-incision vaginal mesh procedures.
Single-incision vaginal mesh (SIVM) procedures for pelvic organ prolapse (POP) differed in mesh fabrication and implantation that may affect treatment outcomes. We aim to evaluate and compare the safety and effectiveness of two SIVM procedures, and explore factors that may have associations with surgical effectiveness. Our data of using two SIVM procedures for a total (anterior and posterior) vaginal mesh repair were studied. Patients who had ≧stage 2 POP and underwent either Elevate (n = 85) using anchored, lightweight meshes or Prosima procedures (n = 95) using non-anchored, original meshes were assessed. A detailed comparison of 1 year outcomes was made. Of the 180 patients, 172 (95.6%) attended the 1-year follow-up. Demographic data were similar between groups except a higher average age (64.5 vs 60.4, P = 0.001) was noted in the Elevate (n = 84) group compared to the Prosima (n = 88) group. Surgical results were also similar except a significantly higher objective cure (POP stage ≦1) rate (89.3% vs 78.4%, P = 0.042) was noted in the Elevate group. The safety profile favored Elevate with a lower, but not statistically significant, rate (4.7% vs 12.5%, P = 0.106) of vaginal mesh exposure. After a statistical analysis, we found anatomic recurrence (POP stage ≧2) after the SIVM procedures had strong (P < 0.05) associations with "early surgical cases," "Prosima procedure," "advanced cystocele (Ba > +3 cm)," and "prior prolapse repair," respectively. Beyond a learning curve, Elevate performed better than Prosima in POP repair regarding surgical effectiveness. Meanwhile, several predisposing factors that may affect recurrence after SIVM procedures were found.


Pertussis toxin reverses adenosine receptor-mediated inhibition of renin secretion in rat renal cortical slices.
Adenosine analogs selective for the A1 subclass of adenosine receptors, such as N6-cyclohexyladenosine (CHA), inhibit renin secretion in in vitro preparations. Ca chelation blocks the inhibitory effect, consistent with mediation by increased intracellular free Ca2+, and it has been suggested that intracellular Ca2+ could increase as a result of receptor-induced inhibition of adenylate cyclase followed by decreased Ca efflux from the renin-secreting cells. Pertussis toxin blocks receptor-induced inhibition of adenylate cyclase in many cells, and in others, it blocks receptor-induced phosphotidylinositol response. In the present studies, pertussis toxin treatment stimulated the basal renin secretory rate of rat renal cortical slices and blocked the inhibitory effect of CHA but not the inhibitory effect of K-depolarization. These data support the hypothesis that a pertussis toxin substrate, such as Ni, is involved in CHA-, but not in K-depolarization, -induced inhibition of renin secretion.


A Toolbox for Mimicking Gastrointestinal Conditions in Children: Simulated Paediatric Breakfast Media (SPBM) for Addressing the Variability of Gastric Contents After Typical Paediatric Breakfasts.
Since co-administration of dosage forms with food can impact drug exposure, food effect studies became an integral part of oral drug product development. Studies are usually performed in healthy adults and the dosage form is co-administered with a high-fat high-calorie standard breakfast meal to mimic worst-case dosing conditions. A corresponding study design for children is lacking but would be essential for a proper risk-assessment in this vulnerable patient group. To protect healthy children from unnecessary in vivo studies, it would be even more desirable to predict food effects based on other than in vivo studies in the target age group. In the present study, typical children's breakfasts in different parts of the world were identified, prepared and physicochemical properties were assessed. Subsequently, Simulated Paediatric Breakfast Media (SPBM) resembling breakfast composition and properties were designed and applied in in vitro dissolution experiments mimicking the initial composition of the postprandial stomach after breakfast ingestion. Study results indicate the impact of different simulated gastric conditions on drug release. SPBM enabled to better estimate the variability of in vivo drug release in fed dosing conditions and their use will aid in better assessing food effects in children in different parts of the world.


Exploring computer-aided health decision-making on cervical cancer interventions through deliberative interviews in Ethiopia.
Cervical cancer is a significant disease burden in Ethiopia. Mathematical models and computer simulations on disease dynamics can support effective resource allocation. The objectives of this work are (i) to explore the perspectives of health decision-makers on computer-aided predictions supporting cervical cancer interventions, (ii) to identify their information needs from these predictions, and (iii) their willingness to apply the results in their work. We conducted deliberative interviews with 15 health decision-makers and advisors in Ethiopia in autumn 2019. We analyze the data using a five steps framework approach drawing on thematic analysis and find that Ethiopian health decision-makers are willing to use computer-aided predictions in their decisions. Data on HPV prevalence and the cervical cancer burden are scarce but valued highly and decision-makers are particularly interested in the identification of local HPV hotspots. Data-driven mathematical models and computer simulations may increasingly influence health decision-making in Ethiopia.


Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors.
The HGF/Met signaling pathway is over-expressed in many types of cancers and closely related to oncogenesis and metastasis. Thus, we developed novel N-phenylpyrimidin-2-amine derivatives to test their inhibitory activities towards c-Met kinase, and most of the compounds (15a-i, 15o-r, 20 and 34a-c) could inhibit the target with IC50 values from 550.8 nM to 15.0 nM. Subsequently, compound 15b, 15d, 15f, 15i, 15o, 15r, 20, 34a and 34b also showed high antiproliferative activities in c-Met sensitive tumor cell lines (PC-3, Panc-1, HepG2, HCT116 and Caki-1) with IC50 values from 0.53 to 1.37 μM. The lead compound 34a displayed outstanding c-Met inhibitory activity (IC50: 15.0 nM) and antiproliferative activities. Furthermore, 34a also performed favorable pharmacokinetic properties in mice (F%: 59.3) and an acceptable safety profile in preclinical studies. Further docking studies showed a common interaction of 34a with c-Met at the ATP-binding site, which indicated that 34a could be a potential candidate for c-Met inhibitors.


Continuous cultivation of the lithoautotrophic nitrate-reducing Fe(II)-oxidizing culture KS in a chemostat bioreactor.
Laboratory-based studies on microbial Fe(II) oxidation are commonly performed for 5-10 days in small volumes with high substrate concentrations, resulting in geochemical gradients and volumetric effects caused by sampling. We used a chemostat to enable uninterrupted supply of medium and investigated autotrophic nitrate-reducing Fe(II)-oxidizing culture KS for 24 days. We analysed Fe- and N-speciation, cell-mineral associations, and the identity of minerals. Results were compared to batch systems (50 and 700 mL-static/shaken). The Fe(II) oxidation rate was highest in the chemostat with 7.57 mM Fe(II) d-1 , while the extent of oxidation was similar to the other experimental setups (average oxidation of 92% of all Fe(II)). Short-range ordered Fe(III) phases, presumably ferrihydrite, precipitated and later goethite was detected in the chemostat. The 1 mM solid phase Fe(II) remained in the chemostat, up to 15 μM of reactive nitrite was measured, and 42% of visualized cells were partially or completely mineral-encrusted, likely caused by abiotic oxidation of Fe(II) by nitrite. Despite (partial) encrustation, cells were still viable. Our results show that even with similar oxidation rates as in batch cultures, cultivating Fe(II)-oxidizing microorganisms under continuous conditions reveals the importance of reactive nitrogen intermediates on Fe(II) oxidation, mineral formation and cell-mineral interactions.


Validation of an immunoassay for anti-Müllerian hormone measurements and reference intervals in healthy Brazilian subjects.
Anti-Müllerian hormone is marker of ovarian and testicular reserve. The clinical use of this hormone requires proper standardization of reference intervals. The aims of this study were to validate the Anti-Müllerian hormone Gen II immunoassay, to establish Anti-Müllerian hormone reference intervals in healthy subjects, and to evaluate the influence of hormonal contraceptives, smoking, and body mass index on Anti-Müllerian hormone. The validation of the Anti-Müllerian hormone Gen II assay (Beckman Coulter Company, TX, USA) was performed using a simplified protocol recommended by Clinical Laboratory Standard Institute. One-hundred and thirty-three healthy females and 120 males were prospectively selected for this study. The analytical and functional sensitivities of the Anti-Müllerian hormone Gen II immunoassay were 0.02 and 0.2 ng/mL, respectively. Intra-assay coefficients ranged from 5.2 to 9.0%, whereas inter-assay precision ranged from 4.6 to 7.8% at different concentrations. In females, Anti-Müllerian hormone showed progressive decline with increasing age (r=-0.4, p<0.001), whereas in males, age showed no influence on Anti-Müllerian hormone concentrations. In females, Anti-Müllerian hormone concentrations did not differ between users and non-users of hormonal contraceptives, smokers, and non-smokers and obese and lean individuals. However, there was a negative and significant correlation between Anti-Müllerian hormone and body mass index in males (r=-0.3, p=0.008). Anti-Müllerian hormone Gen II assay was reliable for determining serum Anti-Müllerian hormone concentrations. Anti-Müllerian hormone concentrations declined with aging and presented a wide inter-individual variability. The lack of influence of hormonal contraceptives, smoking, and obesity on Anti-Müllerian hormone in both sexes allowed us to refine the normative concentrations for the Brazilian population.


Nonclinical and quality assessment of cell therapy products: Report on the 4th Asia Partnership Conference of Regenerative Medicine, April 15, 2021.
The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future.


Validation and quantification of [18F]altanserin binding in the rat brain using blood input and reference tissue modeling.
The 5-hydroxytryptamine type 2a (5-HT(2A)) selective radiotracer [(18)F]altanserin has been subjected to a quantitative micro-positron emission tomography study in Lister Hooded rats. Metabolite-corrected plasma input modeling was compared with reference tissue modeling using the cerebellum as reference tissue. [(18)F]altanserin showed sufficient brain uptake in a distribution pattern consistent with the known distribution of 5-HT(2A) receptors. Full binding saturation and displacement was documented, and no significant uptake of radioactive metabolites was detected in the brain. Blood input as well as reference tissue models were equally appropriate to describe the radiotracer kinetics. [(18)F]altanserin is suitable for quantification of 5-HT(2A) receptor availability in rats.


Risk factors of striae gravidarum.
Stretch marks are a common skin disorder. Pregnancy-related lesions are defined as striae gravidarum. The root cause of striae formation remains unknown. The aim of this paper was to identify the risk factors associated with striae gravidarum (SG) development. The study was conducted at Plastic, Reconstructive and Aesthetic Surgery Clinic and Obstetrics Outpatient Department among 299 Caucasian women maximum 6 months after the delivery, regardless of whether they were primiparas or multiparas. Among the women participating in the study, 71.2% (213 of 299) developed striae gravidarum at least in one site. Logistic regression analysis showed that four of the analysed factors were independent predictors of striae gravidarum occurrence: family history of SG, BMI before pregnancy, the lack of chronic diseases and birthweight (P < 0.0001). It has been found that the presence of striae distensae on the breasts increases the risk of SG development (71.4% vs. 28.6%, P = 0.0008), whereas the presence of these lesions on the thighs decreases the risk (23% vs. 77%, P = 0.0076). In this study, we presented a model that can help to predict the risk of SG formation, including family history of SG, BMI before pregnancy, birthweight and chronic diseases. Moreover, women with stretch marks on their breasts should know that the risk of SG development is significantly higher, whereas lesions on the thighs do not increase such a risk.


The Renal Extracellular Matrix as a Supportive Scaffold for Kidney Tissue Engineering: Progress and Future Considerations.
During the past decades, diverse methods have been used toward renal tissue engineering in order to replace renal function. The goals of all these techniques included the recapitulation of renal filtration, re-absorptive, and secretary functions, and replacement of endocrine/metabolic activities. It is also imperative to develop a reliable, up scalable, and timely manufacturing process. Decellularization of the kidney with intact ECM is crucial for in-vivo compatibility and targeted clinical application. Contemporarily there is an increasing interest and research in the field of regenerative medicine including stem cell therapy and tissue bioengineering in search for new and reproducible sources of kidneys. In this chapter, we sought to determine the most effective method of renal decellularization and recellularization with emphasis on biologic composition and support of stem cell growth. Current barriers and limitations of bioengineered strategies will be also discussed, and strategies to overcome these are suggested.


Cyclin-dependent kinase 4/6 inhibitors in hormone receptor-positive early breast cancer: preliminary results and ongoing studies.
The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitors (CDK4/6i) induce cell cycle arrest in the G1 phase what eventually can prevent the proliferation of cancer cells. The CDK4/6i have changed the landscape of treatment options for ER-positive, HER2-negative metastatic breast cancer. Currently, palbociclib, ribociclib, and abemaciclib are approved by the US Food and Drug Administration in this setting. This success encouraged the researchers to examine CDK4/6i activity in (neo)adjuvant setting. In this review, clinical data to date and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in the early breast cancer are discussed. A literature search of these topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included. Currently, we have the early promising data from Phase II clinical trials of CDK4/6i efficacy in the neoadjuvant setting in women with HR-positive breast cancer. Moreover, there are numerous studies that are in progress today in (neo)adjuvant setting.


Cerebral pan-angiography in rabbit. Technical note.
An open technique of cerebral four-vessel angiography via femoral artery "in vivo" of the rabbit is described. This method allows a good visualization of extracranial and intracranial circulation without direct damage to the cerebral vessels.


Synchronous rectal and hepatic resection of rectal metastatic disease.
The objectives were to determine the feasibility of combined rectal and hepatic resections and analyze the disease-free survival and overall survival. Sixty patients who underwent resection for metastatic rectal disease from 1991 to 2005 at Mayo Clinic were reviewed. Inclusion criteria were: rectal cancer with metastatic liver disease and resectability of metastases. The exclusion criteria were: metachronous resection (n = 15). Kaplan-Meier Survival estimated overall survival (OS) and disease-free survival (DFS). Cox proportional hazard models examined the association between groups and survival. The cohort comprised 22 men and 23 women, with median age of 63 years. Surgical management included: abdominoperineal resection, 13 patients (29%); low anterior resection, 29 (64%); local excision, one; total proctocolectomy, one; and pelvic exenteration, one. Major hepatic resection was performed in 22%. There was no mortality, but there were 26 postoperative complications. Disease-free survival from local recurrence at 1, 2, and 5 years was 92%, 86%, and 80%, respectively. Disease-free survival from distant recurrence at 1, 2, and 5 years was 62%, 43%, and 28%, respectively. Overall survival at 1, 2 and 5 years was 88%, 72%, and 32%, respectively. Combined rectal and hepatic resection is safe. Morbidity and mortality do not preclude concurrent resection. The DFS and OS are comparable to that of patients undergoing a staged procedure.


The nature and dimensions of social support among individuals with severe mental illnesses.
Recent research suggests that social support is associated with recovery from chronic diseases, greater life satisfaction, and enhanced ability to cope with life stressors. To further research in the area of social support and serious psychiatric disabilities, more reliable and valid measures are needed to assess this construct. The purpose of this study was to assess the psychometric properties of a widely used measure of social support (the Interpersonal Support Evaluation Checklist) among people with severe mental illness. We collected data on the ISEL's relationship to quality of life, self-esteem, psychiatric symptoms and vocational status among 147 participants. Factor and reliability analyses, as well as correlational analyses were undertaken. We found evidence for the reliability and validity of the ISEL when used with persons with severe mental illness. Taken together, our findings suggested that self-esteem, quality of life, and psychiatric symptoms were able to predict 38% of the variance in perceived social support. More favorable social supports increased the odds of being employed at 9 months into the study and social support was predictive of experiencing fewer psychiatric symptoms. Some forms of social support were perceived less favorably with age, but no other demographic or clinical variables significantly predicted perceived social supports.


Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry.
Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity.


Pioneering health care. Interview by Carol Davis.
A major overhaul of services means patients in Lancashire can have their heart conditions diagnosed at a single clinic visit.