Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis.
Long-term environmental exposure to metals leads to epigenetic changes and may increase risks to human health. The relationship between the type and level of metal exposure and epigenetic changes in subjects exposed to high concentrations of metals in the environment is not yet clear. The aim of our study is to find the possible association of environmental long-term exposure to metals with DNA methylation changes of genes related to immune response and carcinogenesis. We investigated the association of plasma levels of 21 essential and non-essential metals detected by ICP-MS and the methylation level of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5, IGF2 and H19 genes assessed by targeted bisulfite sequencing in a cohort of 40 subjects living near metal mining area and 40 unexposed subjects. Linear regression was conducted to find differentially methylated positions with adjustment for gender, age, BMI class, smoking and metal concentration. In the metal-exposed group, five CpGs in the NFKB1 promoter region were hypomethylated compared to unexposed group. Four differentially methylated positions (DMPs) were associated with multiple metals, two of them are located on NFKB1 gene, and one each on CDKN2A gene and ESR1 gene. Two DMPs located on NFKB1 (chr4:102500951, associated with Be) and IGF2 (chr11:2134198, associated with U) are associated with specific metal levels. The methylation status of the seven CpGs located on NFKB1 (3), ESR1 (2) and CDKN2A (2) positively correlated with plasma levels of seven metals (As, Sb, Zn, Ni, U, I and Mn). Our study revealed methylation changes in NFKB1, CDKN2A, IGF2 and ESR1 genes in individuals with long-term human exposure to metals. Further studies are needed to clarify the effect of environmental metal exposure on epigenetic mechanisms and pathways involved.


Fibrinogen-coated albumin microcapsules reduce bleeding in severely thrombocytopenic rabbits.
Severe thrombocytopenia frequently occurs in patients receiving chemotherapy and in patients with autoimmune disorders. Thrombocytopenia is associated with bleeding, which may be serious and life threatening. Current treatment strategies for thrombocytopenia may require transfusion of allogeneic platelets, which is associated with serious drawbacks. These include the occurrence of anti-platelet antibodies, which may result in refractoriness to further platelet transfusions, and the potential risk of transfer of blood-borne diseases. Therefore, we have recently developed a platelet substitute product (Synthocytes), which is composed of human albumin microcapsules with fibrinogen immobilized on their surface. Here we show that the intravenous administration of these microcapsules not only corrects the prolonged bleeding time in rabbits rendered thrombocytopenic either by anti-platelet antibodies or by chemotherapy, but also reduces bleeding from surgical wounds inflicted in the abdominal skin and musculature. No potential systemic prothrombotic effect of the microcapsules was observed in a model of rabbit venous thrombosis. As for the mechanism of action, experiments with normal and thrombocytopenic human blood in an endothelial cell matrix-coated perfusion chamber demonstrated an interaction between the fibrinogen-coated albumin microcapsules and native platelets. It was shown that the fibrinogen-coated albumin microcapsules could facilitate platelet adhesion to endothelial cell matrix and correct the impaired formation of platelet aggregates in relatively platelet-poor blood. This study indicates that fibrinogen-coated albumin microcapsules can act to improve primary hemostasis under thrombocytopenic conditions and may eventually be a promising agent for prophylaxis and treatment of bleeding in patients with severe thrombocytopenia.


Lead biomonitoring in different organs of lead intoxicated rats employing GF AAS and different sample preparations.
An analytical procedure was developed for the determination of lead in different tissues from Wistar Hanover rats, previously intoxicated with lead acetate during a toxicological study. About 25 mg of dried sample (bone, liver, kidney, heart, lung and spleen) were mixed with 8.0 mL of 7.00 mol L(-1) nitric acid and digested using microwave radiation in closed vessel. Except for the bone samples, the other tissues could also be analyzed after alkaline solubilization with TMAH. All the digested or solubilized samples were analyzed by graphite furnace atomic absorption spectrometry. Good accuracy and precision were attained when analyzing reference standard materials (for bone, liver and kidney) and also from addition to recovery experiments (for heart, lung and spleen tissues). The method was applied to samples from nine animals and the results suggested that there is a profile for lead bioaccumulation in these animals, which seemed to adapt themselves to continuous lead exposure.


Second harmonic generation microscopy probes different states of motor protein interaction in myofibrils.
The second harmonic generation (SHG) signal intensity sourced from skeletal muscle myosin II strongly depends on the polarization of the incident laser beam relative to the muscle fiber axis. This dependence is related to the second-order susceptibility χ((2)), which can be described by a single component ratio γ under generally assumed symmetries. We precisely extracted γ from SHG polarization dependence curves with an extended focal field model. In murine myofibrillar preparations, we have found two distinct polarization dependencies: With the actomyosin system in the rigor state, γ(rig) has a mean value of γ(rig) = 0.52 (SD = 0.04, n = 55); in a relaxed state where myosin is not bound to actin, γ(rel) has a mean value of γ(rel) = 0.24 (SD = 0.07, n = 70). We observed a similar value in an activated state where the myosin power stroke was pharmacologically inhibited using N-benzyl-p-toluene sulfonamide. In summary, different actomyosin states can be visualized noninvasively with SHG microscopy. Specifically, SHG even allows us to distinguish different actin-bound states of myosin II using γ as a parameter.


Simple reaction time to sinusoidal grating and perceptual integration time: contributions of perceptual and response processes.
For sinusoidal gratings, two experiments were carried out to examine relation between simple reaction time and perceptual and response processes. First, the simple reaction time (RT) was measured as a function of grating contrast with spatial frequency as a parameter. Second, contrast threshold was determined as a function of exposure duration (ED). On the basis of the RT-contrast function and the ED-contrast threshold function empirically obtained, the difference between the RT and the ED was evaluated as a function of grating contrast. The RT-ED difference, in which the perceptual integration time was eliminated, was considered to reflect the transmission time, delay in the response process, and delay in the motor response. As the grating contrast increased, the RT-ED difference decreased rapidly at first, and then gradually, and finally leveled off. The RT-ED difference vs contrast function depended on spatial frequency. Based on the analysis of the characteristics of the RT-ED functions, the effects of grating contrast and spatial frequency on the simple RT could be ascribed to the changing contributions of the perceptual and the response processes.


Meta-analysis for cyclin E in lung cancer survival.
To assess the prognosis value of cyclin E expression in survival of patients with lung cancer (LC), we performed a systematic review of the literature with meta-analysis. Electronic databases were used to identify published studies before August 2011. Pooled hazard ratio (HR) with 95% confidence interval (95% CI) was used to estimate the strength of the association of cyclin E expression with survival of LC patients. Heterogeneity and publication bias were also assessed. Fourteen studies (2606 cases) were eligible and subjected to analysis. Cyclin E over-expression was found to be a strong predictor of poor prognosis in LC patients (HR: 1.38, 95% CI: 1.07-1.79; P=0.014). When only non-small cell lung cancer (NSCLC) was considered, the combined HR was 1.53 (95% CI: 1.19-1.97, P=0.001). A significant association was also evident when the analysis was limited to studies involving adenocarcinoma (AD), but not squamous cell carcinoma (SQ). Publication bias was absent. Sensitivity analyses suggested that the summary statistics obtained should approximate the actual average.


Destabilization of polystyrene latex particles induced by adsorption of polyvinylamine: mass, size and structure characteristics of the growing aggregates.
The obviously visible aggregation of suspended colloidal particles resulting from the addition of polyvinylamine to the aqueous dispersion of polystyrene latex particles bearing surface sulfate groups set in with a delay of 24 h. The aggregation mechanisms and the fractal dimension of the aggregates were derived from the variations with time of the weight and number averaged masses of the aggregates as well as of the weight averaged harmonic mean diameter of the size distribution. Since the establishment of starved layers was determined to be relatively fast and to leave the liquid phase free of polymer, the delay for the obvious destabilization was attributed to the reconformation of adsorbed macromolecules that was expected to be extremely slow. This reconformation promoted the emergence of the diffusion-limited aggregation process that accompanies the permanent reaction-limited aggregation process. The fractal dimension of the latex particles/polyvinylamine aggregates was determined to be 2.12.


An innovative surgical approach: suture fixation of the levonorgestrel-releasing intrauterine system in the treatment of adenomyosis.
Placement of a levonorgestrel-releasing intrauterine system (LNG-IUS) is an effective treatment for adenomyosis, especially for patients who have severe dysmenorrhea symptoms but a strong desire to preserve fertility. Nonetheless, for patients with adenomyosis accompanied by an enlarged uterus, expulsion of the ring is a troublesome problem. In this study, we sewed and fixed the LNG-IUS in the uterus, which provides a good solution to this problem. In this prospective case series approved by the Ethics Committee of Hangzhou Women's Hospital, 12 patients with adenomyosis were successfully enrolled after providing informed consent, and all patients underwent long-term postoperative follow-up. Twelve patients with adenomyosis underwent suture fixation with an LNG-IUS, and during the long-term postoperative follow-up, every patient experienced complete remission of their symptoms: a significant decrease in menstrual flow, relief of dysmenorrhea, and improvement in quality of life. Only one person reported expulsion a year later. In patients with adenomyosis suffering from dysmenorrhea or excessive menstrual blood loss, suture fixation of an LNG-IUS using the hysteroscopic cold knife surgery system is a minimally invasive and effective alternative treatment for adenomyosis and decreases the risk of LNG-IUS expulsion.


Fusion viewer: a new tool for fusion and visualization of multimodal medical data sets.
A new application, Fusion Viewer, available for free, has been designed and implemented with a modular object-oriented design. The viewer provides both traditional and novel tools to fuse 3D data sets such as CT (computed tomography), MRI (magnetic resonance imaging), PET (positron emission tomography), and SPECT (single photon emission tomography) of the same subject, to create maximum intensity projections (MIP) and to adjust dynamic range. In many situations, it is desirable and advantageous to acquire biomedical images in more than one modality. For example, PET can be used to acquire functional data, whereas MRI can be used to acquire morphological data. In some situations, a side-by-side comparison of the images provides enough information, but in most of the cases it may be necessary to have the exact spatial relationship between the modalities presented to the observer. To accomplish this task, the images need to first be registered and then combined (fused) to create a single image. In this paper, we discuss the options for performing such fusion in the context of multimodal breast imaging. Additionally, a novel spline-based dynamic range technique is presented in detail. It has the advantage of obtaining a high level of contrast in the intensity range of interest without discarding the intensity information outside of this range while maintaining a user interface similar to the standard window/level windowing procedure.


Body Image in Preschool Children Following Premature Loss of Primary Teeth: A Cross-sectional Study.
Pediatric dentists often see a good number of children under 6 years of age and are likely to encounter a child with missing anterior teeth. Here the parents are more concerned about the facial esthetics of the child and also about the timing of permanent teeth to erupt. To know the impact on self-esteem or body image of preschool children following the premature loss of primary anterior teeth. The present cross-sectional study was conducted among 780 children in the age group of 4-6 years. The COHIP-SF 19 was utilized to know the social well-being of the child following the premature loss of anterior teeth. The descriptive and inferential analysis of the data was done by using IBM SPSS software. There was a statistically significant association between gender and social well-being. More number of boys were concerned about their looks (p = 0.054). However, girls were found to be significantly more (p = 0.003) shy or withdrawn as compared to boys. There was a statistically significant association between a child's age and social well-being. More number of children between the ages of 4 years (23.1%) and 6 years (25.8%) were worried or anxious due to premature loss of an anterior tooth. Significantly more no of children of age 5 years (48.6%) was uncomfortable when asked about the missing tooth as compared to 4- and 6-year-old children. No statistically significant (p > 0.05) difference in the mean social well-being scores between boys and girls. No statistically significant difference in the mean social well-being scores between children of ages 4, 5, and 6 years (p > 0.05). There is an association between the self-image of younger children and missing anterior teeth. Acharya S, Biswas R. Body Image in Preschool Children Following Premature Loss of Primary Teeth: A Cross-sectional Study. Int J Clin Pediatr Dent 2022;15(3):293-298.


The relationship between religiosity and adjustment among African-American, female, urban adolescents.
African-American female adolescents living in urban environments are at risk for adverse adjustment outcomes, and thus it is imperative to identify protective factors. Religion has been found to be a significant protective resource against many types of maladaptive adjustment outcomes among adolescent samples. The present study accomplishes the following: (1) Provides a description of religiosity in a sample of African-American female teens; (2) examines religion as a resource for these adolescents by focusing on the association between religiosity and sexual activity, self-esteem, and general psychological functioning. Four-hundred ninety-two African-American females, ages 12-19, completed measures on religiosity, sexual activity, self-esteem, and psychological functioning. Most of the adolescents identified as Christian, reported a belief in God, and attended religious services. Greater overall religiosity was associated with greater self-esteem and better psychological functioning. Adolescents at different levels of self-religiosity, as well as family religiosity, evidenced significantly different self-esteem but not psychological distress or sexual activity. Adolescents with varying levels of church attendance demonstrated differences on all three outcomes. By identifying the ways in which religion may exert a positive impact on African-American female teens, mental health professionals can design interventions that have the potential to help improve the quality of life for these adolescents.


Cancer‑associated fibroblast‑derived LRRC15 promotes the migration and invasion of triple‑negative breast cancer cells via Wnt/β‑catenin signalling pathway regulation.
Triple‑negative breast cancer (TNBC) is a highly aggressive tumour subtype associated with poor prognosis. The function of leucine‑rich repeat‑containing protein 15 (LRRC15), a member of the leucine‑rich repeat superfamily, in TNBC has not yet been elucidated. The aim of this study was to identify the combined role of LRRC15 and Wnt/β‑catenin signalling pathway in the development of TNBC. The expression of LRRC15 in TNBC tissues was analysed using data from The Cancer Genome Atlas. Cell migration and invasion assays were conducted to study the function of LRRC15 in TNBC. The expression of Wnt/β‑catenin signalling proteins was analysed via western blotting. The effect of LRRC15 on β‑catenin nuclear localisation was measured by performing western blotting and luciferase assays. It was found that high LRRC15 expression was associated with poor prognosis in patients with TNBC. High expression of LRRC15 in cancer‑associated fibroblasts (CAFs) promoted cell migration and invasion in TNBC cells. In addition, TNBC cells with LRRC15 overexpression in CAFs showed an aberrant increase in β‑catenin activity concomitant with nuclear localisation of β‑catenin, which inhibited its degradation. These results showed that LRRC15 promoted tumour migration and invasion in TNBC cells by regulating the Wnt/β‑catenin signalling pathway.


The basic biology of apoptosis and its implications for pediatric surgery.
Apoptosis, or programmed cell death, is an evolutionarily conserved and highly regulated process of nonfunctional cell death. Through this process, the body disposes of unwanted cells by self-destruction: it is our final defense against damaged cells. In the last decades, many of the essential pathways that control this phenomenon have been elucidated. Apoptosis plays an important role in developmental processes, as well as in cellular homeostasis. This process is known to be accelerated or diminished in many pathologic states. Therefore the understanding of apoptotic regulation has significant clinical ramifications. This article reviews the basic understanding of programmed cell death with respect to areas of interest to pediatric surgeons, including: Hirschsprung disease, intestinal atresias, testicular disorders, short bowel syndrome, ischemia-reperfusion injury and pediatric oncology. Pro or antiapoptotic interventions may become a future target for cell and organ protection in patients suffering from these diseases.


Studies on the conformational features of neomycin-B and its molecular recognition by RNA and bacterial defense proteins.
According to NMR and molecular dynamics simulations, the conformational behavior of natural aminoglycosidesis characterized by a remarkable flexibility, with different conformations, even non-exo-anomericones, in fast exchange. Very probably, this feature allows the adaptation of these ligands to the spatialand electronic requirements of different receptors. The large diversity of structures adopted by aminoglycosidesin the binding pocket of the different RNA receptors and the distinct enzymes involved in bacterial resistanceare consistent with this view. This conformational diversity can, in certain favorable cases, be exploitedin the design of new antibiotic derivatives not susceptible to enzymatic inactivation, by designing tailor-madeconformationally locked aminoglycosides.


[From a randomized assay, Francisella turned out to be epidemiologically present in the studied areas].
In the past Tularemia has largely affected animals, nowadays' in our country it could become actual one more because of wild animals repopulation actuated in many areas. Unlike the other countries, in Italy it's not well known if there are any consequences on population. The authors has conducted a research on this subject studying seroimmunologically samples taken randomly in some areas of south-central Italy. Their results confirm endemism and therefore announce the problem and the consequent pathology.


[Need-information organization of brain activity].
Experimental results and literature data point to the leading role of four brain structures in the genesis of emotional states and in the organization of goal directed behaviour. Owing to the functioning of the frontal parts of the neocortex behaviour is oriented to signals with a high probability of their reinforcement, and owing to the hypothalamus--to satisfaction of the dominant need. Unlike the neocortex the hippocampus is necessary for reactions to signals of lowly probable events, which is typical of emotionally exicted brain. The amygdala complx participates in creation of a balance, a dynamic co-existence between completing needs (motivations) and corresponding emotions. As a result, behaviour becomes more plastic and adequate to the given situation.


An investigation on the effects of the angles between the mitral and aortic orifice during diastolic period using FSI.
It was well documented that the changes in the physiological structure of the heart can alter the hemodynamic behaviour of the human left ventricle. Although there were various imaging tools that can stipulate the blood flow characteristics inside the ventricle, but the effect of the variation in the angles between the mitral and aortic orifices were yet to be determined. Hence the primary focus of this paper was to use Fluid-Structure Interaction scheme throughout the diastolic phase to examine and determine the hemodynamic behaviour inside the cavity under various angles between the mitral and aortic orifices (50°, 55° and 60°). The incompressible Newtonian liquid (time dependent), linear viscous liquid and stress tensor equations were combined together with the Navier-Stoke's equations and Arbitrary Lagrangian Eulerian and for the elasticity of the structure. During diastasis, the position of the vortex was seen to be slightly upwards (55°) compared to 50° and 60°. Also, the influence of the wall shear stress was primarily observed to be much higher with the rise in the inlet velocity but the effect was seen reduced when the inlet velocity was minimal. Moreover, at the end of the filling phase maximum intraventricular pressure was obtained to be at the tip of LV for 50° compared to 55° and 60°. These findings provide significant insights on hemodynamic conditions and structural displacement, which from a clinical point of view would be useful in determining different conditions of cardiac diseases.


Early diagnosis of herpes zoster by polymerase chain reaction.
Herpes zoster is a common disease caused by the varicella-zoster virus. The use of virostatic agents as early as possible is necessary in shortening zoster-associated pain. Rapid diagnosis is necessary for the optimal efficacy of antiviral therapy. The diagnosis in the early stage of infection is often difficult. In the present study skin biopsies of patients with herpes zoster and unclear skin changes were analysed by detecting viral DNA using the polymerase chain reaction (PCR) in order to amplify open reading frames (ORF) 14, 29 and 63. Varicella-zoster virus DNA could be detected with PCR of all three ORF not only from blisters but also from erythematous skin. PCR is the method of choice for the viral diagnosis in herpes zoster before blister eruption.


Prospective, randomized in vivo comparison of a dual-active waterless antiseptic versus two alcohol-only waterless antiseptics for surgical hand antisepsis.
This study aimed to demonstrate the value of adding an active level of a persistent antimicrobial agent, such as chlorhexidine gluconate (CHG), to an alcohol-based surgical hand antiseptic. The persistence of 3 waterless, brushless alcohol-based surgical hand antiseptics, including one product containing CHG, was compared. The test products were applied a total of 12 times over 5 days. Samples of aerobic bacteria were collected on days 1 and 5, on both days immediately after drying and 6 hours later, using the glove juice technique. Relative suppression of regrowth was compared using t tests. Using an equivalence margin of 20%, the alcohol plus CHG product showed noninferiority to the alcohol-only products at all sampling points and, based on significantly lower bacterial regrowth (P = .026), superior persistence to the alcohol-only products after 6 hours of glove wear. Given the primary objective of surgical hand antisepsis of reducing resident skin flora for the duration of the surgical procedure, using an alcohol-based hand antiseptic containing CHG appears to be the most appropriate choice for maintaining microbial levels as low as possible for as long as possible.


The Transsulfuration Pathway Makes, the Tumor Takes.
Cells can take up cysteine or synthesize it de novo from methionine, but synthesis alone does not meet the high demands of cancer cells to proliferate. In this issue, Zhu et al. (2019) identify the SAH:SAM ratio, indicative of the cellular methylation state, as limiting for effective cysteine synthesis and the growth of some tumors.


The Relations Between Immunity, Oxidative Stress and Inflammation Markers, in Childhood Obesity.
Oxidative stress, inflammation and insulin resistance are the principal culprits in childhood obesity. Immune modifications are also important in the development of the obesity complications.The aim of this study is to find the relations for some immunity parameters with markers for oxidative stress and inflammation. Sixty obese children (10-16 years old) and thirty age and sex matched lean children were involved. The activities for erythrocyte superoxid dismutase (SOD), for erythrocyte glutathione peroxidase (GPx) and serum thioredoxin level were measured by ELISA, as oxidative stress markers. Circulating immune complexes (CIC), complement fractions C3, C4 and the self-antibodies, antismooth muscle antibodies (ASMA), antiliver-kidney microsome antibodies (LKM1) were measured by ELISA methods. Ceruloplasmin, haptoglobin and C reactive protein (CRP) were measured as inflammatory markers by immunoturbidimetric methods. ceruloplasmin (p<0.001), haptoglobin (p<0.001), CRP (p<0.05) and activity for SOD (p<0.001) were measured, while thioredoxin concentration (p<0.04) was reduced. The antibodies LKM1 and ASMA and GPx activity were not modified between groups. Positive correlations (for p<0.05) were calculated between SOD activity and LKM1 (r=0.37), GPx activity and ASMA (r=0.27), haptoglobin and C3 (r=0.33), ceruloplasmin and CIC (r=0.41), CRP and C3 (p<0.27) and negative correlations were calculated for C4 both with GPx activity (r= -0.28) and with thioredoxin level (r= -0.27). In the obese children versus the lean ones, higher levels for C3 (p<0.001), C4(p<0.001), CIC (p<0.05), In conclusion, this study demonstrates that immune modifications, inflammation and oxidative stress are related and they act in cluster in childhood obesity.


Rhodium(III)-Catalyzed Ortho-Alkenylation of Anilines Directed by a Removable Boc-Protecting Group.
The rhodium(III)-catalyzed ortho-alkenylation of N-Boc-anilines with alkenes such as acrylate ester and styrene proceeds smoothly through C-H bond cleavage. Obtained o-alkenylanilines can be readily transformed to nitrogen-containing fused heteroaromatic compounds including indoles and quinolines.


Effects of dissolved oxygen tension and agitation rate on the production of heat-shock protein glycoprotein 96 by MethA tumor cell suspension culture in stirred-tank bioreactors.
Heat-shock protein glycoprotein (gp96) serves as a natural adjuvant for chaperoning antigenic peptide into the immune surveillance pathway. In our laboratory, MethA tumor cell suspension culture process has been recently developed for gp96 production in spinner flask. In this work, effects of dissolved oxygen tension (DOT) and agitation rate on this process were studied in stirred-tank bioreactor. The optimal conditions for gp96 production were different with those for MethA tumor cell growth. MethA tumor cell growth pattern was not much changed by various levels of DOT and agitation rate, while gp96 biosynthesis was more sensitive to DOT and agitation rate. Compared with 50% of DOT, the production and specific productivity of gp96 was increased by 27 and 66% at 10% of DOT, respectively. Compared with the agitation rate of 100 rpm, the production and volumetric productivity of gp96 was increased by 48 and 144% at the agitation rate of 200 rpm, respectively. Low DOT (i.e., 10% of air saturation) and high agitation rate (i.e., 200 rpm) were identified to be favorable for gp96 biosynthesis. The results of this work might be useful to scale-up the bioprocess into the pilot scale.


Biofeedback training for children with bladder sphincter incoordination.
We studied 35 children with voiding dysfunction and detrusor-sphincter incoordination. More than 90 per cent of these patients had a history of repeat urinary tract infections, and medication and surgical treatment of the voiding dysfunction had failed. Of the patients 22 (63 per cent) experienced significant improvement or resolution of the voiding dysfunction when biofeedback was used to teach normal bladder sphincter coordination as part of the over-all treatment regimen. A review of our experience with these patients indicates that with proper patient selection an even higher rate of success may be possible.


Positive correlation between fatty liver index and hyperuricemia in hypertensive Chinese adults: a H-type hypertension registry study.
Few studies have examined the relationship between fatty liver index (FLI) and hyperuricemia (HUA). This study explores the relationship between FLI and HUA in hypertensive patients. A total of 13,716 hypertensive subjects were included in the current study. FLI, a simple index calculated from triglycerides (TG), waist circumference (WC), body mass index (BMI), and γ -glutamyltransferase (GGT), was used as a useful predictor of nonalcoholic fatty liver disease (NAFLD) distribution. HUA was defined as serum uric acid ≥ 360 μmol/L for females and ≥ 420 μmol/L for males. The mean value of total FLI was 31.8 ± 25.1. Multiple logistic analyses revealed a significant positive correlation between FLI and HUA (OR, 1.78; 95% CI: 1.69-1.87). A subgroup analysis demonstrated that the correlation between FLI (< 30 vs. ≥ 30) and HUA was significant in both sexes (P for interaction = 0.006). Further analyses stratified by sex indicated a positive correlation between FLI and HUA prevalence among male and female subjects. However, the correlation between FLI and HUA was stronger in female subjects than in males (male: OR, 1.70; 95% CI: 1.58-1.83; female: 1.85; 95% CI: 1.73-1.98). This study demonstrates a positive correlation between FLI and HUA in hypertensive adults, but stronger in females than males.


Multimodal delivery of irinotecan from microparticles with two distinct compartments.
In the last several decades, research in the field of drug delivery has been challenged with the fabrication of carrier systems engineered to deliver therapeutics to the target site with sustained and controlled release kinetics. Herein, we report the fabrication of microparticles composed of two distinct compartments: i) one compartment containing a pH responsive polymer, acetal-modified dextran, and PLGA (polylactide-co-glycolide), and ii) one compartment composed entirely of PLGA. We demonstrate the complete release of dextran from the microparticles during a 10-hour period in an acidic pH environment and the complete degradation of one compartment in less than 24h. This is in congruence with the stability of the same microparticles in neutral pH over the 24-hour period. Such microparticles can be used as pH responsive carrier systems for drug delivery applications where their cargo will only be released when the optimum pH window is reached. The feasibility of the microparticle system for such an application was confirmed by encapsulating a cancer therapeutic, irinotecan, in the compartment containing the acetal-modified dextran polymer and the pH dependent release over a 5-day period was studied. It was found that upon pH change to an acidic environment, over 50% of the drug was first released at a rapid rate for 10h, similar to that observed for the dextran release, before continuing at a more controlled rate for 4 days. As such, these microparticles can play an important role in the fabrication of novel drug delivery systems due to the selective, controlled, and pH responsive release of their encapsulated therapeutics.


The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model.
Newborns are colonized by maternal microbiota that is essential for offspring health and development. The composition of these pioneer communities exhibits individual differences, but the importance of this early-life heterogeneity to health outcomes is not understood. Here we validate a human microbiota-associated model in which fetal mice are cesarean delivered and gavaged with defined human vaginal microbial communities. This model replicates the inoculation that occurs during vaginal birth and reveals lasting effects on offspring metabolism, immunity, and the brain in a community-specific manner. This microbial effect is amplified by prior gestation in a maternal obesogenic or vaginal dysbiotic environment where placental and fetal ileum development are altered, and an augmented immune response increases rates of offspring mortality. Collectively, we describe a translationally relevant model to examine the defined role of specific human microbial communities on offspring health outcomes, and demonstrate that the prenatal environment dramatically shapes the postnatal response to inoculation.


Bruxism, parafunctional oral habits and oral motor problems in children with spastic cerebral palsy: A cross-sectional study.
Individuals with spastic cerebral palsy are more predisposed to parafunctional oral activities and oral motor problems because of spasticity. The aim of the study was to evaluate the relationship between the gross motor function classification system score (GMFCS), age, bruxism, parafunctional oral habits and oral motor problems in children with cerebral palsy. This cross-sectional study included 63 children with spastic cerebral palsy, aged 3-18 years, with developmental disabilities. The relationship between parentally reported bruxism, parafunctional oral activity rates, oral motor problems, and GMFCS was analysed. The prevalence of bruxism was 52.4%, and the rate decreased as age increased. There was a greater likelihood of bruxism in individuals with tongue thrust (OR [95% CI] = 8.15 [1.4-47.3]) and swallowing problems (OR [95% CI] = 5.78 [1.3-24.68]). In children with spastic cerebral palsy, bruxism and the rate of parafunctional oral habits were high, thus affecting oral motor activities. A relationship was found between oral motor problems and increased GMFCS levels, but no relationship was found between bruxism and GMFCS levels. Children with spastic cerebral palsy who display tongue thrust or swallowing problems have an increased likelihood of presenting with bruxism.


Identification and quantification of fungi and mycotoxins from Pu-erh tea.
Pu-erh tea originates from the province of Yunnan in south-western China. As this tea is produced by so called Aspergillus post-fermentation the question arises which molds and mycotoxins may be found in this tea. In total 36 samples of Pu-erh tea were investigated for their content of filamentous fungi and the mycotoxins aflatoxins B1, B2, G1, and G2, fumonisins B1, B2, and B3, and ochratoxin A. Fungi were isolated from all samples in a concentration of 1.0×10(1) to 2.6×10(6) colony forming units (cfu)/g tea, all together 19 fungal genera and 31 species were identified. The most prevalent species were Aspergillus acidus and Aspergillus fumigatus, followed by Zygomycetes and Penicillium species. Aflatoxins and fumonisins were not found in the samples investigated, ochratoxin A was detected in 4 of 36 teas (11.1%).


The AI/RHEUM knowledge-based computer consultant system in rheumatology. Performance in the diagnosis of 59 connective tissue disease patients from Japan.
AI/RHEUM is a knowledge-based computer consultant system for the diagnosis of rheumatic diseases. Its diagnostic accuracy was evaluated using information that was supplied by Japanese rheumatologists on 59 patients with connective tissue diseases. The diagnoses of the AI/RHEUM model were in full or partial agreement with those of the Japanese rheumatologists in 54 of 59 cases (92%). Preliminary evaluation of the criteria tissue disease showed a sensitivity of 90% and a specificity of 96%.


Rapid decline in acetylcholine release and content of rat extensor digitorum longus muscle after denervation.
The amount of acetylcholine (ACh) and choline (Ch) in normal and denervated rat extensor digitorum longus (EDL) muscles, as well as that released spontaneously from these muscles, was determined by an extremely sensitive gas chromatographic-mass spectrometric assay method. We found decreases in ACh content and spontaneous, resting ACh release as early as 8 h after denervation. The ACh content decreased to a plateau of 30% of control by 11 h; ACh release attained a plateau of 50% of control several hours later. These results showed that in denervated EDL muscles ACh content and spontaneous release (measured biochemically) decreased before nerve-evoked and spontaneous quantal release (measured physiologically) ceased at most synapses. The rapid reduction in ACh, or possibly in other substances that may be released with ACh, may be an important factor in initiating postsynaptic degenerative changes after nerve transection. Choline content and choline resting release increased significantly at both 1 and 3 days after nerve transection. These increases may be related to onset of postsynaptic neuromuscular degenerative changes.


A Four Month Randomized Controlled Trial on the Efficacy of Once-daily Fenofibrate Monotherapy in Persons with Spinal Cord Injury.
An open-label, randomized clinical trial of once-daily fenofibrate monotherapy administered for 2- (Mo2) and 4- (Mo4) months using modified intervention thresholds for triglyceride (TG) was performed in persons with chronic spinal cord injury (SCI). Fenofibrate (145 mg tablet) was self-administered daily in 10 persons with SCI for 4 months with monthly blood testing to quantify the lipoprotein profile (e.g., serum TG, LDL-C, and HDL-C concentrations). Eight SCI participants were control subjects. In comparison to the control group, the treatment group at Mo2 had a 40% (±12%; p < 0.05) reduction in serum TG concentration, a 28% (±21%; p < 0.05) increase in HDL-C and 14% (±20%; p < 0.05) decline in LDL-C. In the same comparison at Mo4, the treatment group maintained a 40% (±20%; p < 0.05) reduction in serum TG concentration, had an 18% in reduction in LDL-C (±12%; p < 0.05) and a 23% (±23%; p < 0.05) increase in HDL-C. Fenofibrate monotherapy for Mo2 and Mo4 initiated in persons with SCI resulted in a robust and favorable change in the serum lipoprotein profile and ratios, suggesting reduced risk for cardiovascular disease.


Stress generation by myosin minifilaments in actin bundles.
Forces and stresses generated by the action of myosin minifilaments are analyzed in idealized computer-generated actin bundles, and compared to results for isotropic actin networks. The bundles are generated as random collections of actin filaments in two dimensions with constrained orientations, crosslinked and attached to two fixed walls. Myosin minifilaments are placed on actin filament pairs and allowed to move and deform the network so that it exerts forces on the walls. The vast majority of simulation runs end with contractile minifilament stress, because minifilaments rotate into energetically stable contractile configurations. This process is aided by the bending and stretching of actin filaments, which accomodate minifilament rotation. Stresses for bundles are greater than those for isotropic networks, and antiparallel filaments generate more tension than parallel filaments. The forces transmitted by the actin network to the walls of the simulation cell often exceed the tension in the minifilament itself.


The influence of enteral feedings on sustained-release theophylline absorption.
In a randomized, crossover study the influence of enteral feedings (Ensure) on the absorption of theophylline from a sustained-release preparation (Theo-24) was evaluated. Six healthy, male subjects, age 22 to 37 years, participated. In phase 1 the subjects received a single oral dose of Theo-24 6 mg/kg with 100 ml of water at 8:00 A.M. In phase 2, they received 100 ml boluses of Ensure hourly, beginning 3 hours prior to the oral dose and continuing for a total of 1000 ml. In phase 3, subjects received a single 30-minute intravenous infusion of an equivalent dose of aminophylline. After each dose, serial blood samples were collected for 72 hours. No statistically significant differences in area under the curve (AUC infinity 0) (126.0 vs 127.3 micrograms hr/ml), maximum concentration (3.80 vs 4.08 micrograms/ml), or time to peak plasma level (13 vs 11 hrs) were found between phases 1 and 2. Mean AUC infinity 0 for the intravenous phase (161.4 micrograms hr/ml) was significantly higher than the AUC for either oral study (p less than 0.05). The mean bioavailability was 81% for phase 1 and 80% for phase 2. Percent absorbed versus time plots revealed no difference in rate of absorption between treatments. We conclude that short-term administration of the enteral feeding. Ensure does not influence the absorption of theophylline when administered as the sustained-release product Theo-24.


Macroautoradiographic and densitometric studies of [14C]dimethadione in rats: accumulation of the compound in the pancreas.
Whole-body autoradiographic and densitometric distribution studies were performed on rats to investigate the accumulation of [14C]dimethadione (DMO) in the pancreas. [14C]DMO was intravenously administered at a dose of 167 microCi/0.5 mg/kg. Animals were sacrificed 1, 15, 30, 60 and 180 min after administration of the radioactive compound. The compound was found to rapidly distribute in all body tissues. The distribution pattern of the compound in the pancreas was spotty or linear due to the presence of the radioactive compound in blood of intrapancreatic vessels and in pancreatic ducts at higher levels than parenchyma. The radioactivity of pancreatic ducts became more evident with time, indicating the gradual accumulation of the compound in the ducts. These findings provide morphological evidence that DMO is accumulated in the pancreas and possibly eliminated from pancreatic juice. Densitometry revealed that the levels of radioactive compound in the pancreas were virtually as high as those in the liver and kidney.


Plant-Based Foods for Skin Health: A Narrative Review.
The potential role of plant-based foods in the promotion of skin health is an emerging area of nutrition research. Plant-based foods are rich in bioactive compounds, including vitamin C, vitamin E, beta carotene, polyphenols, and phenolic acids, which can contribute to oxidant defense, lower inflammation, and promote structural support of the skin. Epidemiological studies have associated higher intakes of select fruits and vegetables with positive skin health. Beneficial effects of certain fruits, vegetables, nuts, legumes, and polyphenolic-rich beverages on the skin have been reported, with each of these providing a unique phytochemical composition. Although most studies use extracts, this review will focus on data from whole foods and minimally processed products. Collectively, the evidence to date suggests a promising future for plant-based dietary interventions that promote skin barrier health and function. However, additional research is required to address issues such as the optimal quality and duration of intake as well as potential mechanisms. Studies in the above areas will help formulate specific targeted dietary recommendations.


Comparative efficacy and safety of resection techniques for treating 6 to 20mm, nonpedunculated colorectal polyps: A systematic review and network meta-analysis.
Various endoscopic resection techniques have been proposed for the treatment of nonpedunculated colorectal polyps sized 6-20 mm, however the optimal technique still remains unclear. A comprehensive literature review was conducted for randomized controlled trials (RCTs), investigating the efficacy of endoscopic treatments for the management of 6-20 mm nonpedunculated colorectal polyps. Primary outcomes were complete and en bloc resection rates and adverse event rate was the secondary. Effect size on outcomes is presented as risk ratio (RR; 95% confidence interval [CI]). Fourteen RCTs (5219 polypectomies) were included. Endoscopic mucosal resection(EMR) significantly outperformed cold snare polypectomy(CSP) in terms of complete [(RR 95%CI): 1.04(1.00-1.07)] and en bloc resection rate [RR:1.12(1.04-1.21)]. EMR was superior to hot snare polypectomy (HSP) [RR:1.04(1.00-1.08)] regarding complete resection, while underwater EMR (U-EMR) achieved significantly higher rate of en bloc resection compared to CSP [RR:1.15(1.01-1.30)]. EMR yielded the highest ranking for complete resection(SUCRA-score 0.81), followed by cold-snare EMR(CS-EMR,SUCRA-score 0.76). None of the modalities was different regarding adverse event rate compared to CSP, however EMR and CS-EMR resulted in fewer adverse events compared to HSP [RR:0.44(0.26-0.77) and 0.43(0.21-0.87),respectively]. EMR achieved the highest performance in resecting 6-20 mm nonpedunculated colorectal polyps, with this effect being consistent for polyps 6-9 and ≥10 mm; findings supported by very low quality of evidence.


Rotational thromboelastometry and standard coagulation tests for live liver donors.
To study coagulation of live liver donors with standard coagulation tests (SCT) and rotational thromboelastometry (ROTEM) and investigate their relationship. A descriptive prospective study involving 50 right hepatotomy donors with epidural catheters. ROTEM (EXTEM, INTEM, and FIBTEM represent extrinsic and intrinsic pathways of coagulation and fibrinogen activity, respectively) was measured perioperatively and on days 1, 3, 5, 10, and 30. SCTs include prothrombin time (PT), international normalized ratio (INR) of PT, activated partial thromboplastin time (aPPT), fibrinogen, and platelets. PT and INR reflect hypocoagulability reaching maximum on day one (16.9 ± 2.5 s, 1.4 ± 0.2, p < 0.05 compared with baseline). ROTEM was in normal ranges till day 30 with no hypercoagulability. Fibrinogen showed no correlation with maximum clot firmness (MCF) of FIBTEM (r = 0.35, p > 0.05). CFT of EXTEM was not in significant correlation with PT and INR (r = 0.16, 0.19, p > 0.05), respectively. Significant correlation between platelets and both MCF (EXTEM; r = 0.59, p = 0.004) and MCF (INTEM; r = 0.48, p = 0.027). ROTEM disagreed with SCTs and did not show the temporary hypocoagulability suggested by SCTs. Both ROTEM and SCTs showed no signs of hypercoagulability. Future studies involving ROTEM could help develop new guidelines for coagulation monitoring.


Normal and benzo(a)pyrene-transformed fetal mouse brain cells. II. Ultrastructural study.
An ultrastructural study was performed on normal and Benzo(a)-pyrene(B(a)P)-transformed fetal mouse brain cells. Early subcultures of a strain initiated from whole brain presented three cell types in vitro: astroglial, poorly differentiated glial, and spongioblastic types. After B(a)P-treatment, there was an exclusive transformation and the growth of neuroglia sometimes without gliofibrillary maturation, but with the presence of glial fibrillary acidic protein (GFAP) in the cytoplasm. Early subcultures of another strain initiated from cortex only presented poorly differentiated neuroglial cells. After transformation, cell maturation as evidenced by gliofibrillogenesis and GFAP production by these cells was observed. In both cases, the potentiality of glial differentiation after in vitro malignant transformation by a chemical carcinogen seemed preserved.


Genomic organization, promoter activity of grass carp MDA5 and the association of its polymorphisms with susceptibility/resistance to grass carp reovirus.
MDA5 (melanoma-differentiation-associated gene 5), a member of the RLR (retinoic acid-inducible gene I-like receptor) family, plays a pivotal role in innate immunity against viral infection. In the present study, the organization of grass carp (Ctenopharyngodon idella) MDA5 (CiMDA5) gene sequence was elucidated and promoter activity of its 5'-flanking region was detected. In addition, single nucleotide polymorphisms (SNPs) were investigated to explore their association with susceptibility/resistance to grass carp reovirus (GCRV). The CiMDA5 genomic sequence is composed of 10,906 bp, containing seven exons and six introns, which is distinct from its counterparts with numbers of exons. The 5'-flanking region of CiMDA5 gene, containing several putative transcription factor binding sites, was amplified using genome walking technique, exhibiting promoter activity. Six SNPs were discovered in the complete sequence of CiMDA5. Five of them locate in introns and one in 5'-flanking region. The genotype and allele distribution were examined by PCR-RFLP in susceptible and resistant fish. The results indicate that genotypes at the -713 C/G and 3338 A/C loci were significantly associated with the resistance to GCRV (P<0.05). Furthermore, at -713 C/G site, no CC genotype individual was found; the mortality in GG genotype group was 42.65%, which was significantly lower than that in CG genotype group (73.91%) (P<0.05). The mortality in CC (33.33%) genotype at 3338 A/C locus was significantly lower than that in AA and AC genotype (61.54%, 45.95% respectively) (P<0.05). The data demonstrate that -713 G and 3338 C carrier are resistant to GCRV. These results provide potential markers for further investigation of selective breeding of resistant grass carp to GCRV.


[Studies on chemical constituents in roots of Heracleum rapula].
To study the chemical constituents in roots of Heracleum rapula. The constituents were isolated by column chromatography on silica gel and ODS, and identified by spectroscopic methods. Eight compounds, xanthotoxol (I), 8-geranyloxypsoralen (II), (+)-marmesin (III), beta-sitosterol (IV), stigmasterol (V), oleanolic acid (VI), ferulic (VII), scopoletin (VIII) were isolated and identified. Compounds IV, V, VI, VII, VIII were isolated from this plant for the first time.


The future of bladder cancer care in the USA.
Bladder cancer is the fifth most common malignancy in the USA and the most expensive to treat on a per-patient basis. Despite its prevalence, morbidity, mortality and associated cost of management, bladder cancer remains grossly under-recognized as a public health concern and underfunded scientifically. Although 5-year survival rates for patients with prostate or kidney cancer have improved tremendously in the past 30 years, progress in bladder cancer has stalled. A renewed interest from the clinical and research communities, as well as a young and eager advocacy network, are raising the profile of bladder cancer. As awareness and funding of bladder cancer increase, improved diagnostics, therapeutics and health services for patients with the disease will develop accordingly.


Long non-coding RNA SAP30-2:1 is downregulated in congenital heart disease and regulates cell proliferation by targeting HAND2.
Congenital heart disease (CHD) is the most common birth defect worldwide. Long non-coding RNAs (lncRNAs) have been implicated in many diseases. However, their involvement in CHD is not well understood. This study aimed to investigate the role of dysregulated lncRNAs in CHD. We used Gene Expression Omnibus data mining, bioinformatics analysis, and analysis of clinical tissue samples and observed that the novel lncRNA SAP30-2:1 with unknown function was significantly downregulated in damaged cardiac tissues from patients with CHD. Knockdown of lncRNA SAP30-2:1 inhibited the proliferation of human embryonic kidney and AC16 cells and decreased the expression of heart and neural crest derivatives expressed 2 (HAND2). Moreover, lncRNA SAP30-2:1 was associated with HAND2 by RNA immunoprecipitation. Overall, these results suggest that lncRNA SAP30-2:1 may be involved in heart development through affecting cell proliferation via targeting HAND2 and may thus represent a novel therapeutic target for CHD.


The face, beauty, and symmetry: perceiving asymmetry in beautiful faces.
The relationship between bilateral facial symmetry and beauty remains to be clarified. Here, straight head-on photographs of "beautiful" faces from the collections of professional modeling agencies were selected. First, beauty ratings were obtained for these faces. Then, the authors created symmetrical left-left and right-right composites of the beautiful faces and asked a new group of subjects to choose the most attractive pair member. "Same" responses were allowed. No difference between the left-left and right-right composites was revealed but significant differences were obtained between "same" and the left-left or right-right. These results show that subjects detected asymmetry in beauty and suggest that very beautiful faces can be functionally asymmetrical.


The neurogenetics of sexually dimorphic behaviors from a postdevelopmental perspective.
Most sexually reproducing animal species are characterized by two morphologically and behaviorally distinct sexes. The genetic, molecular and cellular processes that produce sexual dimorphisms are phylogenetically diverse, though in most cases they are thought to occur early in development. In some species, however, sexual dimorphisms are manifested after development is complete, suggesting the intriguing hypothesis that sex, more generally, might be considered a continuous trait that is influenced by both developmental and postdevelopmental processes. Here, we explore how biological sex is defined at the genetic, neuronal and behavioral levels, its effects on neuronal development and function, and how it might lead to sexually dimorphic behavioral traits in health and disease. We also propose a unifying framework for understanding neuronal and behavioral sexual dimorphisms in the context of both developmental and postdevelopmental, physiological timescales. Together, these two temporally separate processes might drive sex-specific neuronal functions in sexually mature adults, particularly as it pertains to behavior in health and disease.


Potential mechanisms for coordinate gene activation in the rheumatoid synoviocyte: implications and hypotheses.
Evidence is reviewed to support the concept that synovial cells in rheumatoid arthritis have undergone distinctive alterations at the cellular and subcellular level that result in their taking on some of the characteristics that are also manifest by transformed cells. These phenotypic modulations could be indirectly driven by cytokines in a paracrine or autocrine fashion. Specific regional patterns of cell phenotype modulation were used to argue against a simple widely diffusing direct inductive effect to cytokines and in favor of microenvironmental determinants. It is hypothesized that these extracellular factors induce novel activation in a coordinate manner by acting through master regulatory genes operating in cells with specific microenvironmental interactions. Two of these regulatory genes, fos and jun, are discussed in detail because of their induction by growth factors and their central role in the transactivation of genes which have been implicated in rheumatoid synovitis. A model for gene activation in the rheumatoid synovium is proposed based on the premise that fos and jun are an important link in the intracellular transduction pathways used by cytokines to induce cellular phenotypic changes.


Percutaneous release of the trigger thumb: is it safe, cheap and effective?
Percutaneous release of the trigger finger and trigger thumb has recently gained popularity. The aim of this study was to determine the clinical results and safety of percutaneous release in trigger thumbs. Twenty-five thumbs of 21 patients were released percutaneously in the polyclinic under local anaesthesia. Steroid injection was performed following the release procedure using the same needle. The thumb function was evaluated by a patient questionnaire, and functional thumb scores (VAS) were calculated in the preoperative and postoperative periods. At the 1 week follow-up, four patients had signs of discomfort and triggering because of incomplete release. These patients underwent open A1 pulley release. Three superficial tendon lacerations were seen during these open procedures. There were no wound complications or signs of digital nerve or artery injury in any of the patients. The preoperative mean VAS was 26.62 (18-36). This decreased to 2.57 (0-5) at the first postoperative month (P<0.001) and to 2.19 (0-3; P<0.001) at the sixth month. When the VAS scores at the first and sixth months were compared, the difference was statistically significant. We concluded that percutaneous release of trigger thumbs is a cheap, safe and effective procedure with a low rate of complications.


Decisions to hospitalize nursing home residents dying with advanced dementia.
To describe the prevalence of, timing of, and factors associated with decisions not to hospitalize nursing home residents with advanced dementia who were dying. Retrospective cohort study. Six hundred seventy five-bed nursing facility in Boston. Two hundred forty residents in a teaching nursing home who died between January 2001 and December 2003 with advanced dementia. The prevalence and timing of do-not-hospitalize (DNH) orders were determined from the medical record. Data describing demographic characteristics, health conditions, advance care planning, sentinel events, and health services usage during the last 6 months of life were examined. Factors associated with having a DNH order were identified. At the time of death, 83.8% of subjects had a DNH order. The prevalence of DNH orders was 50.0% and 34.4%, 30 and 180 days before death, respectively. Hospital transfers were common during the last 6 months of life (24.6%). Factors independently associated with having a DNH order before death included surrogate decision-maker was not the subject's child (adjusted odds ratio (AOR)=4.39, 95% confidence interval (CI)=1.52-12.66), eating problems (AOR=4.17, 95% CI=1.52-11.47), aged 92 and older (AOR=2.78, 95% CI=1.29-5.96), and length of stay 2 years or longer (AOR=2.34, 95% CI=1.11-4.93). For most institutionalized persons with advanced dementia, a decision to forgo hospitalization is not made until death is imminent. Thus, hospital transfers are common near the end of life. The finding that DNH orders are associated with patient and surrogate factors can help clinicians identify cases in which decisions to forgo hospitalizations may be facilitated.


Dynamic event-based state estimation for delayed artificial neural networks with multiplicative noises: A gain-scheduled approach.
This study is concerned with the state estimation issue for a kind of delayed artificial neural networks with multiplicative noises. The occurrence of the time delay is in a random way that is modeled by a Bernoulli distributed stochastic variable whose occurrence probability is time-varying and confined within a given interval. A gain-scheduled approach is proposed for the estimator design to accommodate the time-varying nature of the occurrence probability. For the sake of utilizing the communication resource as efficiently as possible, a dynamic event triggering mechanism is put forward to orchestrate the data delivery from the sensor to the estimator. Sufficient conditions are established to ensure that, in the simultaneous presence of the external noises, the randomly occurring time delays with time-varying occurrence probability as well as the dynamic event triggering communication protocol, the estimation error is exponentially ultimately bounded in the mean square. Moreover, the estimator gain matrices are explicitly calculated in terms of the solution to certain easy-to-solve matrix inequalities. Simulation examples are provided to show the validity of the proposed state estimation method.


Smilax china L.: A review of its botany, ethnopharmacology, phytochemistry, pharmacological activities, actual and potential applications.
Smilax china L., an extensively used traditional Chinese medicine, is known as Baqia in China. It has been used to treat various inflammatory disorders, particularly pelvic inflammation. The present paper aims to provide an up-to-date review at the advancements of the investigations on the ethnopharmacology, phytochemistry, pharmacological effect and actual and potential applications of S. china. Besides, the possible tendency and perspective for future research of this plant are discussed, as well. This article uses "Smilax china L." "S. china" as the keyword and collects relevant information on Smilax china L. plants through electronic searches (Elsevier, PubMed, ACS, CNKI, Google Scholar, Baidu Scholar, Web of Science), relevant books, and classic literature about Chinese herb. 134 chemical constituents, among which steroid saponins and flavonoids are the predominant groups, have been isolated and identified from S. china. S. china with its active compounds is possessed of wide-reaching biological activities, including anti-inflammatory, anti-cancer, anti-oxidant, detoxify nicotine, anti-diabetes, anti-obesity, anti-hyperuricaemia, anti-hypertension, promoting skin wound and barrier repair and anti-bacterial activity. Besides, S. china is also applied to other fields, such as food industry and detection technology. Based on the review of the existing phytochemical studies on Smilax china L., the structural characterization of Smilax china L. extract can continue to be the focus of future research. Pharmacological studies in vitro and in vivo have demonstrated some of the traditional uses of Smilax china L. extract, while other traditional uses still need to be confirmed by research.


Clinical Effects of Synthetic Cannabinoid Receptor Agonists Compared with Marijuana in Emergency Department Patients with Acute Drug Overdose.
Synthetic cannabinoid receptor agonists (SCRAs) are heterogeneous compounds originally intended as probes of the endogenous cannabinoid system or as potential therapeutic agents. We assessed the clinical toxicity associated with recent SCRA use in a large cohort of drug overdose patients. This subgroup analysis of a large (n = 3739) drug overdose cohort study involved consecutive ED patients at two urban teaching hospitals collected between 2009 and 2013. Clinical characteristics of patients with the exposure to SCRAs (SRCA subgroup) were compared with those from patients who smoked traditional cannabinoids (marijuana subgroup). Data included demographics, exposure details, vital signs, mental status, and basic chemistries gathered as part of routine clinical care. Study outcomes included altered mental status and cardiotoxicity. Eighty-seven patients reported exposure to any cannabinoid, of whom 17 reported SCRAs (17 cases, 70 controls, mean age 38.9 years, 77 % males, 31 % Hispanic). There were no significant differences between SRCA and marijuana with respect to demographics (age, gender, and race/ethnicity), exposure history (suicidality, misuse, and intent), vital signs, or serum chemistries. Mental status varied between SRCA and marijuana, with agitation significantly more likely in SCRA subgroup (OR = 3.8, CI = 1.2-11.9). Cardiotoxicity was more pronounced in the SCRA subgroup with dysrhythmia significantly more likely (OR = 9.2, CI = 1.0-108). In the first clinical study comparing the adverse effects of SCRA overdose vs. marijuana controls in an ED population, we found that SCRA overdoses had significantly pronounced neurotoxicity and cardiotoxicity compared with marijuana.


Shikonin impairs T lymphocyte proliferation and thymopoiesis while it may increase myeloid-derived suppressor cells to alleviate immune responses.
Shikonin (SHK) has multifaceted physiological functions, including antitumor, anti-inflammatory, and antimicrobial effects. Recently, SHK has been shown to affect immune responses; however, its detailed immune modulatory function in vivo remains unclear. In this study, we demonstrated that SHK not only inhibited T cell proliferation in vitro, but also intensively inhibited thymopoiesis and eliminated CD4/CD8 double-positive thymic progenitor cells in vivo. Treatment of mice with SHK resulted in immune profile alterations, which promoted myelosis in the bone marrow and increased inhibitory immune cells in central immune organs. A decrease in T cells and B cells was observed in the spleen. Using a murine allogenic skin transplantation model, we revealed that short-term treatment of recipients with SHK significantly inhibited skin graft rejection, in which the levels of myeloid-derived suppressor cells (MDSC) were markedly increased. Taken together, our study suggests that SHK can efficiently eliminate proliferating T cells and inhibit thymopoiesis while promoting the generation of MDSC, indicating its potential role in alleviating immune responses in allogeneic organ/cell transplantation.


Target regions enhance the outgrowth and survival of ganglion cells in embryonic retina transplanted to cerebral cortex in neonatal rats.
In embryonic mouse retina transplanted to occipital cortex of neonatal rats, ganglion cells do not project axons into the host cortex, although they may survive up to but not beyond 6 weeks post-transplantation. By contrast, if embryonic tectum or diencephalon is transplanted along with the retina, ganglion cells exhibit vigorous outgrowth to specific regions of the co-transplant and are able to survive for at least 14 weeks.


Structural basis for the inhibition of cGAS by nucleosomes.
The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy, and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo-electron microscopy structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA. In this configuration, all three known cGAS DNA binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA.


Subcutaneous fat area at the upper thigh level is a useful prognostic marker in the elderly with femur fracture.
The aim of this study was to evaluate prognostic value of body tissue composition at the upper thigh level for 1 year mortality in elderly patients with proximal femur fracture. This retrospective cohort study included consecutive elderly (aged ≥65) patients diagnosed with proximal femur fracture based on the findings of pelvic bone computed tomography (CT) performed at the emergency department of a tertiary care hospital and treated with surgery between 2010 and 2017. The cross-sectional area of subcutaneous fat and skeletal muscle at the upper thigh level was measured using CT. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for 1 year mortality were estimated using a Cox proportional hazards model. Survival based on the SFA quartiles was assessed using nonparametric Kaplan-Meier survival analysis and compared used log-rank tests. Among 876 elderly patients included in this study, the median age was 79.0 years, and 646 (73.7%) patients were female. A total of 93 (10.6%) died within 1 year after admission to the emergency department. Survivors had a significantly higher median subcutaneous fat area (SFA) than non-survivors (170.2 vs. 133.0 cm2 , P < 0.001), but no significant difference was observed between the skeletal muscle area (median, 156.7 vs. 160.3 cm2 , P = 0.504) and muscle density (median, 19.0 vs. 19.1 HU, P = 0.861) of both groups. After adjustment of other clinical characteristics and body compositions, the multivariate Cox proportional hazard analysis showed that SFA (adjusted HR, 0.987; 95% CI, 0.982-0.992; P < 0.001) was independently associated with 1 year mortality. With 384 deaths during 51 322 person-months of follow-up, the median estimated survival duration of all the patients was 92.8 months (95% CI, 80.8-104.7 months). The patients with SFA in the third (165.6-195.0 cm2 ) and fourth (>195.0 cm2 ) quartiles showed significantly longer survival duration than those with SFA in the first (<131.4 cm2 ; median survival time, 51.3 months) and second (131.4-165.5 cm2 ; median survival time, 88.7 months) quartiles (P < 0.001 by log-rank test). The SFAs measured at the upper thigh level and 1 year mortality are positively associated in elderly patients with proximal femur fracture. SFA may be an independent prognostic biomarker for 1 year mortality of femur fracture.


Transforaminal approach versus interlaminar approach: A meta-analysis of operative complication of percutaneous endoscopic lumbar discectomy.
To systematically analyze the differences of complications between percutaneous transforaminal endoscopic discectomy (PTED) and percutaneous interlaminar endoscopic discectomy (PIED) in the treatment of lumbar disc herniation. We performed a systematic search in MEDLINE, EMBASE, PubMed, Web of Science, Cochrane databases, Chinese Biomedical Literature Database, CNKI, and Wanfang Data for all relevant studies. All statistical analysis was performed using Review Manager Version 5.3. A total of 15 articles with 1156 study subjects were included, with 550 patients in PTED group and 606 patients in PIED group. The results of the meta-analysis showed that postoperative dysesthesia (odds ratio [OR] = 0.61, 95% confidence interval [CI], 0.33-1.13), nerve root injury (OR = 1.22, 95% CI, 0.30-5.02), surgical site wound complications (OR = 1.26, 95% CI, 0.29-5.40), recurrence (OR = 1.09, 95% CI, 0.54-2.21), conversion to open surgery (OR = 1.26, 95% CI, 0.33-4.81), incomplete decompression (OR = 1.62, 95% CI, 0.43-6.09), and total complication (OR = 0.72, 95% CI, 0.49-1.06) showed no significant differences between the PTED group and the PIED group, while the PTED group had significantly better results in dural tear compared with the PIED group (OR = 0.31, 95% CI, 0.13-0.79). Dural tear was significantly less occured in PTED compared with PIED. The postoperative dysesthesia, nerve root injury, surgical site wound complications, recurrence, conversion to open surgery, incomplete decompression, and total complication did not differ significantly between PTED and PIED in the treatment of lumbar disc herniation.


Ovarian steroidogenic enzyme activities during the rat estrous cycle.
We have correlated the concentrations of serum LH, estradiol and progesterone with the activities of 2 ovarian steroid biosynthetic enzymes during the rat estrous cycle. Ovarian 3 beta-hydroxysteroid dehydrogenase isomerase (3-beta HSD) activity decreased from 29 +/- 6 nmol/mg protein/min (mean +/- SEM) in diestrus, to 7 +/- 0.4 nmol/mg protein/min in late proestrus (p less than 0.005), and subsequently increased to 36 +/- 9 nmol/mg protein/min in metestrus (p less than 0.01). Ovarian 17-hydroxylase (17-OH) activity decreased from early to late proestrus (3.3 +/- 0.2 vs 2.2 +/- 0.2 nmol/mg protein/min, p less than 0.0025), and subsequently increased to 3.9 +/- 0.2 in metestrus (p less than 0.001). Serum LH, estradiol and progesterone peaked during proestrus, and reached a nadir during estrus. We conclude that the activities of 3-beta HSD and 17-OH in the rat ovary vary markedly during the estrous cycle. These changes may underlie the pattern of steroid secretion characteristic of this process.


MERS-CoV RBD-mRNA vaccine induces potent and broadly neutralizing antibodies with protection against MERS-CoV infection.
Middle East respiratory syndrome coronavirus (MERS-CoV), a highly pathogenic coronavirus in the same Betacoronavirus genus and Coronaviridae family as SARS-CoV-2, continues to post a threat to human health. Mortality remains high; therefore, there is a need to develop effective vaccines to prevent MERS-CoV infection. The receptor-binding domain (RBD) within the MERS-CoV spike (S) protein is a critical vaccine target. The latest mRNA technology has enabled rapid development of much-needed vaccines with high efficiency and scalable manufacturing capacity. Here, we designed a mRNA vaccine encoding the RBD of MERS-CoV S protein (RBD-mRNA) and evaluated its immunogenicity and protective efficacy in a mouse model. The data showed that nucleoside-modified RBD-mRNA, but not RBD-mRNA lacking the nucleoside modification, was stable and elicited broadly and durable neutralizing antibody and cellular immune responses, which neutralized the original strain and multiple MERS-CoV variants. Among all immunization routes tested, the intradermal route was appropriate for this RBD-mRNA to induce strong B-cell responses and the highest neutralizing antibody titers. Importantly, injection of nucleoside-modified RBD-mRNA through the intradermal route protected immunized mice against challenge with MERS-CoV. This protection correlated with serum neutralizing antibody titers. Overall, we have developed an effective MERS-CoV RBD-based mRNA vaccine (with potential for further development) that prevents infection by divergent strains of MERS-CoV.


Social support and suicidal ideation in Japan: are home visits by commissioned welfare volunteers associated with a lower risk of suicidal ideation among elderly people in the community?
Social support has consistently been reported to be effective in reducing suicidal ideation. This cross-sectional study was performed to determine whether home visits by commissioned welfare volunteers (i.e., organizations of community residents appointed by national or prefectural governments) are associated with a lower risk of suicidal ideation among the elderly. In August 2010, questionnaires were sent to all residents aged ≥65 years in three municipalities (n = 21,232) in Okayama prefecture, Japan, and 13,929 returned the questionnaire (response rate: 65.6%). We finally analyzed 11,218 subjects. Both home visits by commissioned welfare volunteers and suicidal ideation within the last 30 days were assessed in the questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) for suicidal ideation were calculated adjusting for age, sex, educational attainment, and marital status. We then additionally adjusted for instrumental and emotional support, separately. The prevalence of suicidal ideation was 10.0% and higher in women than in men (11.4% vs. 8.0%). Home visits were significantly associated with a lower risk of suicidal ideation after adjusting for instrumental and emotional support, respectively (OR: 0.60, 95% CI: 0.53-0.69; OR: 0.67, 95% CI: 0.59-0.78). In sex-stratified analysis, the association was clearer for women than for men: the corresponding ORs among women were 0.55 (95% CI: 0.46-0.65) and 0.61 (95% CI: 0.52-0.73), whereas they were 0.71 (95% CI: 0.56-0.90) and 0.78 (95% CI: 0.61-0.99) among men. Our findings suggest that home visits by commissioned welfare volunteers are significantly associated with lower suicidal ideation among the elderly, particularly in women.


Fine-resolution voxel S values for constructing absorbed dose distributions at variable voxel size.
This article presents a revised voxel S values (VSVs) approach for dosimetry in targeted radiotherapy, allowing dose calculation for any voxel size and shape of a given SPECT or PET dataset. This approach represents an update to the methodology presented in MIRD pamphlet no. 17. VSVs were generated in soft tissue with a fine spatial sampling using the Monte Carlo (MC) code MCNPX for particle emissions of 9 radionuclides: (18)F, (90)Y, (99m)Tc, (111)In, (123)I, (131)I, (177)Lu, (186)Re, and (201)Tl. A specific resampling algorithm was developed to compute VSVs for desired voxel dimensions. The dose calculation was performed by convolution via a fast Hartley transform. The fine VSVs were calculated for cubic voxels of 0.5 mm for electrons and 1.0 mm for photons. Validation studies were done for (90)Y and (131)I VSV sets by comparing the revised VSV approach to direct MC simulations. The first comparison included 20 spheres with different voxel sizes (3.8-7.7 mm) and radii (4-64 voxels) and the second comparison a hepatic tumor with cubic voxels of 3.8 mm. MC simulations were done with MCNPX for both. The third comparison was performed on 2 clinical patients with the 3D-RD (3-Dimensional Radiobiologic Dosimetry) software using the EGSnrc (Electron Gamma Shower National Research Council Canada)-based MC implementation, assuming a homogeneous tissue-density distribution. For the sphere model study, the mean relative difference in the average absorbed dose was 0.20% ± 0.41% for (90)Y and -0.36% ± 0.51% for (131)I (n = 20). For the hepatic tumor, the difference in the average absorbed dose to tumor was 0.33% for (90)Y and -0.61% for (131)I and the difference in average absorbed dose to the liver was 0.25% for (90)Y and -1.35% for (131)I. The comparison with the 3D-RD software showed an average voxel-to-voxel dose ratio between 0.991 and 0.996. The calculation time was below 10 s with the VSV approach and 50 and 15 h with 3D-RD for the 2 clinical patients. This new VSV approach enables the calculation of absorbed dose based on a SPECT or PET cumulated activity map, with good agreement with direct MC methods, in a faster and more clinically compatible manner.


Improved conversion of ginsenoside Rb1 to compound K by semi-rational design of Sulfolobus solfataricus β-glycosidase.
Ginsenoside compound K has been used as a key nutritional and cosmetic component because of its anti-fatigue and skin anti-aging effects. β-Glycosidase from Sulfolobus solfataricus (SS-BGL) is known as the most efficient enzyme for compound K production. The hydrolytic pathway from ginsenoside Rb1 to compound K via Rd and F2 is the most important because Rb1 is the most abundant component in ginseng extract. However, the enzymatic conversion of ginsenoside Rd to F2 is a limiting step in the hydrolytic pathway because of the relatively low activity for Rd. A V209 residue obtained from error-prone PCR was related to Rd-hydrolyzing activity, and a docking pose showing an interaction with Val209 was selected from numerous docking poses. W361F was obtained by rational design using the docking pose that exhibited 4.2-fold higher activity, 3.7-fold higher catalytic efficiency, and 3.1-fold lower binding energy for Rd than the wild-type enzyme, indicating that W361F compensated for the limiting step. W361F completely converted Rb1 to compound K with a productivity of 843 mg l-1 h-1 in 80 min, and showed also 7.4-fold higher activity for the flavanone, hesperidin, than the wild-type enzyme. Therefore, the W361F variant SS-BGL can be useful for hydrolysis of other glycosides as well as compound K production from Rb1, and semi-rational design is a useful tool for enhancing hydrolytic activity of β-glycosidase.


DeltaNp63/BMP-7-dependent expression of matrilin-2 is involved in keratinocyte migration in response to wounding.
p63 is expressed as multiple variants including TA and DeltaN forms. Since p63-deficient mice displayed profound defects of stratified epithelia, p63 is an essential transcription factor required for epidermal morphogenesis. However, precise molecular mechanisms behind contribution of p63 to normal skin formation and healing skin wounds remained unclear. In this study, we demonstrated that DeltaNp63/BMP-7 signaling pathway modulates wound healing process through the regulation of extracellular matrix protein matrilin-2. Knocking down of DeltaNp63 in human keratinocyte HaCaT cells led to a significant reduction of matrilin-2. Intriguingly, BMP-7 which is one of DeltaNp63-target gene products, induced matrilin-2 and attenuated inhibitory effect of siRNA against DeltaNp63 on matrilin-2. Furthermore, a remarkable cell migration in response to wounding took place in DeltaNp63- or matrilin-2-knocked down cells. Taken together, our present findings indicate that DeltaNp63/BMP-7 signaling pathway modulates wound healing process through the regulation of matrilin-2.


Disorders of sleep in spinal and bulbar muscular atrophy (Kennedy's disease).
Spinal and bulbar muscular atrophy (SBMA) is a progressive, X-linked lower motor neuron disorder exclusively affecting men. Since knowledge on sleep disorders in SBMA is scarce compared to other motoneuron diseases, this retrospective case-control study aimed to investigate sleep and sleep-related breathing in patients with SBMA. In 23 non-ventilated patients with SBMA (median age 52 years), clinical disease characteristics, forced vital capacity and diagnostic polysomnographies were retrospectively evaluated. In 16 patients, overnight transcutaneous capnometry was available. Twenty-three male control subjects with chronic insomnia were matched for age and body mass index. In patients with SBMA obstructive sleep apnoea (OSA, apnoea-hypopnoea index/AHI > 5/h) was more frequent than in control subjects (14/23 or 61% vs. 6/23 or 26%, p = 0.02), and median AHI was significantly higher in patients (9.0/h vs. 3.4/h, p < 0.01). Among SBMA patients, the AHI was not related to age or body mass index. Alveolar hypoventilation as reflected by nocturnal hypercapnia was found in 3/16 patients. Rapid eye movement (REM) sleep without atonia was present in 44% of SBMA patients but only in 4% of controls (p < 0.01). During REM and non-REM sleep, no behavioural abnormalities were observed in either group. Periodic limb movements in sleep (index > 15/h) were frequent in SBMA patients but rarely disrupted sleep. In patients with SBMA, sleep-disordered breathing may comprise both OSA and nocturnal hypoventilation. REM sleep without atonia may also be found, but its clinical significance remains unclear. In patients complaining of sleep-related symptoms, cardiorespiratory polysomnography and transcutaneous capnometry are recommended.


RBCs labeled at two biotin densities permit simultaneous and repeated measurements of circulating RBC volume.
The extend potential applications of a nonradioactive method for measuring circulating RBC volume, we tested the hypothesis that RBC volume could be determined independently using two populations of RBCs labeled with low-density biotin (LDB1) and high-density biotin (HDB). In 10 healthy adults, autologous RBCs were labeled with HDB, LDB, or 51Cr. The labeled RBCs were mixed and transfused. RBC volume was measured in postinfusion peripheral venous blood by quantitating dilution of each population of labeled RBCs. RBC volume measured using either LDB or HDB cells agreed well with RBC volume measured using 51Cr. For the regression of RBC volume by LDB versus RBC volume by 51Cr, correlation = 0.994 and slope = 0.933. For HDB versus 51Cr, correlation = 0.982 and slope = 0.953. RBC volume measured a second time in four subjects with HDB agreed well; mean CV for the differences between HDB and 51Cr were less than 5 percent. Using RBCs labeled with two different densities of biotin, RBC volume can be accurately measured simultaneously and repeatedly in the same subject without radiation exposure.


Sex hormone binding globulin and free levonorgestrel index in the first week after insertion of Norplant implants.
Levonorgestrel has an inhibitory effect on sex hormone binding globulin (SHBG). This decrease in SHBG leads to an increase in the free levonorgestrel index (FLI), which has a stronger biological effect. The interaction between serum levels of levonorgestrel and SHBG in long-term users of Norplant implants has been described. This study was designed to understand the same interaction immediately after the insertion of the implants, in a group of 16 women, sampled at 0 and 6 h and at 1, 3, and 7 days after Norplant implant insertion. Peak serum levonorgestrel levels were achieved at 24 h after insertion, remaining stable on day 3 and decreasing by > 10% by day 7. SHBG did not change during the first 24 h, but decreased by 19% and 60% on days 3 and 7, respectively. FLI more than doubled from day 1 to day 7 after insertion. The large decrease in SHBG and doubling of FLI is not followed by a similar reduction in levonorgestrel, which is hard to explain without an increase in the release rate of the steroid from the capsule.


Analysis of plant genomes. V. Comparative study of molecular properties of DNAs of seven Allium species.
The genomes of seven plant species belonging to the genus Allium and exhibiting a threefold variation in their nuclear DNA content were analyzed by studying their reassociation kinetics, equilibrium centrifugation behavior in neutral CsCl gradients, and melting properties. The reassociation kinetics experiments revealed the presence of 44-65% repeated DNA sequences. A comparison between DNA contents and the proportion of repeated DNA sequences indicated that, in Allium, increase in the genome size is not exclusively due to variations in the proportions of repetitive DNA. The total DNA as well as the various repetitive DNA fractions in all the Allium species examined exhibited, in spite of a few differences, a gross similarity in their behavior in neutral CsCl gradients and in their melting properties.


Deep learning system for paddy plant disease detection and classification.
Automatic detection and analysis of rice crop diseases is widely required in the farming industry, which can be utilized to avoid squandering financial and other resources, reduce yield losses, and improve treatment efficiency, resulting in healthier crop output. An automated approach was proposed for accurately detecting and classifying diseases from a supplied photograph. The proposed system for the recognition of rice plant diseases adopts a computer vision-based approach that employs the techniques of image processing, machine learning, and deep learning, reducing the reliance on conventional methods to protect paddy crops from diseases like bacterial leaf blight, false smut, brown leaf spot, rice blast, and sheath rot, the five primary diseases that frequently plague the Indian rice fields. Following image pre-processing, image segmentation is employed to determine the diseased section of the paddy plant, with the diseases listed above being identified purely on the basis of their visual contents. An integration of a support vector machine classifier and convolutional neural networks are used to recognize and classify specific varieties of paddy plant diseases. With ReLU and softmax functions, the suggested deep learning-based strategy attained the highest validation accuracy of 0.9145. Following recognition, a predictive remedy is recommended, which can assist agriculture-related individuals and organizations in taking suitable measures to combat these diseases.


The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity.
Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.


A Comparison of Vitamin E Status and Associated Pregnancy Outcomes in Maternal⁻Infant Dyads between a Nigerian and a United States Population.
Oxidative stress is associated with adverse pregnancy outcomes, and vitamin E has powerful anti-oxidant properties with the potential to impact health outcomes. Tocopherol isomers of vitamin E differ in their ability to modulate inflammation and vary in concentration in diets containing high proportions of processed versus unprocessed foods. The purpose of this study was to compare vitamin E status and associated pregnancy outcomes (mode of delivery, chorioamnionitis, APGARs (measure of appearance, pulse, grimace, activity, respiration), gestational age at delivery, and fetal growth) between maternal⁻infant dyads in a developed and a developing nation to identify potentially modifiable differences that may impact pregnancy and neonatal outcomes and provide a way to improve maternal and neonatal health. Plasma tocopherol levels were evaluated in 189 Midwestern United States (US) mother⁻infant pairs and 99 Central Nigerian mother⁻infant pairs. Maternal and infant concentrations of α-, γ-, and δ-tocopherol were measured using HPLC with diode-array detection. Descriptive statistics were calculated and tocopherol concentrations were associated with clinical outcomes such as mode of delivery, chorioamnionitis, APGARS, and fetal growth. Alpha- and γ-tocopherol levels were higher in the US mothers, (alpha: 12,357.9 (175.23⁻34,687.75) vs. 8333.1 (1576.59⁻16,248.40) (mcg/L); p < 0.001) (gamma: 340.7 (224.59⁻4385.95) vs. 357.5 (66.36⁻1775.31) (mcg/L); p < 0.001), while δ-tocopherol levels were higher in the Nigerian mothers (delta: 261.7 (24.70⁻1324.71) vs. 368.9 (43.06⁻1886.47) (mcg/L); p < 0.001). US infants had higher γ-tocopherol levels than Nigerian infants (203.1 (42.53⁻1953.23) vs. 113.8 (0.00⁻823.00) (mcg/L); p < 0.001), while both the Nigerian mothers and infants had higher α:γ-tocopherol ratios (8.5 vs. 26.2, and 8.9 vs. 18.8, respectively; p < 0.001). Our results in both populations show associations between increased circulating γ-tocopherol and negative outcomes like Caesarian sections, in contrast to the associations with positive outcomes such as vaginal delivery seen with increased α:γ-tocopherol ratios. Growth was positively associated with α- and γ-tocopherols in cord blood in the US population, and with cord blood δ-tocopherols in the Nigerian population. Tocopherol levels likely impact health outcomes in pregnancy in a complicated metabolism across the maternal⁻fetal axis that appears to be potentially influenced by culture and available diet.


CMOS direct time interval measurement of long-lived luminescence lifetimes.
We describe a Complementary Metal-Oxide Semiconductor (CMOS) Direct Time Interval Measurement (DTIM) Integrated Circuit (IC) to detect the decay (fall) time of the luminescence emission when analyte-sensitive luminophores are excited with an optical pulse. The CMOS DTIM IC includes 14 × 14 phototransistor array, transimpedance amplifier, regulated gain amplifier, fall time detector, and time-to-digital convertor. We examined the DTIM system to measure the emission lifetime of oxygen-sensitive luminophores tris(4,7-diphenyl-1, 10-phenanthroline) ruthenium(II) ([Ru(dpp)(3)](2+)) encapsulated in sol-gel derived xerogel thin-films. The DTIM system fabricated using TSMC 0.35 μm process functions to detect lifetimes from 4 μs to 14.4 μs but can be tuned to detect longer lifetimes. The system provides 8-bit digital output proportional to lifetimes and consumes 4.5 mW of power with 3.3 V DC supply. The CMOS system provides a useful platform for the development of reliable, robust, and miniaturized optical chemical sensors.


Land use synergies and conflicts identification in the framework of compatibility analyses and spatial assessment of ecological, socio-cultural and economic values.
Land-use conflicts can be costly and time-consuming and cause social burden to all parties. In this study, we developed an approach for mapping synergy and conflict potential between land uses and tested it on nature protection, nature-based tourism, forestry and mining. First, we calculated the ecological and socio-cultural values for the study area, and further the economic values related to forestry and mining. Second, we conducted an integrated spatial assessment of these values and used it jointly with a variant of a value compatibility analysis to locate areas with possible synergistic and conflicting land uses. This study was carried out in Finnish Lapland where land use conflicts have occurred due to the need to develop forestry and mining in areas that are also important for nature-based tourism. The method operated well as it identified sites with ongoing land-use disputes. Synergy potential between biodiversity and socio-cultural values was identified in protected areas and other sites of natural beauty, and conflict potential concerning forestry near tourist resorts and concerning mining at proposed mining project sites. The developed framework can assist in locating sites that may need proactive measurements to avoid conflicts, and sites that would benefit from multi-purpose management thereby supporting sustainable and adaptive land-use planning.


Topology and neighbor analysis of the photosynthetic reaction center from Rhodopseudomonas sphaeroides.
The subunit arrangement of the reaction center complex (RC) of Rhodopseudomonas sphaeroides was studied by chemical modification with four different cross-linking reagents using purified RC in lauryldimethylamine oxide, RC incorporated into liposomes, and intact chromatophore membranes, from which RCs are isolated. The RC of R. sphaeroides is composed of three polypeptide subunits, H, M, and L, apparent molecular mass as determined in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, of 28,000, 24,000, and 21,000, respectively. The intra-complex products produced, were found to contain the polypeptides H-M-L, H-M, H-L, and M-L linked together. In addition, the cross-linking of cytochrome c to solubilized and membrane-bound RCs was observed with all four reagents. The products were found to be only a cytochrome c linked to either the M or L polypeptide. These results indicate that a portion of the L and M subunits of the RC must be exposed in situ on the periplasmic surface of the membrane near a binding site for cytochrome c on the RC, and all three subunits must be in close proximity to one another.


Implementation and Assessment of a Urology Education Curriculum for Nursing Residents.
Urethral catheter placement is a common hospital procedure, and the urology service is often consulted for difficult catheterizations. Simulation-based education is used to improve procedural proficiency and could be used to increase confidence and comfort with difficult catheter placement. This study provides simulation-based education to help new nursing residents learn to perform independent Foley catheter placement and maintenance. All incoming nursing residents at our institution prospectively participated in this curriculum beginning in January 2020 (n = 291). Participants watched an instructional video and participated in a hands-on simulation. Nursing trainees rated pre- to post-curriculum gains in content knowledge (p < .001) and confidence (p < .001). Participants reported that the curriculum increased their understanding of the procedure (p < .001) and that they would recommend it to peers (p < .001). This educational initiative is a partnership between the Department of Urology and Department of Nursing to introduce and reinforce best practices for the care of patients who need Foley catheter placement and maintenance. [J Contin Educ Nurs. 2021;52(11):511-516.].


Design of experiments for the precise estimation of dose-response parameters: the Hill equation.
Optimal experimental designs were evaluated for the precise estimation of parameters of the Hill model. The optimally effective designs were obtained by using the criterion of D-optimization. For the Hill model, optimal designs replicate 3 sampling points. These points were shown to be quite sensitive to the behavior of the experimental error. Since an investigator is often uncertain about error conditions in biological studies, a practical approach would use the sampling scheme calculated for an intermediate error condition. Thus, if the behavior of error variances is not known, precise parameters of the Hill model are obtained by choosing concentrations which yield fractional responses (responses divided by their asymptotic, maximum value) of 0.086, 0.581 and 1.0. When experimental constraints limit the maximum attainable concentration and response, all design points are lowered. Appropriate designs can be constructed based on the design which is optimal when constraints result in a maximum attainable fractional response of 0.5. The optimal designs were found to be robust when the parameter values assumed by the investigator did not equal their true values. The estimating efficiencies obtained by using two frequently applied designs were assessed. Uniformly spaced concentrations yielded imprecise parameters. Six-point, geometrically spaced designs gave generally good results. However, their estimating efficiency was generally exceeded by the recommended sampling schemes even in the presence of uncertainty about error conditions. The method exemplified in this paper can be used for other models.