Oxidative metabolism of bunitrolol by complementary DNA-expressed human cytochrome P450 isozymes in a human hepatoma cell line (Hep G2) using recombinant vaccinia virus.
We examined the oxidative metabolism of a beta-blocker bunitrolol (BTL) by 10 human cytochromes P450 (CYP) (1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A3, 3A4 or 3A5), which were individually expressed in Hep G2 cells with a vaccinia virus complementary DNA expression system. Among the 10 isozymes, only CYP2D6 and 1A2 at a substrate concentration of 5 microns, and CYP2C8 and 2C9 in addition to the two isozymes at a BTL concentration of 1 mM, exhibited detectable BTL 4-hydroxylase activities. The activities at 1 mM BTL were on the order of CYP2D6 (100% as relative activity) > CYP1A2 (86%) >> CYP2C8 and 2C9 (7-8%). Enzyme kinetic parameters of CYP2D6 were calculated to be 4.41 microns as a Km value and 0.442 nmol min-1 per nmol CYP as a Vmax value. Kinetic parameters of CYP1A2 were calculated as 295 microns and 0.411 nmol min-1 per nmol CYP for Km and Vm values, respectively. These results suggest that both CYP2D6 and 1A2 primarily catalyse BTL 4-hydroxylation, but that the former is a predominant isozyme responsible for the reaction at a low substrate concentration range of BTL in human liver.


A comprehensive analysis comparing linear and generalized linear models in detecting adaptive SNPs.
To understand how organisms adapt to their environment, a gene-environmental association (GEA) analysis is commonly conducted. GEA methods based on mixed models, such as linear latent factor mixed models (LFMM) and LFMM2, have grown in popularity for their robust performance in terms of power and computational speed. However, it is unclear how the assumption of a Gaussian distribution for the response variables influences model performance. In this paper, we develop a generalized linear model (GLM) that allows for non-Gaussian distribution in the genotypic response variables, and treatment of multiallelic nucleotide polymorphisms. Moreover, this multinomial logistic regression model (MLR) is combined with an admixture-based model or principal components analysis to correct for population structure (MLR-ADM and MLR-PC). Using simulations, we evaluate the type 1 error, false discovery rates (FDR), and power to detect selected SNPs, to guide model choice and best practices. With genomic control, MLR-PC and LFMM2 have similar type 1 error, FDRs, and power when analysing biallelic SNPs, while dramatically outperforming models not accounting for population structure. Differences in performance occur under continuous population structure where MLR-PC outperforms LFMM/LFMM2, especially when a larger number of clusters or triallelic SNPs are analysed. The Human Genome Diversity Project (HGDP) data set shows that both MLR-PC and LFMM2 control the inflation of P -values. Analysis of the 1,000 Genome Project Phase 3 data set illustrates that MLR-PC and LFMM2 produce consistent results for most significant SNPs, while MLR-PC discovered additional SNPs corresponding to certain genes, suggesting MLR-PC may be a useful alternative to GEA inference.


Evidence of oxidative injury during aging of the liver in a mouse model.
The aim of the present study was to determine whether oxidative stress contributes to aging of the liver in a mouse model. Liver was obtained from young (3-5 months old) and aged (18-24 months old) mice. No age-induced gross changes in liver morphology were detected by light microscopy. Apoptosis was measured using the fragment end labeling of DNA for the immunohistochemical identification of the apoptotic nuclei. The total apoptotic cells represented 1% of the total cells in livers of young mice and 8% in those of aged mice. Among the total apoptotic cells in livers of aged animals, 15% were hepatocytes, 40% sinusoidal endothelial cells, and 45% bile duct cells. Hepatic lipid peroxidation, expressed as malonaldehyde levels, protein oxidation, measured by protein carbonyl content, and DNA oxidation, measured as 8-hydroxy-2'-deoxyguanosine (oxo(8)dG), were significantly increased in the livers of aged animals as compared to younger mice. The apoptotic cells presented elevated levels of oxidized DNA, detected by immunohistochemistry using an antibody directed against oxo(8)dG in serial sections. These results suggest that livers of aged animals presents evidence of increased oxidative injury and apoptosis. Because the apoptotic cells in the aged livers are mostly bile duct cells and sinusoidal endothelial cells, the cells most sensitive to oxidative stress injury, it can be hypothesized that reactive oxygen species-induced apoptosis in these cells contributes to the aging of the liver.


Patterns of cortical thickness and the Child Behavior Checklist in childhood epilepsy.
The purpose of this investigation was to characterize the neuroanatomical correlates (cortical thickness) of variations in parent-reported Child Behavior Checklist (CBCL) scores. Ninety children with epilepsy (aged 8-18) underwent brain MRI, and their parents completed the CBCL. FreeSurfer-derived measures of cortical thickness were examined in relation to the CBCL broad and narrow band competence and behavioral problem scales, as well as the newer DSM-oriented scales. Parent reports of higher (better) social competence skills were associated with increased cortical thickness, especially in frontal regions. Parent reports of behavioral problems were associated with patterns of decreased cortical thickness that varied as a function of the specific behavioral issue under investigation. Congruence of patterns of cortical thinning between the DSM-oriented scales and conceptually related specific problem scales (e.g., ADHD Problems and Attention Problems) was generally weak. The parent-report version of the CBCL is associated with variations in cortical thickness among children with epilepsy. Anatomic abnormalities specific to selected competence and behavioral problem scales can be identified, with more reliable and robust patterns of thinning across scales assessing externalizing behaviors, with generally less prominent findings on scales assessing internalizing behaviors.


A conceptual framework for patient-professional communication: an application to the cancer context.
We present a conceptual framework of one-to-one, in-person communication that occurs between a health-care professional and a patient. The framework is intended as a tool for organizing and summarizing relevant research but it can also help guide assessing the communication process and can help guide development of interventions to improve the process. The framework includes four key components, with a focus on elements that can be modified. The first component is the focus of the interaction: each participant's communication goals. The second component consists of the participants themselves, each with five key attributes that determine, in part, how they address their goals. The third component is the communication process: each person both conveys messages and receives messages, and the messages themselves can be verbal, non-verbal, or silent. The communication process is iterative and extended in time with one act having an impact on following acts. Finally, the fourth component is the environment in which the communication occurs, both the immediate physical setting and the context beyond. Important aspects of the environment, identified as external factors, affect the communication process through their impact on the participants' attributes. The framework builds on classic communication frameworks to which it adds unique elements. Some of its unique aspects include the prominent role of the participants' goals and its distinct recognition that messages are conveyed through silence. The framework serves as a common conceptualization of factors important to successful communication for the remaining review papers in this series and for future studies of practitioner-patient communication.


Learning the ropes: strategies program directors use to facilitate organizational socialization of newcomer residents, a qualitative study.
Many residents experience their transitions, such as from medical student to resident, as demanding and stressful. The challenges they face are twofold: coping with changes in tasks or responsibilities and performing (new) social roles. This process of 'learning the ropes' is known as Organizational Socialization (OS). Although there is substantial literature on transitions from the perspective of residents, the voices of program directors (PDs) who facilitate and guide residents through the organizational socialization process have not yet been explored. PDs' perspectives are important, since PDs are formally responsible for Postgraduate Medical Education (PGME) and contribute, directly or indirectly, to residents' socialization process. Using the lens of OS, we explored what strategies PDs use to facilitate organizational socialization of newcomer residents. We conducted semi-structured interviews with 17 PDs of different specialties. We used a theory-informing inductive data analysis study design, comprising an inductive thematic analysis, a deductive interpretation of the results through the lens of OS and, subsequently, an inductive analysis to identify overarching insights. We identified six strategies PDs used to facilitate organizational socialization of newcomer residents and uncovered two overarching insights. First, PDs varied in the extent to which they planned their guidance. Some PDs planned socialization as an explicit learning objective and assigned residents' tasks and responsibilities accordingly, making it an intended program outcome. However, socialization was also facilitated by social interactions in the workplace, making it an unintended program outcome. Second, PDs varied in the extent to which they adapted their strategies to the newcomer residents. Some PDs used individualized strategies tailored to individual residents' needs and skills, particularly in cases of poor performance, by broaching and discussing the issue or adjusting tasks and responsibilities. However, PDs also used workplace strategies requiring residents to adjust to the workplace without much intervention, which was often viewed as an implicit expectation. PDs' used both intentional and unintentional strategies to facilitate socialization in residents, which may imply that socialization can occur irrespective of the PD's strategy. PDs' strategies varied from an individual-centered to a workplace-centered approach to socialization. Further research is needed to gain a deeper understanding of residents' perceptions of PD's efforts to facilitate their socialization process during transitions.


Enhanced carbon capture, lipid and lutein production in Chlamydomonas reinhardtii under meso-thermophilic conditions using chaperone and CRISPRi system.
Microalgae are widely recognized as a promising bioresource for producing renewable fuels and chemicals. Microalgal biorefinery has tremendous potential for incorporation into circular bioeconomy, including sustainability, cascading use, and waste reduction. In this study, genetic engineering was used to enhance the growth, lipid and lutein productivity of Chlamydomonas reinhardtii including strains of CC400, PY9, pCHS, and PG. Notably, CRISPRi mediated on phosphoenolpyruvate carboxylase (PEPC1) gene to down-regulate the branch pathway from glycolysis to partitioning more carbon flux to lipid was explored under meso-thermophilic condition. The best chassis PGi, which has overexpressed chaperone GroELS and applied CRISPRi resulting in the highest biomass of 2.56 g/L and also boosted the lipids and lutein with 893 and 23.5 mg/L, respectively at 35°C. Finally, all strains with CRISPRi exhibited higher transcriptional levels of the crucial genes from photosynthesis, starch, lipid and lutein metabolism, thus reaching a CO2 assimilation of 1.087 g-CO2/g-DCW in mixotrophic condition.


Dimensions of neutrophil life and fate.
The earliest reported observations on neutrophils date from 1879 to 1880, when Paul Ehrlich utilized a set of coal tar dyes to interrogate differential staining properties of the granules from white blood cells. While acidic and basic dyes identified eosinophils and basophils respectively, neutrophils were revealed by neutral dyes. Unknowingly, his work staining blood films set the stage for one of the most exciting features of immune cells discovered in the last decade, myeloid heterogeneity. Since then, advances in live imaging and high-resolution sequencing technologies have revolutionized how we analyze and envision those cells that Ehrich fixed in blood smears. Neutrophil plasticity and heterotypic interactions with immune and non-immune compartments are increasingly appreciated as an important part of their biology. In this review, we highlight early and recent work that will help the reader to appreciate our current view of the neutrophil life cycle -from maturation to elimination-, and how neutrophils behave and dynamically modulate tissue immunity, both in steady-state and in disease.


Long-Term Retention Rate of Tofacitinib in Rheumatoid Arthritis: An Italian Multicenter Retrospective Cohort Study.
Background: Tofacitinib (TOFA) was the first Janus kinase inhibitor (JAKi) to be approved for the treatment of rheumatoid arthritis (RA). However, data on the retention rate of TOFA therapy are still far from definitive. Objective: The goal of this study is to add new real-world data on the TOFA retention rate in a cohort of RA patients followed for a long period of time. Methods: A multicenter retrospective study of RA subjects treated with TOFA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was conducted in 23 Italian tertiary rheumatology centers. The study considered a treatment period of up to 48 months for all included patients. The TOFA retention rate was assessed with the Kaplan-Meier method. Hazard ratios (HRs) for TOFA discontinuation were obtained using Cox regression analysis. Results: We enrolled a total of 213 patients. Data analysis revealed that the TOFA retention rate was 86.5% (95% CI: 81.8-91.5%) at month 12, 78.8% (95% CI: 78.8-85.2%) at month 24, 63.8% (95% CI: 55.1-73.8%) at month 36, and 59.9% (95% CI: 55.1-73.8%) at month 48 after starting treatment. None of the factors analyzed, including the number of previous treatments received, disease activity or duration, presence of rheumatoid factor and/or anti-citrullinated protein antibody, and presence of comorbidities, were predictive of the TOFA retention rate. Safety data were comparable to those reported in the registration studies. Conclusions: TOFA demonstrated a long retention rate in RA in a real-world setting. This result, together with the safety data obtained, underscores that TOFA is a viable alternative for patients who have failed treatment with csDMARD and/or biologic DMARDs (bDMARDs). Further large, long-term observational studies are urgently needed to confirm these results.


Pancreatic Cancer: From Genetic Mechanisms to Translational Challenges.
Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive malignancies in industrialized countries, is predicted to become the second leading cause of cancer deaths by 2040 [...].


Adenovirus-mediated over-expression of p21Waf-1 differentially affects the proliferation, telomerase activity, and expression of glial fibrillary acidic protein in human glioma cells.
Over-expression of p21Waf-1 was performed in 5 human glioma cell lines (U251MG, U87MG, T98G, NMC-G1, and KALS-1). p53 gene status was examined by PCR-SSCP and direct sequence method. The endogenous p21Waf-1 expression was evaluated by RT-PCR. Adenovirus-mediated over-expression of p21Waf-1 inhibited the proliferation of human glioma cells expressing wild-type p53 (U87MG, NMC-G1, KALS-1) irrespective of endogenous p21Waf-1 expression. Telomerase activity was also reduced in these cells. In U87MG, GFAP expression was stimulated by the transfection with p21Waf-1, but was reduced in NMC-G1. Over-expression of p21Waf-1 thus affects the cellular behavior of human glioma cells in a cell-type specific manner.


Double Filtration Plasmapheresis in the Treatment of Antineutrophil Cytoplasmic Autoantibody Associated Vasculitis With Severe Renal Failure: A Preliminary Study of 15 Patients.
Our aim was to investigate the clinical efficacy of double filtration plasmapheresis (DFPP) in the treatment of antineutrophil cytoplasmic autoantibody-(ANCA) associated vasculitis (AAV) with severe renal involvement. Fifteen AAV patients who had severe renal failure (median SCr 5.6(IQR 5.2-9.0) mg/dL) and needed initial renal replacement therapy (RRT) were treated with DFPP and immunosuppressive therapy. Two plasma volumes were processed during each DFPP session. The changes of serum ANCA and renal function were investigated. After the DFPP treatment for three to five sessions, serum MPO-ANCA level decreased from 250.0 ± 86.9 RU/mL to 70.5 ± 64.7RU/mL (P = 0.00), with a median reduction rate of 67.6%. Eleven patients (73.3%) no longer needed from RRT 3 months after DFPP treatment, while another four patients remained on dialysis. During the follow up for median 10 (IQR 6-24) months, SCr level decreased to normal in one patient, one patient progressed into ESRD. The 1 year renal survival rate was 62.9%. Five (33.3%) patients were complicated with pulmonary infection. DFPP combined with immunosuppressive therapy could increase the renal recovery rate through rapidly decreasing serum ANCA levels for AAV patients with severe renal failure, but its clinical efficacy and impact on long-term renal survival require further studies.


Transformation of morphine by resting cells and cell-free systems of Arthrobacter sp.
Morphine can be transformed into 14-hydroxymorphine and a related unidentified material by resting cells of an Arthrobacter species. Cell-free extracts containing the transforming enzyme(s) have been obtained. O2, Fe2+, and reduced nicotinamide adenine dinucleotide stimulate the transformation.


Removal of a fragment of catheter entrapped in a Bjork-Shiley aortic valvular prosthesis. Transarterial approach using a modified loop-snare technique.
Fracture of a left atrial catheter made of polyethylene and its subsequent embolization and entrapment in a Bjork-Shiley aortic valvular prosthesis is reported in a 62-year-old woman. The entrapped fragment of the catheter was retrieved by a transarterial approach using a homemade modified snare-loop device. Measures to prevent such a complication should be directed towards avoidance of force when removing such catheters. In addition, their length should be determined prior to insertion and again after removal, in order to detect their possible fracture and loss at once.


The association between exacerbation of chronic obstructive pulmonary disease and timing of paracetamol use: a cohort study in elderly Australians.
In elderly populations, paracetamol may be used regularly for conditions such as osteoarthritis. Paracetamol has been associated with respiratory disease through a proposed mechanism of glutathione depletion and oxidative stress. Given that chronic obstructive pulmonary disease (COPD) is frequently co-morbid with osteoarthritis, this study investigated whether the dose and timing of paracetamol exposure may induce COPD exacerbations. The study population was 3523 Australian Government Department of Veterans' Affairs full entitlement holders who had existing COPD on 1 January 2011, who were dispensed at least one prescription of paracetamol between 1 January 2011 and 30 September 2015, and had no paracetamol dispensed in the 6 months prior to 1 January 2011. The outcome was time to first hospitalisation for COPD exacerbation after initiation of paracetamol. A weighted cumulative exposure approach was used. The association between paracetamol exposure and COPD exacerbation was protective or harmful depending on the dose, duration, and recency of exposure. Compared to non-use, current use at the maximum dose of 4 g daily for 7 days was associated with a lower risk (HR = 0.78, 95% CI = 0.67-0.92) and a higher risk after 30 days (HR = 1.27, 95% CI = 1.06-1.52). Risk declined to baseline after 2 months. For past use, there was a short-term increase in risk on discontinuation depending of dose, duration and time since stopping. Patients and doctors should be aware of the possible risk of COPD exacerbation with higher dose paracetamol 1 to 6 weeks after initiation or discontinuation, but no increased risk after 2 months.


[Clinical case of the month. Adult onset Still's disease: a rare cause of acute febrile hepatitis].
A 63-year-old woman was hospitalized for the third time in one year for asthenia, fever and chills, jaundice, cytolysis and cholestasis. An adult onset Still's disease was diagnosed. Hepatic manifestations, diagnostic criteria and efficient therapy of AOSD will be reviewed.


The characteristics and clinical prognosis analysis of ASXL1 mutations in Chinese adult patients with primary cytogenetically normal acute myeloid leukemia by next-generation sequencing.
We analyzed 156 adult patients with primary cytogenetically normal AML for ASXL1 mutations and co-mutations using targeted next-generation sequencing with a panel of 34 genes associated with myeloid neoplasms. ASXL1mut were identified in 15(10%) patients, more frequent at an older age (≥60years) (p = .014), and had significant associations with co-mutations in TET2, KIT, CBL and SRSF2, whereas inversely correlated to NPM1 and CEBPA mutations. ASXL1mut clustered in ELN2017 intermediate-risk group (p = .028). In the context of intermediate-risk, ASXL1mut had a worse overall survival(OS) (p = .038) and Relapse-free survival(RFS) (p = .016) than ASXL1wt. When coexisting DNMT3A or TET2 mutations, ASXL1mut/DNMT3Amut genetype revealed a superior OS than ASXL1mut/DNMT3Awt (p = .027), and ASXL1mut/TET2mut confered a worse RFS than ASXL1mut/TET2wt (p = .031). No significant prognosis impact of VAF (a cutoff value of 30%) and clone ranks of ASXL1mut were observed in this corhort. Our study provided a new understanding of characteristics of ASXL1mut AML.


Lifestyle Habits Associated with Weight Regain After Intentional Loss in Primary Care Patients Participating in a Randomized Trial.
Though long-term weight loss maintenance is the treatment goal for obesity, weight regain is typical and few studies have evaluated lifestyle habits associated with weight regain. To identify dietary and physical activity habits associated with 6- and 24-month weight regain among participants in a weight loss maintenance clinical trial. Secondary analysis of randomized clinical trial data. Adult primary care patients with recent, intentional weight loss of at least 5%. Lifestyle habits included consumption of low-fat foods, fish, desserts, sugary beverages, fruits, and vegetables and eating at restaurants from the Connor Diet Habit Survey; moderate-vigorous physical activity by self-report; steps recorded by a pedometer; and sedentary behavior by self-report. The outcome variable was weight change at 6 and 24 months. Linear regression models estimated adjusted associations between changes in weight and changes in dietary and physical activity habits. Overall, participants (mean (SD): 53.4 (12.2) years old; 26% male; 88% white) maintained weight loss at 6 months (n = 178, mean (SD): - 0.02 (5.70)% change) but began to regain weight by 24 months (n = 157, mean (SD): 4.22 (9.15)% increase). When considered all together, more eating at restaurants, reduced fish consumption, and less physical activity were most consistently associated with weight regain in fully adjusted models at both 6 and 24 months of follow-up. In addition, more sedentary behavior was associated with weight regain at 6 months while reduced consumption of low-fat foods, and more desserts and sugary beverages were associated with weight regain at 24 months. Consuming less fish, fewer steps per day, and more frequent restaurant eating were most consistently associated with weight regain in primary care patients. Primary care providers may consider addressing specific lifestyle behaviors when counseling patients after successful weight loss. ClinicalTrials.gov Identifier: NCT01946191.


'Ancient' DNA in the resting egg bank of a microcrustacean can serve as a palaeolimnological database.
Recent work on the diapausing egg banks of zooplankton, such as Daphnia (Crustacea: Anomopoda), indicates that these eggs can remain viable for decades while, theoretically, DNA can remain intact for even longer periods (i.e. centuries or millennia). We isolated diapausing eggs of Daphnia from a 30 m long sediment core taken from a hypereutrophic, northern German lake (Belauer See), with some eggs found in dated core material as old as 4500 years. Using microsatellite markers, we analysed the genetic structure of the resting eggs dated as old as ca. 200 years, and found that, although levels of heterozygosity remained remarkably stable, significant genetic differentiation (Nei's D = 0.36; F(ST) = 0.15) between recent and 'ancient' resting eggs (including allele frequency shifts and private alleles) was detected. These shifts represent either species-level changes in this complex (i.e. species-specific characters of ephippia are not always robust), or intraspecific shifts in genetic variation, or a combination of both. This study demonstrates that the egg banks of aquatic zooplankton can serve as repositories of both genetic (intrapopulational) and ecological (interspecific) information. The use of molecular markers, such as microsatellites, on diapausing egg/seed banks may open new avenues of enquiry related to tracking the long-term genetic (and/or species) shifts that are associated with long-term environmental changes.


Dyslipidemias in clinical practice.
Most dyslipidemic conditions have been linked to an increased risk of cardiovascular disease. Over the past few years major advances have been made regarding the genetic and metabolic basis of dyslipidemias. Detailed characterization of the genetic basis of familial lipid disorders and knowledge concerning the effects of environmental factors on the expression of dyslipidemias have increased substantially, contributing to a better diagnosis in individual patients. In addition to these developments, therapeutic options to lower cholesterol levels in clinical practice have expanded even further in patients with familial hypercholesterolemia and in subjects with cardiovascular disease. Finally, promising upcoming therapeutic lipid lowering strategies will be reviewed. All these advances will be discussed in relation to current clinical practice with special focus on common lipid disorders including familial dyslipidemias.


On the development of the cerebellum of the trout, Salmo gairdneri. IV. Development of the pattern of connectivity.
Synaptogenesis has been studied in the corpus cerebelli of the trout Salmo gairdneri, Richardson, 1836. The first synapses are observed in hatchlings and occur between parallel fibres and the shafts of Purkinje dendrites. Subsequently the axosomatic synapses of Purkinje axon collaterals on the neurons of the ganglionic layer appear, and finally the synapses made by climbing fibres and mossy fibres, and by stellate cell axons develop. Young synapses in the cerebellum of the trout resemble the mature structures so closely that the criteria for the identification of the latter can also be applied to the former. The number of parallel fibre synapses and of Purkinje axon collateral synapses increases considerably during development. Eurydendroid cells, the axons of which leave the cerebellum, receive an abundance of Purkinje axon collaterals on their somata and main dendritic trunks. Mossy fibre synapses are numerous in the granular layer. Climbing fibre contacts and synapses of stellate cell axons, both with Purkinje cells, are found occasionally. The following pattern of connectivity is proposed. The main input-output system is formed by the mossy fibres, the granule cells, the Purkinje cells and the eurydendroid cells. Additional pathways are formed by (1) the mossy fibres, granule cells and eurydendroid cells, and (2) the climbing fibres, Purkinje cells and eurydendroid cells. The afferent-efferent systems, mentioned above, are influenced by a number of internuncial elements: (1) The Golgi cells receive their input from the parallel fibres and contact with their axon collaterals the dendrites of granule cells. (2) Axon collaterals of Purkinje cells are in synaptic relation with Golgi cells. (3) Axon collaterals of Purkinje cells impinge upon the somata and main dendrites of other Purkinje cells. (4) Stellate cells, which derive their input from the parallel fibres, synapse with dendrites and somata of Purkinje cells. The possible functional roles of all of these neuronal elements are discussed.


Drag force acting on a neuromast in the fish lateral line trunk canal. II. Analytical modelling of parameter dependencies.
In Part I of this two-part study, the coupled flows external and internal to the fish lateral line trunk canal were consecutively calculated by solving the Navier-Stokes (N-S) equations numerically in each domain. With the external flow known, the solution for the internal flow was obtained using a parallelepiped to simulate the neuromast cupula present between a pair of consecutive pores, allowing the calculation of the drag force acting on the neuromast cupula. While physically rigorous and accurate, the numerical approach is tedious and inefficient since it does not readily reveal the parameter dependencies of the drag force. In Part II of this work we present an analytically based physical-mathematical model for rapidly calculating the drag force acting on a neuromast cupula. The cupula is well approximated as an immobile sphere located inside a tube-shaped canal segment of circular cross section containing a constant property fluid in a steady-periodic oscillating state of motion. The analytical expression derived for the dimensionless drag force is of the form |F(N)/(|P(L) - P(R)|pi(D/2)(2) = f(d/D, L(t)/D, omega(*)(D), where |F(N)| is the amplitude of the drag force; |P(L)-P(R)| is the amplitude of the pressure difference driving the flow in the interpore tube segment; d/D is the ratio of sphere diameter to tube diameter; L(t)/D is the ratio of interpore tube segment length to tube diameter; and omega(*)(D) = omega(D/2)(2) /v is the oscillating flow kinetic Reynolds number (a dimensionless frequency). Present results show that the dimensionless drag force amplitude increases with decreasing L(t)/D and maximizes in the range 0.65< or =d/D< or =0.85, depending on the values of L(t)/D and omega(*)(D). It is also found that in the biologically relevant range of dimensionless frequencies 1< or = omega(*)(D) < or =20 and segment lengths 4< or =L(t)/D< or =16, the sphere tube (neuromast-canal) system acts as a low-pass filter for values d/D< or =0.75, approximately. For larger values of d/D the system is equally sensitive to all frequencies, but the drag force is significantly decreased. Comparisons with N-S calculations of the drag force show good agreement with the analytical model results. By revealing the parameter dependencies of the drag force, the model serves to guide biological understanding and the optimized design of corresponding bioinspired artificial sensors.


Immunohistochemical study on the liver in autopsy cases with disseminated intravascular coagulation (DIC) with reference to clinicopathological analysis.
Immunohistochemical and clinicopathological studies were performed in 27 autopsy cases with indisputable DIC, which had been selected from 1,800 autopsy cases of elderly people based on the following two criteria; 1. presence of fibrin thrombi in glomeruli, and 2. presence of fresh patchy necrotic foci in myocardium and/or fibrin thrombi in splenic sinuses. A high incidence of liver lesions (22/27) was revealed in autopsy cases with indisputable DIC. The liver lesions could be classified into four groups. Group-I (Central degeneration) was characterized by massive precipitation of fibrin irregularly around the central vein, causing parenchymal damage. Group-II (Central necrosis), showed coagulation necrosis in the central zone due to circulatory disturbance caused by either shock as a cause of DIC or abrupt cessation of blood flow into the lobules following fibrin thrombus formation in vessels of Glisson's sheath. Both group-I and -II showed a short clinical duration of DIC. Group-III (Sinusoidal thrombosis), showed the presence of fibrin thrombi in sinusoids with mild parenchymal damage and long clinical duration of DIC. Group-IV (No thrombosis), showed neither parenchymal damage nor fibrin thrombi in sinusoids, but a long clinical duration of DIC.


Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia.
The efficacy of the inhibitors of HMG CoA reductase shows considerable interindividual variation and intense research has focused in the recent years to identify the genetic loci and environmental factors responsible for this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG CoA reductase inhibitor, was conducted in 63 adolescents (47 treated versus 17 controls) with heterozygous FH. The patients were grouped according to known low-density lipoprotein (LDL) receptor gene mutation class. After 6 weeks of treatment with 20 mg/d of simvastatin, the mean reduction in plasma LDL-cholesterol in patients with a receptor-negative mutation (n=33) was 39% whereas, in the receptor-defective mutation group (n=14), it was 31% (P=0.01). Multiple regression analyses showed that there was a significant association between the apo E polymorphism and LDL-cholesterol response to simvastatin only among heterozygotes for a receptor-negative mutation. In subjects carrying a receptor-defective mutation, however, we observed that 51% of the variability in LDL-cholesterol response was explained by variations in the dosage of simvastatin expressed in mg/kg/day (P=0.0028). There was no significant association between LDL-cholesterol response and the dosage of simvastatin among heterozygotes for a receptor-negative mutation. The results of the present study have shown that the contribution of apo E polymorphism and the dosage of simvastatin to the LDL-cholesterol responsiveness is influenced by the nature of the LDL receptor gene mutation.


Morphological changes in the amniotic epithelium in relation to placental weight and fetal maturity.
A series of 52 placentas from the 36th week of gestation up to post-maturity was studied. The amniotic epithelium was studied with special regard to the morphological signs of maturation known to occur during this period. The results of the dating were compared with the presumed clinical age of the pregnancy and with the placental weight. A good correlation was found in 42.3% of the cases; the clinical age was overscored in 17.3% and underestimated in 40.4% of the subjects. No clear correlation was found between placental weight and histologic dating of the amniotic epithelium. The significance of the lipid laden amnios cells is discussed.


The role of fludrocortisone in a child with cerebral salt wasting.
Cerebral salt wasting (CSW) is a syndrome of hyponatremia due to excessive natriuresis described in patients with central nervous system insult. We present a 29-month-old black male with tuberculous meningitis who developed CSW with depressed mineralocorticoid activity. The patient required hypertonic saline and ionotropic support. Mineralocorticoid supplementation effectively treated CSW.


Publication and level of evidence trends in the American Journal of Sports Medicine from 1996 to 2011.
There has been recent increased emphasis on the publication quality and levels of evidence in orthopaedic sports medicine clinical research. The American Journal of Sports Medicine (AJSM) began publishing levels of evidence in the abstracts of clinical articles in 2005. To analyze trends in the characteristics and levels of evidence of articles published in AJSM. Meta-analysis. All articles in AJSM from 1996, 2001, 2006, and 2011 were analyzed. Articles were analyzed for type: clinical original research, basic science, current concepts review, and case report. Clinical articles were assigned a level of evidence from 1 to 4 and categorized as therapeutic, prognostic, diagnostic, or economic. Descriptive information was collected regarding funding, authorship, and study characteristics. Statistics were calculated using χ2 tests. A total of 795 articles were analyzed. From 1996 to 2011, there has been a significant increase in the percentage of level 1 and 2 articles (9.4% to 23.0%; P=.007) and a significant decrease in the percentage of level 3, 4, and 5 articles (55.1% to 45.1%; P=.037). There was a significant increase in the percentage of therapeutic studies (46.8% to 68.6%; P=.004) and a decrease in prognostic studies (36.7% to 22.2%; P=.03). Publishing authors were from 31 countries, notable for a significant increase in the percentage of studies published by authors from outside the United States from 1996 to 2011 (20.3% to 53.0%; P<.001). The percentage of articles reporting a financial conflict of interest significantly increased during this time (26.1% to 42.2%; P=.006). From 1996 to 2011, the proportion of level 1 and 2 evidence studies published in AJSM has increased significantly. There has been an increase in therapeutic studies and a decrease in prognostic studies. There has been an increase in the number of international studies published.


Prostate-specific antigen and other serum and urine markers in prostate cancer.
Prostate-specific antigen (PSA) is one of the most widely used tumor markers, and strongly correlates with the risk of harboring from prostate cancer (PCa). This risk is visible already several years in advance but PSA has severe limitations for PCa detection with its low specificity and low negative predictive value. There is an urgent need for new biomarkers especially to detect clinically significant and aggressive PCa. From all PSA-based markers, the FDA-approved Prostate Health Index (phi) shows improved specificity over percent free and total PSA. Other serum kallikreins or sarcosine in serum or urine show more diverging data. In urine, the FDA-approved prostate cancer gene 3 (PCA3) has also proven its utility in the detection and management of early PCa. However, some aspects on its correlation with aggressiveness and the low sensitivity at very high values have to be re-examined. The detection of a fusion of the androgen regulated TMPRSS2 gene with the ERG oncogene (from the ETS family), which acts as transcription factor gene, in tissue of ~50% of all PCa patients was one milestone in PCa research. When combining the urinary assays for TMPRSS2:ERG and PCA3, an improved accuracy for PCa detection is visible. PCA3 and phi as the best available PCa biomarkers show an equal performance in direct comparisons.


[ROLE OF microRNA IN SKIN DEVELOPMENT AND WOUND HEALING].
To review the role of microRNA (miRNA) in skin development and wound healing. The recent literature about miRNA in skin development and wound healing was reviewed and analyzed. miRNA extensively involved in the development of the skin, including epidermal cell proliferation, differentiation, aging and hair follicle development; miR-203 known as the "skin-specific miRNA" can directly inhibit the expression of p63 and promote the differentiation of the epidermis. Meanwhile, miRNA also involved in various stages of skin regeneration and wound healing. Abnormal expression of miRNA is closely related with abnormal wound healing. miRNA play an important role in maintaining normal skin physiology and skin regeneration. To explore their roles in the healing of skin wounds and their regulatory mechanism can provide a new target for the treatment, which has a potential value and broad prospects.


Cytotoxicity of Fusarium T-2 in cultured Madin-Darby bovine kidney (MDBK) and primary fetal bovine kidney (PFBK) cells.
Cytotoxicity of Fusarium T-2 toxin was evaluated in cultured Madin-Darby bovine kidney (MDBK) and primary fetal bovine kidney (PFBK) cells. The criteria for evaluation included number of adherent cells, phase contrast microscopy, and the scanning and transmission electron microscopy. The primary cells were more sensitive to the toxic effects of T-2 toxin than MDBK cultures.Cytotoxicity was observed when the cultures were exposed to the toxin for only 1 hour and then incubated with untreated media. Cell multiplication was decreased in both systems in 72 hour cultures. Scanning electron microscopy indicated loss of inter-cell contact and marked alterations in cell shape. Transmission electron microscopy indicated extensive proliferation of lysosomal bodies and proliferation of endoplasmic reticulum. The membrane system and mitochondria were not affected. Results indicated the kidney cells are highly sensitive to the toxic effects of T-2 toxin.


Facilitating the Work of Unmanned Aerial Vehicle Operators Using Artificial Intelligence: An Intelligent Filter for Command-and-Control Maps to Reduce Cognitive Workload.
Evaluating the ability of a Gibsonian-inspired artificial intelligence (AI) algorithm to reduce the cognitive workloads of military Unmanned Aerial Vehicle (UAV) operators. Military UAV operators use the command-and-control (C2) map for developing mission-relevant situation awareness (SA). Yet C2 maps are overloaded with information, mostly irrelevant to the mission, causing operators to neglect the map altogether. To reduce irrelevant information, an intelligent filtering algorithm was developed. Here we evaluate its effectiveness in reducing operators' cognitive workloads. Two-stage operational scenarios were conducted with professional ex-military UAV operators, using two filter protocols and a no-filter control. High-end real-time techniques were used to continuously assess workload from muscle behavior and machine learning models. Lower cognitive workload was found when applying the algorithm's protocols, especially when fatigue started to accumulate (Stage II). However, concerns about the quality of SA arose. The algorithm was positively evaluated for its ability to reduce operators' cognitive workloads. More evaluations of operators' SA are required. The algorithm demonstrates the possibility of integrating AI to improve human performance in complex systems, and can be applied to other domains where spatial-temporal information needs to be contextually filtered in real time.


Building care amid navigating liability risks: The possibility of policy-driven care in China's drug-control arena.
For Chinese policymakers, shouldering responsibility is often associated with high liability risk, thus resulting in low-level care for risky and stigmatized populations such as drug users. Therefore, it is crucial to explore ways to improve care access in such an uneasy policy environment. Based on long-term ethnographic fieldwork conducted in Yunnan province in southwestern China from 2013 to 2021, this paper traces the policy-making process of the Yunnan Province Methadone Oral Solution Take-Home Treatment Work Proposal. All stakeholders involved considered this policy attempt "impossible" at first, as the highly addictive methadone becomes an illegal drug once it is taken outside a clinical setting. By analyzing how a group of local government officials, together with medical practitioners and drug users, strive to legitimize and ultimately implement the policy, I argue that people's concern over liability risks strengthens the boundary between methadone as a "drug" and methadone as a "medicine," between methadone solution drinkers as "drug users" and as "patients," and between "inside the clinic" and "outside the clinic." By utilizing a culturalist approach to explore the possibility of care in such a context, this paper reveals that a "heqing heli hefa worthy-of-being-cared-for" discourse is crucial in that it acts as symbolic capital to dissolve the above boundaries embedded in the dominant political culture. Moreover, it is the key cultural logic of the "building" of care. The findings also illustrate how local policymakers negotiate and balance responsibility and liability to create a potential policy space for enabling care practices. Additionally, this study sheds light on the inclusion of care for the most stigmatized and marginalized populations, and has broad implications for policy-making in other contexts.


Clinical evaluation of sibutramine in obese type 2 diabetic patients refractory to dietary management.
An open, non-comparative study was carried out to assess the efficacy and toleration profile of sibutramine, a new antiobesity drug, in promoting weight loss in obese type 2 diabetes mellitus subject who failed to reduce weight after strict dietary control. Twenty seven patients completed the study. Sibutramine was started as a single morning dose of 10 mg and was subsequently increased to 15 mg daily if weight loss was not satisfactory. The total duration of the study was twelve weeks with followup at every four weeks. Effect of drug was monitored in terms of weight reduction, changes in body mass index, waist circumference, hip circumference, waist/hip ratio and other metabolic parameters. A fixed dietary prescription and concomitant therapy with drugs, if required and not likely to interfere with the trial therapy, was permitted but was not changed during the study period. At the end of 12 week, mean weight reduction in study subjects was 4.16 kg (p < 0.001), the corresponding BMI decreased by 1.6 (p < 0.0001) and hip circumference by 3.68 (p < 0.001). However, there was no significant change in fasting blood glucose and Hb(A1c) values. The study indicates sibutramine to be an effective and well tolerated agent leading to significant reduction in parameter of obesity in obese type 2 diabetic subjects.


Nuclear magnetic resonance study of the solution structure of alpha 1-purothionin. Sequential resonance assignment, secondary structure and low resolution tertiary structure.
The solution structure of the 45-residue plant protein, alpha 1-purothionin, is investigated by nuclear magnetic resonance (n.m.r.) spectroscopy. Using a combination of two-dimensional n.m.r. techniques to demonstrate through-bond and through-space (less than 5 A) connectivities, the 1H n.m.r. spectrum of alpha 1-purothionin is assigned in a sequential manner. The secondary structure elements are then delineated on the basis of a qualitative interpretation of short-range nuclear Overhauser effects (NOE) involving the NH, C alpha H and C beta H protons. There are two helices extending from residues 10 to 19 and 23 to 28, two short beta-strands from residues 3 to 5 and 31 to 34 which form a mini anti-parallel beta-sheet, and five turns. In addition, a number of long-range NOE connectivities are assigned and a low resolution tertiary structure is proposed.


Novel Chimeric Endolysin Conjugated Chitosan Nanocomplex as a Potential Inhibitor Against Gram-Positive and Gram-Negative Bacteria.
Resistance to antimicrobial agents has created potential problems in finding efficient treatments against bacteria. Thus, using new therapeutics, such as recombinant chimeric endolysin, would be more beneficial for eliminating resistant bacteria. The treatment ability of these therapeutics can be further improved if they are used with biocompatible nanoparticles like chitosan (CS). In this work, covalently conjugated chimeric endolysin to CS nanoparticles (C) and non-covalently entrapped endolysin in CS nanoparticles (NC) were effectively developed and, consequently, qualified and quantified using analytical devices, including FT-IR, dynamic light scattering, and TEM. Eighty to 150 nm and 100 nm to 200 nm in diameter were measured for CS-endolysin (NC) and CS-endolysin (C) using a TEM, respectively. The lytic activity, synergistic interaction, and biofilm reduction potency of nano-complexes were investigated on Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Pseudomonas aeruginosa (P. aeruginosa) strains. The outputs revealed a good lytic activity of nano-complexes after 24 h and 48 h of treatment, especially in P. aeruginosa (approximately 40% cell viability after 48 h of treatment with 8 ng/mL), and potential biofilm reduction performance was attained in E. coli strains (about 70% reduction after treatment with 8 ng/mL). The synergistic interaction between nano-complexes and vancomycin was exhibited in E. coli, P. aeruginosa, and S. aureus strains at 8 ng/mL concentrations, while the synergistic effects of pure endolysin and vancomycin were not remarkable in E. coli strains. These nano-complexes would be more beneficial in suppressing the bacteria with a high level of antibiotic resistance.


Recombinant human soluble thrombomodulin ameliorates cerebral ischemic injury through a high-mobility group box 1 inhibitory mechanism without hemorrhagic complications in mice.
It has been reported that recombinant human soluble thrombomodulin (rhsTM) has a high-mobility group box (HMGB)1 inhibitory effect. Some investigators reported that HMGB1 is associated with ischemic stroke. However, there have been no previous studies to determine whether rhsTM can ameliorate cerebral ischemic injury through its HMGB1 inhibitory mechanism in ischemic stroke. We investigated the effects of rhsTM on cerebral ischemic injury in a 4-h middle cerebral artery occlusion (MCAO) murine model. rhsTM (1 or 5mg/kg, i.v.) was administered immediately after 4-h MCAO. Infarct volume, motor coordination, plasma HMGB1 level, and hemorrhage volume were evaluated 24h after 4-h MCAO. The infarct volume (P<0.05) was reduced by rhsTM in mice subjected to 4-h MCAO in a dose-dependent manner. Moreover, rhsTM (5mg/kg) significantly improved motor coordination determined by the rotarod test (P<0.05), and significantly decreased plasma HMGB1 level compared with vehicle-treated controls (P<0.001). In addition, there was no difference in hemorrhage volume between vehicle-treated controls and the rhsTM treatment group. This represents the first report that rhsTM ameliorates cerebral ischemic injury through an HMGB1 inhibitory mechanism without hemorrhagic complications in mice. Taken together, these observations indicate a palliative effect of rhsTM and suggest new therapeutic possibilities for treatment of ischemic stroke via inhibition of HMGB1.


The effect of thioredoxin-1 in a rat model of traumatic brain injury depending on diurnal variation.
Traumatic brain injury (TBI) is a public health concern with limited treatment options because it causes a cascade of side effects that are the leading cause of hospital death. Thioredoxin is an enzyme with neuroprotective properties such as antioxidant, antiapoptotic, immune response modulator, and neurogenic, among others; it has been considered a therapeutic target for treating many disorders. The controlled cortical impact (CCI) model was used to assess the effect of recombinant human thioredoxin 1 (rhTrx1) (1 μg/2 μL, intracortical) on rats subjected to TBI at two different times of the light-dark cycle (01:00 and 13:00 h). We analyzed the food intake, body weight loss, motor coordination, pain perception, and histology in specific hippocampus (CA1, CA2, CA3, and Dental Gyrus) and striatum (caudate-putamen) areas. Body weight loss, reduced food intake, spontaneous pain, motor impairment, and neuronal damage in specific hippocampus and striatum regions are more evident in rats subjected to TBI in the light phase than in the dark phase of the cycle and in groups that did not receive rhTrx1 or minocycline (as positive control). Three days after TBI, there is a recovery in body weight, food intake, motor impairment, and pain, which is more pronounced in the rats subjected to TBI at the dark phase of the cycle and those that received rhTrx1 or minocycline. Knowing the time of day a TBI occurs in connection to the neuroprotective mechanisms of the immune response in diurnal variation and the usage of the Trx1 protein might have a beneficial therapeutic impact in promoting quick recovery after a TBI.


Automated determination of total polyphenols in apple juice.
An automated method of total polyphenols analysis in apple juice using the Folin-Ciocalteu reagent is presented. Chlorogenic acid was selected as the standard since a similar kinetic behaviour, standard-sample, was observed. A straightforward method with good reproducibility (CV < 1%), sampling frequency (48 h-1) and correlation with the traditional batch method (r = 0.9924) is proposed.


Pre-procedural platelet transfusion thresholds in hospitalised children - Protocol for a scoping review.
Thrombocytopenia is a common condition in hospitalised critically ill children and most platelet transfusions are given as prophylaxis to non-bleeding children prior to invasive procedures such as central venous catheterisation and lumbar puncture. Platelet transfusion may reduce bleeding complications but have also been associated with potential adverse effects and variation in clinical practice exist. To direct future research, we aim to assess the current evidence regarding prophylactic platelet transfusion prior to procedures in hospitalised thrombocytopenic children. We will conduct a scoping review of all study designs in accordance with the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) statement. We will include studies on hospitalised children undergoing invasive procedures where the prevalence of thrombocytopenia and the predefined outcome measures, including bleeding, transfusion-related adverse events and use of blood products and life support are reported. We will provide descriptive analyses of the included studies/trials and the quality of evidence will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The outlined scoping review will provide an overview on the benefits and harms of prophylactic platelet transfusion prior to invasive procedures in thrombocytopenic hospitalised children.


Mutation of the zinc-binding metalloprotease motif affects Bacteroides fragilis toxin activity but does not affect propeptide processing.
To evaluate the role of the zinc-binding metalloprotease in Bacteroides fragilis toxin (BFT) processing and activity, the zinc-binding consensus sequences (H348, E349, H352, G355, H358, and M366) were mutated by site-directed-mutagenesis. Our results indicated that single point mutations in the zinc-binding metalloprotease motif do not affect BFT processing but do reduce or eliminate BFT biologic activity in vitro.


Measurement error due to self-absorption in calibration-free laser-induced breakdown spectroscopy.
Self-absorption of spectral lines is known to lower the performance of analytical measurements via calibration-free laser-induced breakdown spectroscopy. However, the error growth due to this effect is not clearly assessed. Here we propose a method to quantify the measurement error due to self-absorption based on the calculation of the spectral radiance of a plasma in local thermodynamic equilibrium. Validated through spectroscopic measurements for a binary alloy thin film of compositional gradient, the method evidences that measurement performance lowering due to self-absorption depends on the spectral shape of the analytical transition and on the intensity measurement method. Thus, line-integrated intensity measurements of Stark broadened lines enable accurate analysis, even at large optical thickness, if line width and plasma size are precisely known. The error growth due to self-absorption is significantly larger for line shapes dominated by Doppler broadening and for line-center intensity measurements. The findings present a significant advance in compositional measurements via calibration-free laser-induced breakdown spectroscopy, as they enable straightforward selection of most appropriate analytical lines.


Corynoline protects ang II-induced hypertensive heart failure by increasing PPARα and Inhibiting NF-κB pathway.
Heart failure is a fairly common outcome of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertensive heart failure via inducing cardiac inflammation. Drugs that disrupt Ang II-induced cardiac inflammation may have clinical utility in the treatment of hypertensive heart failure. A naturally occurring compound, corynoline, exhibit anti-inflammatory activities in other systems. C57BL/6 mice were injected with Ang II via a micro-osmotic pump for four weeks to develop hypertensive heart failure. The mice were treated with corynoline by gavage for two weeks. RNA-sequencing analysis was performed to explore the potential mechanism of corynoline. We found that corynoline could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. RNA-sequencing analysis indicates that the PPARα pathway is involved Ang II-induced cardiac fibrosis and cardiac remodeling. Corynoline reversed Ang II-induced PPARα inhibition both in vitro and in vivo. We further found that corynoline increases the interaction between PPARα and P65 to inhibit the NF-κB pro-inflammatory pathway in H9c2 cells. Our studies show that corynoline relieves Ang II-induced hypertensive heart failure by increasing the interaction between PPARα and P65 to inhibit the NF-κB pathway.


Effect of the In Situ Screw Implantation Region and Angle on the Stability of Lateral Lumbar Interbody Fusion: A Finite Element Study.
To investigate the effect of the in situ screw implantation region and angle on the stability of lateral lumbar interbody fusion (LLIF) from a biomechanical perspective. A validated L2-4 finite element (FE) model was modified for simulation. The L3-4 fused segment undergoing LLIF surgery was modeled. The area between the superior and inferior edges and the anterior and posterior edges of the vertebral body (VB) is divided into four zones by three parallel lines in coronal and horizontal planes. In situ screw implantation methods with different angles based on the three parallel lines in coronal plane were applied in Models A, B, and C (A: parallel to inferior line; B: from inferior line to midline; C: from inferior line to superior line). In addition, four implantation methods with different regions based on the three parallel lines in horizontal plane were simulated as types 1-2, 1-3, 2-2, and 2-3 (1-2: from anterior line to midline; 1-3: from anterior line to posterior line; 2-2: parallel to midline; 2-3: from midline to posterior line). L3-4 ROM, interbody cage stress, screw-bone interface stress, and L4 superior endplate stress were tracked and calculated for comparisons among these models. The L3-4 ROM of Models A, B, and C decreased with the extent ranging from 47.9% (flexion-extension) to 62.4% (lateral bending) with no significant differences under any loading condition. Types 2-2 and 2-3 had 45% restriction, while types 1-2 and 1-3 had 51% restriction in ROM under flexion-extension conditions. Under lateral bending, types 2-2 and 2-3 had 70.6% restriction, while types 1-2 and 1-3 had 61.2% restriction in ROM. Under axial rotation, types 2-2 and 2-3 had 65.2% restriction, while types 1-2 and 1-3 had 59.3% restriction in ROM. The stress of the cage in types 2-2 and 2-3 was approximately 20% lower than that in types 1-2 and 1-3 under all loading conditions in all models. The peak stresses at the screw-bone interface in types 2-2 and 2-3 were much lower (approximately 35%) than those in types 1-2 and 1-3 under lateral bending, while no significant differences were observed under flexion-extension and axial rotation. The peak stress on the L4 superior endplate was approximately 30 MPa and was not significantly different in all models under any loading condition. Different regions of entry-exit screws induced multiple screw trajectories and influenced the stability and mechanical responses. However, different implantation angles did not. Considering the difficulty of implantation, the ipsilateral-contralateral trajectory in the lateral middle region of the VB can be optimal for in situ screw implantation in LLIF surgery.


Phenomenon of heparin-induced thrombocytopenia associated with skin necrosis.
Heparin, an anticoagulant medication used therapeutically and prophylactically, may have thrombotic complications that are paradoxical in nature. There is growing awareness, as evidenced by recent reports, that heparin has a small but definite incidence of causing thrombocytopenia (6 to 8 days after initiation of therapy) associated with platelet aggregation causing intravascular thrombosis, with potentially devastating morbidity and mortality. We review this phenomenon and bring attention to a recent case that resulted in a 10 X 19 cm full-thickness skin necrosis of the thigh. This case clearly implicates heparin as the "aggregating factor" of platelets, resulting in intravascular thrombosis. No risk factors have been identified that place a patient at increased risk for this phenomenon. This disorder occurs in patients who have received all forms of heparin. Therefore all patients receiving heparin are considered at risk. Early recognition of thrombocytopenia in patients receiving heparin will alert the physician to this disorder.


Views of what's wrong: diagnosis and patients' concepts of illness.
A group of women were interviewed about their construction of their illness experiences before they saw a physician and subsequently over a period of several months following consultation. It was found that the physician's input was one of many components of their post-consultation understanding of their illnesses. The women built up their understandings in an interactive process, drawing significantly on their prior histories, ongoing experiences and social worlds. They continually tried out, adjusted and reworked the construction of their illnesses to adapt them to the exigencies of everyday life. We conclude that illness explanations are dynamic entities whose adequacy is determined by their usefulness within the extra-medical social environment.


Time course of lipid peroxidation during incomplete ischaemia followed by reperfusion in rat brain.
The time course of lipid peroxidation was studied in the rat brain cortex after ischaemia and reperfusion. The ischaemia was induced by 4-hour occlusion of both common carotid arteries and was followed by reperfusion of different duration (10, 30 or 60 min). The extent of lipid peroxidation was determined by measurement of conjugated dienes (CD) and TBA reactive products. Maximal values of CD and TBA reactive products were found after 10- and 30-minute reperfusion. This indicated the most suitable time interval for studying the effect of antioxidants and oxygen radical scavengers in this model of brain ischaemia.


Correlation between pathogenesis of dampness syndrome and interleukin-2, interleukin-8 in rats.
To explore the pathogenesis of dampness syndrome by detecting the changes of interleukin-2 (IL-2) and interleukin-8 (IL-8) levels. Female Sprague Dawley rats were divided randomly into five groups according to the random number table: a normal group (Group I), an external dampness group (Group II), an internal dampness group (Group III), and an external and internal dampness group (Group IV). Twenty days after the model made, IL-2 and IL-8 levels were detected by radioimmunoassay method. The IL-2 and IL-8 levels among groups were significant (F = 3.102, P < 0.05; F = 2.657, P < 0.05, respectively). The level of IL-2 in Group II and Group III were higher than that in Group I (P < 0.05, P < 0.01, respectively), especially higher in the Group III compared with Group II (P < 0.05). The level of IL-8 in Group III were higher than those in Group I, Group II and Group IV (P < 0.05, P < 0.01, P < 0.05, respectively). In the Group III, the 24-hour water and body weight were higher than that in the Group IV (all P < 0.05), and spontaneous movement frequency was higher than those in Group II and Group IV (P < 0.05). Immune activation and inflammatory reaction might be easily caused by external dampness other than internal dampness.


The nature of conditioned anti-analgesia: spinal cord opiate and anti-opiate neurochemistry.
The central nervous system contains circuitry that inhibits pain sensitivity (analgesia), as well as circuitry that opposes pain inhibition (anti-analgesia). Activation of analgesia systems and anti-analgesia systems can each be brought under environmental control using classical conditioning procedures. Analgesia can be produced by cues present before and during aversive events such as electric shock, while active inhibition of analgesia comes to be produced by cues never present immediately before or during shock and therefore signal safety. We have recently reported that these analgesia and anti-analgesia systems interact at the level of the spinal cord. A series of 3 experiments were performed to examine how such interactions occur. First, potential opioid mediation of conditioned analgesia was investigated using systemic and intrathecal (i.t.) delivery of opiate antagonists. Conditioned analgesia was found to be mediated by activation of spinal mu and delta opiate receptors. Second, analgesia produced by each of these receptor subtypes was challenged by environmental signals for safety. Analgesias produced by mu and delta opiate agonists were each abolished by safety signals. Third, antagonists/antisera directed against several putative anti-opiate neurotransmitters were tested i.t. to identify which mediate conditioned anti-analgesia at the level of the spinal cord. A cholecystokinin antagonist abolished conditioned anti-analgesia. In contrast, neuropeptide FF antiserum and a kappa opiate antagonist were without effect.


Why there might not be an evolutionary explanation for psychological altruism.
The existence of psychological altruism is hotly debated in the psychological and philosophical literature. In this paper I argue that even if psychological altruism does exist in some (or all) human groups, there may be no purely evolutionary explanation for existence of psychological altruism.


Synergistic chemopreventive effects of curcumin and berberine on human breast cancer cells through induction of apoptosis and autophagic cell death.
Curcumin (CUR) and berberine (BBR) are renowned natural compounds that exhibit potent anticancer activities through distinct molecular mechanisms. However, the anticancer capacity of either CUR or BBR is limited. This prompted us to investigate the chemopreventive potential of co-treatment of CUR and BBR against breast cancers. The results showed that CUR and BBR in combination synergistically inhibited the growth of both MCF-7 and MDA-MB-231 breast cancer cells than the compounds used alone. Further study confirmed that synergistic anti-breast cancer activities of co-treatment of these two compounds was through inducing more apoptosis and autophagic cell death (ACD). The co-treatment-induced apoptosis was caspase-dependent and through activating ERK pathways. Our data also demonstrated that co-treatment of CUR and BBR strongly up-regulated phosphorylation of JNK and Beclin1, and decreased phosphorylated Bcl-2. Inhibition of JNK by SP600125 markedly decreased LC3-II and Beclin1, restored phosphorylated Bcl-2, and reduced the cytotoxicity induced by the two compounds in combination. These results strongly suggested that JNK/Bcl-2/Beclin1 pathway played a key role in the induction of ACD in breast cancer cells by co-treatment of CUR and BBR. This study provides an insight into the potential application of curcumin and berberine in combination for the chemoprevention and treatment of breast cancers.


Age, sex and source of hamster affect experimental cholesterol cholelithiasis.
In the present study, we examined the effect of the following factors on a hamster model of cholesterol cholelithiasis: (i) the source of the golden Syrian hamsters (Sasco, Omaha, NE or Charles River, Wilmington, MA), (ii) the sex of the experimental animals and (iii) their age (4 wk vs. 8 wk of age). All hamsters were fed a semipurified diet which contained cholesterol (0.3%) and palmitic acid (1.2%). No cholesterol gallstones formed in any of the female hamsters regardless of age or source. The 4-week-old male hamsters from Sasco had the greatest incidence of gallstones (93%). The 8-week-old male hamsters tended to have a lower incidence of cholesterol gallstones than the younger ones, regardless of the commercial supplier (67 vs. 93% for Sasco and 27 vs. 40% for Charles River). Female hamsters had higher liver and serum cholesterol levels than the male hamsters; Charles River hamsters had lower serum cholesterol concentrations than the Sasco animals. Total biliary lipid concentrations were highest in Sasco male hamsters, but biliary cholesterol (mol%) was lower in the males than in the females (4.2-4.5% vs. 6.1-7.1%) regardless of age. The cholesterol saturation indices were higher in the Sasco females than the corresponding males; these values were lower in the Sasco hamsters than the Charles River animals, regardless of age or sex. The male Sasco hamsters had a higher total biliary bile acid concentration (98.9 mg/mL) than the Sasco females (58.9 mg/mL) and the Charles River animals (24.6 mg/mL for males and 38.2 mg/mL for females). The percentage of chenodeoxycholic acid in bile was significantly lower, and the percentage of cholic acid was higher in all females as compared to males.(ABSTRACT TRUNCATED AT 250 WORDS)


[Frequency and Maternals risk factors of fœtal intra uterin death at Kamina, Democratic Republic of Congo].
Fetal intrauterine death constitutes a frequent problem in obstetric practice. The objectives of this study were to determine the frequency and to identify risk factors of fetal death at Reference General Hospital of Kamina. The study was done in two times. First, a cross-sectional descriptive study of 379 deliveries which allowed to determine the frequency of fetal death. Then, the determination of risk factors was made using a case-control study in which the characteristics of 53 fetal deaths were compared to 106 controls constituted of live births. The fetal intrauterine death's frequency at Reference General Hospital of Kamina was at 13,98%. After adjustment, maternal age over 35 years (OR = 6,23; IC= (1,30-29,80)), antecedent of fetal intrauterine death (OR = 3,13; IC= (1,06-9,27)) and diseases during pregnancy (OR = 31,6, IC= [7,66-130,71]) have been identified as factors significantly associated with increased occurrence fetal death. The high maternal education (OR = 0,11; IC= (0,03-0,42)) and Kamina's residency (OR = 0,23; IC= (0,08-0,62)) decreased this risk. The frequency of fetal death was 13,9%. The advanced maternal age, the history of fetal death and disease during pregnancy was associated with fetal intra uterin death but the high maternal instruction and the Kamina residence reduced the risk. The monitoring of at-risk pregnant, screening and the treatment of diseases during pregnancy are necessary in view of reducing prevalence of fetal death in our midst.


The dose response of theophylline in the treatment of apnea of prematurity.
In an effort to establish the minimum effective dose of theophylline in the treatment of idiopathic apnea of prematurity, a prospective trial of 22 infants with at least 0.33 episodes of apnea per hour were studied. Apnea was diagnosed exclusively by continuous recording of heart rate, respiratory impedance, end-tidal CO2, and either or both transcutaneous oxygen and pulse oximetry. Four discrete serum concentrations of theophylline (23 mumol/l or 4.2 mg/L, 47 mumol/L or 8.5 mg/L, 70 mumol/L or 12.7 mg/L, and 84 mumol/L or 15.3 mg/L) were attained by using repeated loading doses of 4 mg/kg and increasing the maintenance dose from 1 to 1.5 mg/kg to 2 to 2.5 mg/kg, given every 8 hours. Before treatment and 24 hours after each loading dose, airway occlusions and measures of tidal volume, minute ventilation, and respiratory timing were performed. The effectiveness of therapy was assessed by either a continuous computer data-acquisition system or paper recording for the duration of the study. Of the 22 infants, three responded at level 1, three at level 2, and 10 at level 3. One of the four infants loaded to the fourth level had a sustained response for a total cumulative response of 77%. The five remaining infants required additional treatment with doxapram or continuous positive airway pressure. There was a significant increase in inspiratory pressure 100 msec after airway occlusion, maximum inspiratory pressure during airway occlusion, tidal volume, ratio of tidal volume to inspiratory time (mean inspiratory flow), and minute ventilation from the pretreatment measurements to those at the maximum dose of theophylline. The apnea response did not correlate with these improvements in ventilation measures.


Microbial communities and flavor formation in the fermentation of Chinese strong-flavor Baijiu produced from old and new Zaopei.
Differences between the old and young pit mud in a pit cellar enlarged differences in Zaopei (ZP) fermentation to varying degrees, ultimately affecting the aromatic quality of the Baijiu that is produced. The whole fermentation process could be divided into two phases, namely phase I (0_15 days) and phase II (25_40 days) based on the dynamics of the diversity of microbial communities. Starch and reducing sugar in phase I were used more rapidly by microflora, leading to a higher ethanol production in ZP within an old pit mud (OZP) and a higher acidity in ZP within a new pit mud (NZP), and resulting in different microbial succession patterns therein. Lactobacillus became the dominant bacteria more rapidly in OZP but maintained its abundance in NZP. Monascus and Trichosporon were the unique dominant functional fungi observed in the phase II of OZP. Two bacterial and six fungal genera were identified as core functional microorganisms linked to the variations in volatile metabolites during the fermentation process, ultimately resulting in a higher ester content in OZP and improved liquor quality. This study demonstrated the effect of new and old pit muds on ZP fermentation, and its findings can guide the future artificial regulation of NZP.


Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial.
CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.


Hyaluronic acid-based fillers: theory and practice.
This article is aimed at providing information about the cross-linked hyaluronic acid marketing at present. It is also aimed at helping the lectors improve their knowledge about injection modalities and patient manage.


A spin-label study of the effect of gamma radiation on erythrocyte membrane. Influence of lipid peroxidation on membrane structure.
Gamma-irradiation of bovine erythrocyte membranes (0.1-4 Mrad) resulted in a decrease in the degree of order of membrane lipids, as measured by spin-labelled fatty acid esters, at the depth of C12 but not at the depth of C5. Dose dependence of this phenomenon corresponded to dose dependence of malondialdehyde formation in the membranes. On this basis a mechanism for the effect of lipid peroxidation on the membrance structure is proposed. Membrane proteins underwent radiation-induced conformational transitions revealed by maleimide spin label which could be also connected with lipid peroxidation.


Gestational diabetes mellitus (GDM) is associated with a number of complications, including developmental disorders in the child but the specific association is unclear. The purpose of this review is to summarize the latest knowledge about the association between GDM and one of the developmental disorders, namely autism spectrum disorder (ASF) in the child. Large cohort studies found that GDM increases the risk of ASF in the child, and that the risk increases the earlier the mother is diagnosed with GDM.


Management of scaphoid nonunion.
The primary risk factor for nonunion of the scaphoid is displacement/instability, but delayed or missed diagnosis, inadequate treatment, fracture location, and blood supply are also risk factors. Untreated nonunion leads to degenerative wrist arthritis-the so-called scaphoid nonunion advanced collapse wrist. However, the correlation of symptoms and disease is poor; the true "natural history" is debatable because we evaluate only symptomatic patients presenting for treatment. It is not clear that surgery can change the natural history, even if union is attained. The diagnosis of nonunion is made on radiographs, but computed tomography or magnetic resonance imaging scans can be useful to assess deformity and blood supply. Treatment options vary from percutaneous fixation to open reduction and internal fixation with vascularized or nonvascularized bone grafting to salvage procedures involving excision and/or arthrodesis of carpals.


Steady state kinetics of 4-hydroxyphenylpyruvate dioxygenase from human liver (III).
Kinetic experiments have been made with an apparently homogenous preparation of human liver 4-hydroxyphenylpyruvate dioxygenase Form 3 (4-hydroxyphenylpyruvate: oxygen oxidoreductase (hydroxylating, decarboxylating), EC 220.127.116.11) at 37 degrees in 0.2 M Tris/HCL, pH 7.5, by measuring the evolved carbon dioxide from the 1-14C-labeled substrate or the formation of homogentisate from the U-14C-labeled substrate. The effect of variations in the concentrations of substrates, products, and metal chelators on the velocity of the forward reaction was studied. The results agree with an Ordered Bi Bi kinetic mechanism (Cleland, W. W. (1963) Biochim. Biophys. Acta 67, 104--137), where 4-hydroxyphenylpyruvate is added prior to oxygen and CO2 released before homogentisate. A Theorell-Chance mechanism has not been excluded.


Changes in detection of retinopathy in type 2 diabetes in the first 4 years of a population-based diabetic eye screening program: retrospective cohort study.
Annual diabetic eye screening has been implemented in England since 2008. This study aimed to estimate changes in the detection of retinopathy in the first 4 years of the program. Participants included 32,340 patients with type 2 diabetes resident in three London boroughs with one or more screening records between 2008 and 2011. Data for 87,570 digital images from 2008 to 2011 were analyzed. Frequency of sight-threatening diabetic retinopathy (STDR) was estimated by year of screen for first screens and for subsequent screens according to retinopathy status at first screen. Among 16,621 first-ever screens, the frequency of STDR was 7.1% in 2008, declining to 6.4% in 2011 (P = 0.087). The proportion with a duration of diabetes of <1 year at first screen increased from 18.7% in 2008 to 48.6% in 2011. Second or later screens were received by 26,308 participants. In participants with mild nonproliferative retinopathy at first screen, the proportion with STDR at second or later screen declined from 21.6% in 2008 to 8.4% in 2011 (annual change -2.2% [95% CI -3.3 to -1.0], P < 0.001). In participants with no retinopathy at first screen, STDR declined from 9.2% in 2008 to 3.2% in 2011 (annual change -1.8% [-2.0 to -1.7], P < 0.001). Declining trends were similar in sociodemographic subgroups. After the inception of population-based diabetic eye screening, patients at lower risk of STDR contribute an increasing proportion to the eligible population, and the proportion detected with STDR at second or subsequent screening rounds declines rapidly.


Mineral nutrition and water relations of hemiparasitic mistletoes: a question of partitioning. Experiments with Loranthus europaeus on Quercus petraea and Quercus robur.
Hemiparasitic mistletoes thrive on xylem sap diverted from the host through direct xylem connections. There is no phloem link and no exchange of photosynthates. Mineral nutrition is therefore closely coupled with water consumption.Mineral nutrient partitioning between the mistletoe Loranthus europaeus and its host Quercus petraea was studied by monitoring nutrient incorporation into 3-year-old twigs of both species over 1 year. The mistletoes accumulated large amounts of potassium in comparison to other elements. It is hypothesized that this phenomenon is a consequence of the absence of a phloem connection between host and hemiparasite. In the host potassium is cycled between leaves and sites of photosynthate utilization in the wake of photosynthate transport in the phloem. In the hemiparasite it cannot cycle beyond the host-parasite interface and potassium imported with the xylem sap is thus trapped in the hemiparasite phytomass.The control of water partitioning in a host-hemiparasite system is another important aspect. As host and hemiparasite receive water from a common supply the otherwise independent stomatal control systems of both species become linked when transpiration demand exceeds supply. By measuring diurnal curves of transpiration and leaf water status in both species, by use of a special cuff-freezing technique to study stomatal response when water supply is cut off, and by measurements of leaf water capacitance with a pressure-volume curve technique, the fundamental data for a descriptive model of water partitioning in a L. europaeus - Q. robur system were collected. This model may be used to gain deeper insight into stomatal control of plant water status.


Substance P in the chick retina: effects of light and dark.
Monoclonal antibodies against substance P were used to study the distribution of the peptide in the retinae of chicks that had been kept in either total darkness or brightly lit conditions. In retinae from light-adapted chicks, substance P was found to be in normal sized amacrine cells and giant cells in the inner nuclear layer, in fibres in sublaminae 1,3-5 in the inner plexiform layer, in cells in the ganglion cell layer which may have been mostly displaced amacrine cells and in a few fibres in the optic nerve fibre layer. There was no apparent concentration of immunoreactive cell bodies in any part of the retina. After dark-adaption of the birds, the immunoreactivity in the retinae was much reduced; there were fewer visible cells in all parts of the retina and there was no reaction in the inner plexiform layer. When birds were taken from the dark and kept in the light for different periods, there was a gradual increase in the number of cells and in the overall immunoreaction. Substance P is thus like several other putative retinal neurotransmitters in that its concentration in the retina is regulated by light/dark. These experiments do not indicate how the changes occur, but they underline the need for a strict control of lighting conditions in experiments with these relatively slowly metabolized neurotransmitters.


Statistically Defined Parkinson's Disease Executive and Memory Cognitive Phenotypes: Demographic, Behavioral, and Structural Neuroimaging Comparisons.
Some individuals with Parkinson's disease (PD) experience working memory and inhibitory difficulties, others learning and memory difficulties, while some only minimal to no cognitive deficits for many years. To statistically derive PD executive and memory phenotypes, and compare PD phenotypes on disease and demographic variables, vascular risk factors, and specific neuroimaging variables with known associations to executive and memory function relative to non-PD peers. Non-demented individuals with PD (n = 116) and non-PD peers (n = 62) were recruited to complete neuropsychology measures, blood draw, and structural magnetic resonance imaging. Tests representing the cognitive domains of interest (4 executive function, 3 memory) were included in a k-means cluster analysis comprised of the PD participants. Resulting clusters were compared demographic and disease-related variables, vascular risk markers, gray/white regions of interest, and white matter connectivity between known regions involved in executive and memory functions (dorsolateral prefrontal cortices to caudate nuclei; entorhinal cortices to hippocampi). Clusters showed: 1) PD Executive, n = 25; 2) PD Memory, n = 35; 3) PD Cognitively Well; n = 56. Even after disease variable corrections, PD Executive had less subcortical gray matter, white matter, and fewer bilateral dorsolateral-prefrontal cortex to caudate nucleus connections; PD Memory showed bilaterally reduced entorhinal-hippocampal connections. PD Cognitively Well showed only reduced putamen volume and right entorhinal cortex to hippocampi connections relative to non-PD peers. Groups did not statistically differ on cortical integrity measures or cerebrovascular disease markers. PD cognitive phenotypes showed different structural gray and white matter patterns. We discuss data relative to phenotype demographics, cognitive patterns, and structural brain profiles.


Differential induction of human monocyte transforming growth factor beta 1 production and its regulation by interleukin 4.
We have previously shown that trauma patients' monocytes which are in vivo activated by multiple injury-induced mediators have elevated transforming growth factor-beta (TGF beta) bioactivity. Interleukin-4 (IL-4), a Th2 and B lymphocyte stimulatory factor, has been shown to inhibit monocyte production of a number of mediators both after lipopolysaccharide stimulation and after trauma-induced stimulation. However, IL-4 inhibitory effects appears to vary, depending on the mixture of inducing stimuli. Here we describe the in vitro IL-4 inhibition of human monocyte TGF beta bioactivity using several stimulation induction protocols: muramyl dipeptide stimulation alone, or after Fc gamma RI (CD64) cross-linking induction, interferon-gamma (IFN gamma) priming, or trauma-generated in vivo mediator induction. IL-4 suppressed both muramyl dipeptide-induced TGF beta bioactivity and TGF beta mRNA in a dose-dependent fashion and was most effective when IL-4 was administered at initiation of normal monocyte stimulation. Muramyl dipeptide (MDP)-induced increases in trauma patients' monocyte TGF beta bioactivity were also inhibited by high doses of IL-4 (25 ng/ml). Fc gamma RI cross-linking increased MDP-induced normal monocyte TGF beta bioactivity, but this increase could be consistently inhibited only by very high IL-4 concentrations (50 ng/ml). IL-4 did not consistently downregulate MDP-induced TGF beta bioactivity in IFN gamma-primed monocytes. IL-4 can suppress monocyte TGF beta production, as well as other monocyte mediators, but its efficiency depends on the stimuli combination present in the microenvironment.


A comparative study on various immunological parameters influencing embryo survivability in crossbred dairy cows.
Since long embryonic mortality has remained an area of concern affecting the reproduction, production, and profitability of dairy cows. We investigated the possible interaction between interleukins, hormones, and neutrophil associated CD markers during the implantation window in Karan Fries (KF) cows naturally coming to heat. Blood collection was done on days 0 i.e. day of Artificial Insemination (AI), 10, 18, 21, 30 and on day 40 post-AI. Total leucocyte count (TLC) and neutrophil to lymphocyte (N:L) ratio were recorded. Blood neutrophils were isolated and their number, phagocytic activity (PA), myeloperoxidase (MPO) concentration and relative mRNA expression of cell adhesion molecules (CD-11b, CD-31, CD-44, CD-62L) as well as progesterone-inducing-blocking-factor (PIBF) and glucocorticoid receptor alpha (GRα) were examined. Plasma progesterone, cortisol, IL-2, IL-8, IL-6, and IL-10 were also measured. Pregnancy was confirmed by non-return to heat, ultrasonography and per rectal examination along with progesterone assay. Cows were further divided into pregnant (P), early embryonic mortality (EEM) and late embryonic mortality (LEM) groups. Embryonic losses cows showed lower plasma concentration of IL-10 (<100 pg/ml) and a higher concentration of IL-2 (>500 pg/ml). Also, a 4 fold increase in the relative mRNA expression of CD-11b and 2.5 fold changes in CD-44 expression were observed in embryonic mortality. We observed a 1.5 fold increase in the relative mRNA expression of PIBF and a 0.5 fold increase in GRα expression in pregnant cows compared to EEM (on day 21) and LEM (on days 30 and 40) cows. Our results depicted that the hyperimmune status of the dam which could be due to multifactorial events that led to the pregnancy failure. The above basic values may be used for checking the immune status and thus timely management strategies can be taken to prevent embryonic losses.


Preparation and evaluation of an Arg-Gly-Asp-modified chitosan/hydroxyapatite scaffold for application in bone tissue engineering.
Bone tissue engineering has become a promising method for the repair of bone defects, and the production of a scaffold with high cell affinity and osseointegrative properties is crucial for successful bone substitute. Chitosan (CS)/hydroxyapatite (HA) composite was prepared by in situ compositing combined with lyophilization, and further modified by arginine‑glycine‑aspartic acid (RGD) via physical adsorption. In order to evaluate the cell adhesion rate, viability, morphology, and alkaline phosphatase (ALP) activity, the RGD‑CS/HA scaffold was seeded with bone marrow stromal cells (BMSCs). The osseointegrative properties of the RGD‑CS/HA scaffold were evaluated by in vivo heterotopic ossification and in vivo bone defect repair. After 4 h culture with the RGD‑CS/HA scaffold, the adhesion rate of the BMSCs was 80.7%. After 3 days, BMSCs were fusiform in shape and evenly distributed on the RGD‑CS/HA scaffold. Formation of extracellular matrix and numerous cell‑cell interactions were observed after 48 h of culture, with an ALP content of 0.006 ± 0.0008 U/l/ng. Furthermore, the osseointegrative ability and biomechanical properties of the RGD‑CS/HA scaffold were comparable to that of normal bone tissue. The biocompatibility, cytocompatibility, histocompatibility and osseointegrative properties of the RGD‑CS/HA scaffold support its use in bone tissue engineering applications.


Applicability of the coefficient of variation method for analyzing synaptic plasticity.
The classical coefficient of variation method for "quantal" analysis of synaptic responses allows unambiguous identification of pre- and postsynaptic loci underlying synaptic plasticity only when extensive simplifying restrictions are made. They include invariance of quantal parameters and the assumption that a single afferent produces the evoked potentials or currents. More general theoretical formulations and simulations demonstrate that the standard criteria do not always provide useful guidelines because when the other sources of physiological variance are included, putative pre- and postsynaptic domains may overlap. For example, data typically interpreted as indicating modifications at both sites can be due to a mechanism localized to only one of the two, if parameter variances are taken into consideration in the case of a single input cell, or if there are multiple inputs and the stimulus does not activate all of them reliably. With this perspective, other physiologically realistic hypotheses relevant to the expression of synaptic plasticity, such as that during long-term potentiation, can be envisioned.


Recombinant Newcastle disease virus rL-RVG enhances the apoptosis and inhibits the migration of A549 lung adenocarcinoma cells via regulating alpha 7 nicotinic acetylcholine receptors in vitro.
The aim of this study were to investigate the possible pro-apoptotic mechanisms of the recombinant Newcastle disease virus (NDV) strain rL-RVG, which expresses the rabies virus glycoprotein, in A549 lung adenocarcinoma cells via the regulation of alpha 7 nicotinic acetylcholine receptors (α7 nAChRs) and to analyze the relationships between α7 nAChR expression in lung cancer and the clinical pathological features. α7 nAChR expression in A549, LΑ795, and small-cell lung carcinoma (SCLC) cells, among others, was detected using reverse transcription polymerase chain reaction (RT-PCR). The optimal α7 nAChR antagonist and agonist concentrations for affecting A549 lung adenocarcinoma cells were detected using MTT assays. The α7 nAChR expression in A549 cells after various treatments was assessed by Western blot, immunofluorescence and RT-PCR analyses. Apoptosis in the various groups was also monitored by Western blot and TUNEL assays, followed by the detection of cell migration via transwell and scratch tests. Furthermore, α7 nAChR expression was examined by immunohistochemistry in lung cancer tissue samples from 130 patients and 40 pericancerous tissue samples, and the apoptotis in lung adenocarcinoma tissue was detected by Tunel assay, Then, the expression levels and clinicopathological characteristics were analyzed. Of the A549, LΑ795, SCLC and U251 cell lines, the A549 cells exhibited the highest α7 nAChR expression. The cells infected with rL-RVG exhibited high RVG gene and protein expression. The rL-RVG group exhibited weaker α7 nAChR expression compared with the methyllycaconitine citrate hydrate (MLA, an α7 nAChR antagonist) and NDV groups. At the same time, the MLA and rL-RVG treatments significantly inhibited proliferation and migration and promoted apoptosis in the lung cancer cells (P < 0.05). The expression of α7 nAChR was upregulated in lung cancer tissue compared with pericancerous tissue (P = 0.000) and was significantly related to smoking, clinical tumor-node-metastases stage, and histological differentiation (P < 0.05). The AI in lung adenocarcinoma tissue in high-medium differentiation group was lower than that in low differentiation group (p < 0.01). An antagonist of α7 nAChR may be used as a molecular target for lung adenocarcinoma therapy. Recombinant NDV rL-RVG enhances the apoptosis and inhibits the migration of A549 lung adenocarcinoma cells by regulating α7 nAChR signaling pathways.


17beta-Estradiol responsiveness of MCF-7 laboratory strains is dependent on an autocrine signal activating the IGF type I receptor.
BACKGROUND: Human MCF-7 cells have been studied extensively as a model for breast cancer cell growth. Many reports have established that serum-starved MCF-7 cells can be induced to proliferate upon the sole addition of 17beta-estradiol (E2). However, the extent of the mitogenic response to E2 varies in different MCF-7 strains and may even be absent. In this study we compared the E2-sensitivity of three MCF-7 laboratory strains. RESULTS: The MCF-7S line is non-responsive to E2, the MCF-7 ATCC has an intermediate response to E2, while the MCF-7 NKI is highly E2-sensitive, although the levels and activities of the estrogen receptor (ER) are not significantly different. Both suramin and IGF type I receptor blocking antibodies are able to inhibit the mitogenic response to E2-treatment in MCF-7 ATCC and MCF-7 NKI cells. From this we conclude that E2-induced proliferation is dependent on IGF type I receptor activation in all three MCF-7 strains. CONCLUSIONS: The results presented in this article suggest that E2-responsiveness of MCF-7 cells is dependent on the secretion of an autocrine factor activating the IGF-IR. All three strains of MCF-7 breast cancer cells investigated do not respond to E2 if the IGF-RI-pathway is blocked. Generally, breast cancer therapy is targeted at inhibiting estrogen action. This study suggests that inhibition of IGF-action in combination with anti-estrogen-treatment may provide a more effective way in treatment or even prevention of breast cancer.


Parental presence, clowns or sedative premedication to treat preoperative anxiety in children: what could be the most promising option?
A significant number of children undergo surgery experience high levels of anxiety in the presurgical period. The aim of this study is to investigate which intervention is more effective in reducing preoperative anxiety. The sample was composed of 75 subjects (aged 5-12 years) who had to undergo minor day surgery. Children were randomly assigned to: the Clowns group (N = 25) accompanied to the preoperative room by the clowns and by a parent; Premedication group (N = 25) premedicated with oral midazolam and accompanied to the preoperative room by one parent; or the Control group (N = 25) only accompanied by one parent. Anxiety in the preoperative period was measured by using the Modified Yale Preoperative Anxiety Scale (m-YPAS). Parental anxiety was measured by using the State-Trait Anxiety Inventory (STAI Y-1/Y-2). The Clown group was significantly less anxious during the induction of anesthesia compared with Premedication group and Control group. There were not any significant differences between Control group and Premedication group. There was an increased level of anxiety in the induction room in comparison with the waiting room: this difference was statistically significant for Control group and Premedication group, whereas it was not significant in Clown group. PPIA+clown intervention is more effective in reducing anxiety in children during the preoperative period than PPIA alone or PPIA+oral midazolam.