Possible significance of transferrin levels in seminal plasma of fertile and infertile men.
Human seminal plasma contains large amounts of transferrin, which is a protein secreted mostly by Sertoli cells. It has been suggested that the concentration of transferrin may serve as a possible clinical marker of Sertoli cell function. Therefore the concentration of this protein in human seminal plasma from fertile and infertile men has been evaluated in order to find a relationship between transferrin concentrations and human semen parameters and plasma FSH levels. Findings show that seminal transferrin in subjects with oligozoospermia or azoospermia is significantly lower than in controls, and that it is strongly related to sperm count. Results also indicate that transferrin secretion can be impaired when plasma FSH levels are still normal, suggesting that seminal transferrin is an early and specific marker of Sertoli cell function. These results, however, do not clarify whether impairment of transferrin secretion by Sertoli cells is due to an organic dysfunction or to an organic secretory alteration.


Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie.
Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells integrate these distinct inputs to generate organs of the appropriate size and shape is largely unknown. The transcriptional coactivator Yorkie (Yki, a YES-Associated Protein, or YAP) acts downstream of patterning morphogens and other tissue-intrinsic signals to promote organ growth. Yki activity is regulated primarily by the Warts/Hippo (Wts/Hpo) tumour suppressor pathway, which impedes nuclear access of Yki by a cytoplasmic tethering mechanism. Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing. Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes. When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes--a phenomenon we term "nuclear seclusion." Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability.


Identifying Social-Behavioral Health Needs of Adults with Sickle Cell Disease in the Emergency Department.
Sickle cell disease (SCD) is a complex illness with many social-behavioral co-morbidities. The aim of this project was to describe unmet social-behavioral health needs for adults with SCD who presented to the emergency department for treatment of vaso-occlusive episodes (VOEs). A descriptive study using 1:1 interviews during an ED visit for a VOE was conducted; a brief social behavioral health screening interview guide was used. A convenience sample of adults with SCD treated in the emergency department for a VOE were eligible for inclusion. We conducted 147 interviews over 14 months. Patients reported transportation and/or scheduling difficulties with clinic appointments in one third of the interviews. Four major themes emerged: clinic appointment barriers, medication barriers, other care barriers, and social-behavioral issues. A majority of patients (53%) reported being brought to the emergency department by a family member at their current visit. Patients cited having insurance coverage issues in more than one quarter (27%) of the interviews. Difficulties in obtaining prescriptions were cited as a result of a financial copay (17%), transportation (11%), and pharmacy (9%) issues. Almost one third of patients (29%) reported feeling depressed, and 20% reported feeling anxious. Many patients with SCD who are treated in the emergency department have social or behavioral health risk factors. Emergency departments have an opportunity to screen and refer patients for follow-up. Future research should investigate referral outcomes and their effect on ED and hospital use.


The Th17 immune response in renal inflammation.
The discovery of interleukin (IL)-17-producing CD4(+) T (Th17) cells as a unique T-helper cell lineage has revised our understanding of T-cell-mediated tissue injury. Recent data from studies in humans and mice indicate that autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, classically believed to be Th1-mediated, are predominantly driven by a Th17 immune response. IL-17 (IL-17A), IL-17F, IL-21, IL-22, and possibly also IL-9 produced by Th17 cells promote inflammation by directly causing tissue injury and enhancing secretion of pro-inflammatory cytokines and chemokines by resident cells. This results in augmented infiltration of leukocytes, in particular neutrophils, to the affected tissue where they induce organ inflammation and injury. Recent studies have highlighted the potential importance of the Th17 immune response also in renal inflammatory disease. This includes the identification and characterization of IL-17-producing T cells in nephritic kidneys of mice and humans, as well as evidence for the contribution of IL-17 and the IL-23/Th17 axis to renal tissue injury in glomerulonephritis. In this review, we will briefly summarize general characteristics of Th17 cells and discuss in detail the potential role of the Th17 immune response in human and experimental renal inflammation with a special focus on glomerulonephritis.


Characterization of a pressure measuring system for the evaluation of medical devices.
The purpose of this study is to evaluate the possible use of four "FSA" thin and flexible resistive pressure mapping systems, designed by Vista Medical (Winnipeg, Manitoba, Canada), for the measurement of interface pressure exerted by lumbar belts onto the trunk. These sensors were originally designed for the measurement of low pressure applied by medical devices on the skin. Two types of tests were performed: standard metrology tests such as linearity, hysteresis, repeatability, reproducibility and drift, and specific tests for this application such as curvature, surface condition and mapping system superposition. The linear regression coefficient is between 0.86 and 0.98; hysteresis is between 6.29% and 9.41%. Measurements are repeatable. The location, time and operator, measurement surface condition and mapping system superposition have a statistically significant influence on the results. A stable measure is verified over the period defined in the calibration procedure, but unacceptable drift is observed afterward. The measurement stays suitable on a curved surface for an applied pressure above 50 mmHg. To conclude, the sensor has acceptable linearity, hysteresis and repeatability. Calibration must be adapted to avoid drift. Moreover, when comparing different measurements with this sensor, the location, the time, the operator and the measurement surface condition should not change; the mapping system must not be superimposed.


A National Survey on the Use of Electronic Directly Observed Therapy for Treatment of Tuberculosis.
An increasing number of tuberculosis (TB) programs are adopting electronic directly observed therapy (eDOT), the use of technology to supervise patient adherence remotely. Pilot studies show that treatment adherence and completion were similar with eDOT compared with the standard in-person DOT. In December 2015, the National Tuberculosis Controllers Association administered an online survey to determine the extent to which eDOT is used in the United States. Sixty-eight Centers for Disease Control and Prevention (CDC)-funded health department TB programs across the United States and a convenient sample of local health department TB programs. Fifty-six (82%) of 68 CDC-funded health department TB programs and an additional 57 local TB programs responded to the survey. Forty-seven (42%) of 113 TB programs are currently using eDOT, 41 (36%) are planning to implement it in the next year, and 25 (22%) have no plans to implement eDOT. Of the 47 TB programs using eDOT, 31 (66%) use synchronous video DOT, 4 (9%) asynchronous video DOT, 11 (23%) a combination of both, and 1 (2%) ingestible sensor to conduct electronic observations. Forty-one (87%) indicated that treatment adherence and 40 (85%) indicated that treatment completion were about the same or higher than in-person DOT. More than 80% indicated that eDOT resulted in program cost savings, and almost all (91%) reported benefits in patient and staff satisfaction. However, 25 (53%) of the 47 TB programs that use eDOT encountered technical challenges and 37 (79%) offer eDOT to less than a third of their patients. Results from this survey indicate that eDOT is a promising tool that can be utilized to efficiently and effectively manage TB treatment. Findings will inform other TB programs interested in implementing eDOT. However, further evaluation is needed to assess eDOT acceptability to understand barriers to eDOT implementation from the patient and provider perspectives.


Assessing nondrinking outcomes in combined pharmacotherapy and psychotherapy clinical trials for the treatment of alcohol dependence.
This article argues that nondrinking outcomes are essential to include in complex trials such as COMBINE to assess the hypothesized mechanisms of action and behavioral change associated with both medications and psychotherapy. Toward this end, COMBINE is used as a case study for (1) discussing hypothesized mechanisms of action for behavior change, (2) discussing distinctive design features of combined studies, (3) highlighting issues in the selection of outcome measures, (4) providing a framework for organizing outcome domains and measures and (5) providing a dose-response model for assessing alcoholism treatment outcomes. A review of the literature and discussion of methodological issues in assessing nondrinking outcomes is provided as well as a case study in developing a conceptual framework for selecting outcome measures. The results of the review and case study include the development of a framework for categorizing outcome dimensions and measures into condition-specific clinical status, condition-specific symptoms and personal and interpersonal functioning outcomes. In addition, a model is provided for assessing the dose-response of combined alcoholism treatment with multiple dimensions of outcome during and after treatment. Consistent with previous observations that recovery from alcohol dependence is a multidimensional developmental process, the COMBINE Study will examine the effects of different combinations of pharmacotherapy and behavioral interventions on the magnitude and pattern of changes in various outcome dimensions (both drinking and nondrinking) over time.


Rapid purification of human albumin with immunomagnetic microsphere technology.
To develop a rapid and inexpensive method for purification of human albumin, a method of immunomagnetic microspheres (IMMS) based on enzyme-linked immunosorbent assay (ELISA) for the purification of human albumin from human serum. Polystyrene magnetic microspheres with carboxyl groups as carriers were prepared, and then the carboxyl groups on the surface of the microspheres were activated by ethylcarbodiimide (EDC). Finally rabbit anti-human serum albumin (HSA) antibodies were covalently bound to it and the complex can specifically capture HSA. After the procedure of capturing HSA, through taking rabbit anti-human albumin protein antibodies as a capture antibody, and goat anti-human albumin protein antibodies as a detection antibody, an ELISA on IMMS was developed, which can determine the recovery yield of HSA from the human serum. The result of the experiment was that the recovery of human albumin with IMMS was (86 +/- 4)%, and IMMS were reused for two other purifying cycles, the results of which were (69.0 +/- 0.6)% and (40.8 +/- 0.8)%, and the purity of the product was about 90%. The results above prove that the immunomagnetic purifiying strategy was shown to be efficient and offers an new thought for a large scale production of high-purity HSA.


Pigmentation of Peutz-Jeghers syndrome occurring in psoriatic plaques.
We report a patient with late-onset mucocutaneous pigmentation characteristic of Peutz-Jeghers syndrome, who also developed hyperpigmented macules within pre-existing psoriatic plaques. This has rarely been reported. Macular pigmentation of the forehead and dorsum of the fingers was also a prominent feature. It is important to consider other causes of mucocutaneous pigmentation including Addison's disease, the Laugier-Hunziker syndrome, chemotherapeutic agents and HIV disease.


Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.
Neurodegenerative diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to experience exponential growth thanks to numerous advancements in technology, shifts in the understanding of the disease as a phenomenon, and the change in the perspective regarding gene editing and the advantages of this action. The aim of this paper is to analyze the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We intend through this review to focus on the newest treatment, diagnosis, and predictions regarding this large group of diseases, in order to obtain a more accurate analysis and to identify the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide evidence of future possible novel therapies that target the specific genes and that could be useful to be taken into consideration when the classical approaches fail to shed light.


Aspirate from human stented saphenous vein grafts induces epicardial coronary vasoconstriction and impairs perfusion and left ventricular function in rat bioassay hearts with pharmacologically induced endothelial dysfunction.
Stent implantation into aortocoronary saphenous vein grafts (SVG) releases particulate debris and soluble vasoactive mediators, for example, serotonin. We now analyzed effects of the soluble mediators released into the coronary arterial blood during stent implantation on vasomotion of isolated rat epicardial coronary artery segments and on coronary flow and left ventricular developed pressure in isolated perfused rat hearts. Coronary blood was retrieved during percutaneous SVG intervention using a distal occlusion/aspiration protection device in nine symptomatic patients with stable angina pectoris and a flow-limiting SVG stenosis. The blood was separated into particulate debris and plasma. Responses to coronary plasma were determined in isolated rat epicardial coronary arteries and in isolated, constant pressure-perfused rat hearts (±nitric oxide synthase [NOS] inhibition and ±serotonin receptor blockade, respectively). Coronary aspirate plasma taken after stent implantation induced a stronger vasoconstriction of rat epicardial coronary arteries (52 ± 8% of maximal potassium chloride induced vasoconstriction [% KClmax = 100%]) than plasma taken before stent implantation (12 ± 8% of KClmax); NOS inhibition augmented this vasoconstrictor response (to 110 ± 15% and 24 ± 9% of KClmax). Coronary aspirate plasma taken after stent implantation reduced in isolated perfused rat hearts only under NOS inhibition coronary flow by 17 ± 3% and left ventricular developed pressure by 25 ± 4%. Blockade of serotonin receptors abrogated these effects. Coronary aspirate plasma taken after stent implantation induces vasoconstriction in isolated rat epicardial coronary arteries and reduces coronary flow and left ventricular developed pressure in isolated perfused rat hearts with pharmacologically induced endothelial dysfunction.


Surface-state enhancement of tunneling thermopower on the Ag(111) surface.
Thermoelectric effects in tunnel junctions are currently being revisited for their prospects in cooling and energy harvesting applications, and as sensitive probes of electron transport. Quantitative interpretation of these effects calls for advances in both theory and experiment, particularly with respect to the electron transmission probability across a tunnel barrier which encodes the energy dependence and the magnitude of tunneling thermopower. Using noble metal surfaces as clean model systems, we demonstrate a comparatively simple and quantitative approach where the transmission probability is directly measured experimentally. Importantly, we estimate not only thermovoltage, but also its energy and temperature dependencies. We have thus resolved surface-state enhancement of thermovoltage, which manifests as 10-fold enhancement of thermopower on terraces of the Ag(111) surface compared to single-atom step sites and surface-supported nanoparticles. To corroborate experimental analysis, the methodology was applied to the transmission probability obtained from first-principles calculations for the (111) surfaces of the three noble metals, finding good agreement between overall trends. Surface-state effects themselves point to a possibility of achieving competitive performance of all-metal tunnel junctions when compared to molecular junctions. At the same time, the approach presented here opens up possibilities to investigate the properties of nominally doped or gated thermoelectric tunnel junctions as well as temperature gradient in nanometer gaps.


Analyzing the Burden of Revision Total Knee Arthroplasty in the United States between 2009 and 2016.
As the number of total knee arthroplasties (TKAs) increases, it is reasonable to expect the number of revision TKAs (rTKAs) to rise in parallel. The patient-related and societal burdens of rTKA are poorly understood. Therefore, the purpose of this study was to determine temporal changes in: (1) the incidence of rTKA; (2) patient and hospital characteristics; (3) complications, hospital lengths of stay (LOSs), and discharge dispositions; and (4) costs, charges, and payer types. All patients who underwent rTKA between 2009 and 2016 were identified from the National Inpatient Sample database using International Classification of Diseases, Ninth Revision and Tenth Revision codes and were studied. Univariate analyses were performed to compare the incidence of rTKA, patient and hospital characteristics, LOS and discharge dispositions, as well as costs, charges, and payer types. A multivariate logistic regression model was built to compare the odds of complications in 2009 and 2016. Over our study period, there was a 4.3% decrease in the incidence of rTKA. The mean age of patients who underwent rTKA was 65 years and a majority were female (58%). Mean hospital LOS decreased from 4.1 days in 2009 to 3.3 days in 2016 (p < 0.001). The rate of several complications decreased significantly over our study period including myocardial infarction, cardiac arrest, transfusion, pneumonia, urinary tract infection, and mortality. A significantly lower percentage of rTKA patients were discharged to a skilled nursing facility in 2016 (26.5%) compared with 2009 (31.6%; p < 0.001). There was an 18.7% increase in the mean costs, and a 43.3% increase in the mean charges (p < 0.001). Over the study period, there was a decrease in the incidence of rTKAs. Despite potential improvements in primary TKA, the burden associated with rTKA remains large. This report can be used to help educate medical providers about outcomes that may result from a primary and/or revised TKA.


LncRNA SNHG15 regulates autophagy and prevents cerebral ischaemia-reperfusion injury through mediating miR-153-3p/ATG5 axis.
Ischaemic stroke is a common cerebrovascular disease. Long non-coding RNA (lncRNA) of small nucleolar RNA host gene (SNHG15) has been supposedly performed a regulatory role in many diseases. Nonetheless, the function of SNHG15 in cerebral ischaemia-reperfusion injury has not been clarified. The OGD/R of Neuro2A cells simulated the ischaemic and reperfused states of the brain. Neuro2a cell line with stable transfection of plasmid with silent expression of SNHG15 was constructed. Neuro2a cell lines transfected with miR-153-3p mimic (miR-153-3p-mimics) and miR-153-3p inhibitor (miR-153-3p-inhibition) were constructed. Expression of SNHG15, mi R-200a, FOXO3 and ATG7 in mouse brain tissue and N2a cells was identified by qRT-PCR. Western blot (WB) analysis of mouse brain tissue and Neuro2a cells revealed the presence of the proteins ATG5, Cle-caspase-3, Bax, Bcl-2, LC3 II/I and P62 (WB). The representation and distribution of LC3B were observed by immunofluorescence. The death of cells was measured using a technique called flow cytometry (FACS). SNHG15 was highly expressed in cerebral ischaemia-reperfusion injury model. Down-regulation of SNHG15 lead to lower apoptosis rate and decreased autophagy. Dual luciferase assay and co-immunoprecipitation (CoIP) found lncRNA SNHG15/miR-153-3p/ATG5. Compared to cells transfected with NC suppression, cells transfected with miR-153-3p-inhibition had substantially greater overexpression of LC 3 II/I, ATG5, cle-Caspase-3, and Bax, as determined by a recovery experiment, the apoptosis rate was elevated, yet both P62 and Bcl-2 were significantly lower and LC3+ puncta per cells were significantly increased. Co-transfection of miR-153-3p-inhibition and sh-SNHG15 could reverse these results. LncRNA SNHG15 regulated autophagy and prevented cerebral ischaemia-reperfusion injury through mediating the miR-153-3p/ATG5 axis.


Prevalence of Deep Vein Thrombosis in Hospitalized Patients With Suspected Pulmonary Embolism Ruled Out by Multislice CT Angiography.
Current evidence suggests that for outpatients with suspected pulmonary embolism (PE), multislice computed tomographic angiography (CTPA) is sufficient to rule out PE. However, the accuracy of CTPA alone has not been established for hospitalized patients. Our goal was to determine the prevalence of deep vein thrombosis (DVT) in hospitalized patients who had PE ruled out by CTPA. We conducted a prospective cohort study of patients who developed symptoms indicative of PE, after being admitted to the hospital for any reason other than PE and were evaluated with multislice CTPA. The main outcome was proximal DVT. Between November 2011 and December 2014, 191 hospitalized patients were screened. A total of 99 patients satisfied our inclusion criteria. The average length of hospitalization for this group was 14 days (range: 2-127 days). While hospitalized, 54 (28%) patients underwent a major surgical procedure and 80 (79%) were receiving thromboprophylaxis. Of the 99 patients included, 7 (7.07%; 95% confidence intervals [CIs]: 3.4-13.8) were diagnosed with a proximal DVT. The likelihood of developing a proximal DVT was higher for those with subtle and nonspontaneously reported symptoms of DVT, odds ratio [OR] was 50.93 (95% CI: 5.35-2572) and for those classified as PE likely OR was 37.54 (95% CI: 4.05-186.1). Given the prevalence of DVT in hospitalized patients with suspected PE ruled out by a negative multislice CTPA, our study suggests that compression ultrasonography would, in fact, be justified for patients with these characteristics.


Identification of TL-Om1, an adult T-cell leukemia (ATL) cell line, as reference material for quantitative PCR for human T-lymphotropic virus 1.
Quantitative PCR (qPCR) for human T-lymphotropic virus 1 (HTLV-1) is useful for measuring the amount of integrated HTLV-1 proviral DNA in peripheral blood mononuclear cells. Many laboratories in Japan have developed different HTLV-1 qPCR methods. However, when six independent laboratories analyzed the proviral load of the same samples, there was a 5-fold difference in their results. To standardize HTLV-1 qPCR, preparation of a well-defined reference material is needed. We analyzed the integrated HTLV-1 genome and the internal control (IC) genes of TL-Om1, a cell line derived from adult T-cell leukemia, to confirm its suitability as a reference material for HTLV-1 qPCR. Fluorescent in situ hybridization (FISH) showed that HTLV-1 provirus was monoclonally integrated in chromosome 1 at the site of 1p13 in the TL-Om1 genome. HTLV-1 proviral genome was not transferred from TL-Om1 to an uninfected T-cell line, suggesting that the HTLV-1 proviral copy number in TL-Om1 cells is stable. To determine the copy number of HTLV-1 provirus and IC genes in TL-Om1 cells, we used FISH, digital PCR, and qPCR. HTLV-1 copy numbers obtained by these three methods were similar, suggesting that their results were accurate. Also, the ratio of the copy number of HTLV-1 provirus to one of the IC genes, RNase P, was consistent for all three methods. These findings indicate that TL-Om1 cells are an appropriate reference material for HTLV-1 qPCR.


Quantification of mineralized bone response to prostate cancer by noninvasive in vivo microCT and non-destructive ex vivo microCT and DXA in a mouse model.
To compare nondestructive in vivo and ex vivo micro-computed tomography (muCT) and ex vivo dual-energy-X-ray-absorptiometry (DXA) in characterizing mineralized cortical and trabecular bone response to prostate cancer involving the skeleton in a mouse model. In vivo microCT was performed before and 10 weeks after implantation of human prostate cancer cells (MDA-PCa-2b) or vehicle into SCID mouse femora. After resection, femora were imaged by nondestructive ex vivo specimen microCT at three voxel sizes (31 micro, 16 micro, 8 micro) and DXA, and then sectioned for histomorphometric analysis of mineralized bone. Bone mineral density (BMD), trabecular parameters (number, TbN; separation, TbSp; thickness, TbTh) and mineralized bone volume/total bone volume (BV/TV) were compared and correlated among imaging methods and histomorphometry. Statistical tests were considered significant if P<0.05. Ten weeks post inoculation, diaphyseal BMD increased in the femur with tumor compared to the opposite femur by all modalities (p<0.005, n = 11). Diaphyseal BMD by in vivo microCT correlated with ex vivo 31 and 16 microm microCT and histomorphometry BV/TV (r = 0.91-0.94, P<0.001, n = 11). DXA BMD correlated less with bone histomorphometry (r = 0.73, P<0.001, n = 11) and DXA did not distinguish trabeculae from cortex. By in vivo and ex vivo microCT, trabecular BMD decreased (P<0.05, n = 11) as opposed to the cortex. Unlike BMD, trabecular morphologic parameters were threshold-dependent and when using "fixed-optimal-thresholds," all except TbTh demonstrated trabecular loss with tumor and correlated with histomorphometry (r = 0.73-0.90, P<0.05, n = 11). Prostate cancer involving the skeleton can elicit a host bone response that differentially affects the cortex compared to trabeculae and that can be quantified noninvasively in vivo and nondestructively ex vivo.


Tuberculous peritonitis following intestinal perforation in malignancy.
Tuberculous peritonitis is one of the most common causes of exudative ascites, especially in the young, and is an important cause of extra-pulmonary disease. However, tuberculous peritonitis is challenging to diagnose because there are no pathognomonic clinical features or imaging findings. Therefore, it is commonly misdiagnosed as another type of peritoneal disease, especially so in elderly patients with malignant disease. In this report, we described two cases of tuberculous peritonitis that were observed after intestinal perforation in elderly patients with malignancies. These diagnoses were established by laparoscopic peritoneal biopsy or AFB cultures of the ascitic fluid. Both patients were treated with anti-TB medications.


How far can virtual screening take us in drug discovery?
Virtual screening (VS) has emerged as an important tool in identifying bioactive compounds through computational means, by employing knowledge about the protein target or known bioactive ligands. VS has appeared as an adaptive response to the massive throughput synthesis and screening paradigm as necessity has forced the computational chemistry community to develop tools that screen against any given target and/or property millions or perhaps billions of molecules in short period of time. This editorial review attempts to catalog most commonly exercised VS methods, available databases for screening, advantages of VS methods along with pitfalls and technical traps with the aim to make VS as one of the most effective tools in drug discovery process. Finally, several case studies are cited where the VS technology has been applied successfully. In recent times, many successful examples have been demonstrated in the field of computer-aided VS with the objective of increasing the probability of finding novel hit and lead compounds in terms of cost-effectiveness and commitment in time and material. Despite the inherent limitations, VS is still the best option now available to explore a large chemical space.


Mechanism of the protective effects of the combined treatment with rhynchophylla total alkaloids and sinapine thiocyanate against a prothrombotic state caused by vascular endothelial cell inflammatory damage.
The aim of the present study was to investigate the effect and the underlying mechanism of the combined treatment of rhynchophylla total alkaloids (RTA) and sinapine thiocyanate for protection against a prothrombotic state (PTS) associated with the tumor necrosis factor-alpha (TNF-α)-induced inflammatory injury of vascular endothelial cells (VECs). A TNF-α-induced VEC inflammatory injury model was established, and cell morphology of VECs was evaluated using scanning electron microscopy. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to examine the mRNA and protein expression of coagulation-related factors, including nuclear factor-κB (NF-κB), transforming growth factor-β1 (TGF-β1), tissue factor (TF), plasminogen activator inhibitor (PAI-1), protease-activation receptors (PAR-1) and protein kinase C (PKC-α) in VECs. Combined treatment with RTA and sinapine thiocyanate was demonstrated to reduce, to a varying extent, the mRNA and protein expression of NF-κB, TGF-β1, TF, PAR-1, PKC-α and PAI-1. Furthermore, combined treatment with RTA and sinapine thiocyanate was able to downregulate the expression of coagulation-related factors in injured VECs, thereby inhibiting the PTS induced by vascular endothelial injury. The underlying mechanism is partially associated with the TF-mediated activation of the thrombin-receptor signaling pathway that suppresses coagulation during inflammation and balances fibrinolysis in order to inhibit fibrin generation and deposition.


Monoclonal antibody to type IV collagen with selective basement membrane localization.
A monoclonal antibody (MCA IV-1) has been developed to a determinant of the high molecular weight fractions of human placental collagen, present also in bovine lens capsule and glomerular basement membrane type IV collagens. This unique determinant is pepsin and collagenase resistant and is apparently distinct from the alpha 1(IV) and alpha 2(IV) helical peptides. As part of the high molecular weight molecules, the determinant is located in a region additively deformable by reduction and sodium dodecyl sulfate denaturation. However, when a 20-kilodalton, largely collageneous, fragment containing this determinant is separated from the larger fraction by 37 degrees C collagenase treatment, the determinant is insensitive to reduction or sodium dodecyl sulfate denaturation. Immunohistologic analysis and comparison with a polyclonal antibody to type IV collagen shows a marked selectivity of localization in the glomerular basement membrane. MCA IV-1 reacts in the inner aspect of the glomerular basement membrane but primarily in the mesangium, where it selectively expands in diabetic nephropathy. Tissue selectivity is also evident in lens and corneal basement membrane.


FOXD1 Regulates the Sensitivity of Cetuximab by Regulating the Expression of EGFR in Head and Neck Squamous Cell Cancer.
Previous experiments have shown that growth factor receptors play important role in tumor proliferation, metastasis, and therapeutic effect of chemotherapeutic drugs. At the same time, forkhead box D1 (FOXD1) plays an important role in a variety of signal transmission, but its expression profile was known little about head and neck cancer. The purpose of this experiment was to explore the regulation of FOXD1 on the tumor progression of head and neck cancer and to explore the correlation of FOXD1 on the expression of growth factor receptors (EGFR). The bioinformatics online database analyzed the expression of FOXD1 and EGFR in tumor tissues and nontumor tissues. Real-time quantitative PCR was used to detect the FOXD1 and EGFR expression in 45 tumor tissues and 15 nontumor tissues. The plasmid was used to construct FOXD1 overexpressing head and neck squamous cell cancer lines and observe the clonal formation and invasion of tumor cells under the intervention of EGFR-specific antibody-cetuximab. The expression of FOXD1 and EGFR in tumor tissues was higher than that in nontumor tissues. The higher expression of FOXD1 and EGFR was not conducive to the prognosis of patients. The expression of FOXD1 and EGFR was positively correlated, and immunohistochemical analysis showed the high expression of FOXD1 and EGFR has close relation to the advanced stage of the tumor. In vitro cell experiments proved that overexpression of FOXD1 can partially offset the cloning ability of cetuximab on head and neck tumor cells. FOXD1 has an important regulatory role in the progression of head and neck cancer, and its abnormally high expression was not conducive to the prognosis of cancer patients. FOXD1 can regulate the expression of growth factor receptors in head and neck cancer, which provides a new idea for the better use of tumor growth factor receptor-specific antibodies for collaborative therapy.


Crystal structure of the PH-BEACH domains of human LRBA/BGL.
The beige and Chediak-Higashi syndrome (BEACH) domain defines a large family of eukaryotic proteins that have diverse cellular functions in vesicle trafficking, membrane dynamics, and receptor signaling. The domain is the only module that is highly conserved among all of these proteins, but the exact functions of this domain and the molecular basis for its actions are currently unknown. Our previous studies showed that the BEACH domain is preceded by a novel, weakly conserved pleckstrin homology (PH) domain. We report here the crystal structure at 2.4 A resolution of the PH-BEACH domain of human LRBA/BGL. The PH domain has the same backbone fold as canonical PH domains, despite sharing no sequence homology with them. However, our binding assays demonstrate that the PH domain in the BEACH proteins cannot bind phospholipids. The BEACH domain contains a core of several partially extended peptide segments that is flanked by helices on both sides. The structure suggests intimate association between the PH and the BEACH domains, and surface plasmon resonance studies confirm that the two domains of the protein FAN have high affinity for each other, with a K(d) of 120 nM.


The effect of misonidazole on the radiation response of clonogenic human pancreatic carcinoma cells.
An enhancing effect of misonidazole on the in vivo radiation response of clonogenic human tumour cells from a pancreatic carcinoma xenograft has been demonstrated using both a soft agar in vitro assay and an agar in diffusion chamber assay. Enhancement ratios of 1.8 and 1.3 were found when cells were assayed at 0 h and 18 h respectively after irradiation. No enhancement was seen with in vitro irradiation of oxygenated cells. The potential of these assay systems as a perclinical screening test for new radiosensitizers is discussed.


Thin Layer Chromatography-Bioautography and Gas Chromatography-Mass Spectrometry of Antimicrobial Leaf Extracts from Philippine Piper betle L. against Multidrug-Resistant Bacteria.
This study isolated and identified the antimicrobial compounds of Philippine Piper betle L. leaf ethanol extracts by thin layer chromatography- (TLC-) bioautography and gas chromatography-mass spectrometry (GC-MS). Initially, TLC separation of the leaf ethanol extracts provided a maximum of eight compounds with R f values of 0.92, 0.86, 0.76, 0.53, 0.40, 0.25, 0.13, and 0.013, best visualized when inspected under UV 366 nm. Agar-overlay bioautography of the isolated compounds demonstrated two spots with R f values of 0.86 and 0.13 showing inhibitory activities against two Gram-positive multidrug-resistant (MDR) bacteria, namely, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. The compound with an R f value of 0.86 also possessed inhibitory activity against Gram-negative MDR bacteria, namely, carbapenem-resistant Enterobacteriaceae-Klebsiella pneumoniae and metallo-β-lactamase-producing Acinetobacter baumannii. GC-MS was performed to identify the semivolatile and volatile compounds present in the leaf ethanol extracts. Six compounds were identified, four of which are new compounds that have not been mentioned in the medical literature. The chemical compounds isolated include ethyl diazoacetate, tris(trifluoromethyl)phosphine, heptafluorobutyrate, 3-fluoro-2-propynenitrite, 4-(2-propenyl)phenol, and eugenol. The results of this study could lead to the development of novel therapeutic agents capable of dealing with specific diseases that either have weakened reaction or are currently not responsive to existing drugs.


Mathematical model for positioning the FtsZ contractile ring in Escherichia coli.
During bacterial cytokinesis, a proteinaceous contractile ring assembles in the cell middle. The Z ring tethers to the membrane and contracts, when triggered, to form two identical daughter cells. One mechanism for positioning the ring involves the MinC, MinD and MinE proteins, which oscillate between cell poles to inhibit ring assembly. Averaged over time, the concentration of the inhibitor MinC is lowest at midcell, restricting ring assembly to this region. A second positioning mechanism, called Nucleoid Occlusion, acts through protein SlmA to inhibit ring polymerization in the location of the nucleoid. Here, a mathematical model was developed to explore the interactions between Min oscillations, nucleoid occlusion, Z ring assembly and positioning. One-dimensional advection-reaction-diffusion equations were built to simulate the spatio-temporal concentrations of Min proteins and their effect on various forms of FtsZ. The resulting partial differential equations were numerically solved using a finite volume method. The reduced chemical model assumed that the ring is composed of overlapping FtsZ filaments and that MinC disrupts lateral interactions between filaments. SlmA was presumed to break long FtsZ filaments into shorter units. A term was developed to account for the movement of FtsZ subunits in membrane-bound filaments as they touch and align with other filaments. This alignment was critical in forming sharp stable rings. Simulations qualitatively reproduced experimental results showing the incorrect positioning of rings when Min proteins were not expressed, and the formation of multiple rings when FtsZ was overexpressed.


[Development of the angioarchitecture and microcirculatory characteristics in rat tumor].
Using a rat transparent chamber and a device for measurement of microvascular pressure, we observed tumor vascularization process in vivo and measured the daily change in pressure of a "starting vessel" which supplies blood to the tumor vascular network. Results were summarized as follows: (1) The position from which tumor vessels originated was usually the terminal portion of a terminal arteriole (starting vessel). The frequency with which new capillaries originated from vein and venule was very low. (2) Pressure of a starting vessel increased from 30-40 cm H2O (22-30 mmHg) to 120-130 cm H2O (88-96 mmHg) with enlargement of the tumor vascular network. As soon as pressure of a starting vessel reached a plateau, no-flow vessels appeared in places within a tumor. (3) Pressure of a starting vessel was elevated by angiotensin II. In turn, the elevated pressure of a starting vessel brought about a marked increase in tumor blood flow, resulting in the blood flow in no-flow vessels.


Human papillomavirus type 18 DNA is integrated at a single chromosome site in cervical carcinoma cell line SW756.
SW756, a cervical carcinoma cell line, has multiple copies of human papillomavirus type 18 DNA sequences. The integration site of human papillomavirus type 18 DNA was localized by in situ hybridization to chromosome 12 at band q13. This single integration site corresponds to a heritable fragile site, which may have facilitated the integration of the viral DNA.


Glycine Receptor Activation Impairs ATP-Induced Calcium Transients in Cultured Cortical Astrocytes.
In central nervous system, glycine receptor (GlyR) is mostly expressed in the spinal cord and brainstem, but glycinergic transmission related elements have also been identified in the brain. Astrocytes are active elements at the tripartite synapse, being responsible for the maintenance of brain homeostasis and for the fine-tuning of synaptic activity. These cells communicate, spontaneously or in response to a stimulus, by elevations in their cytosolic calcium (calcium transients, Ca2+T) that can be propagated to other cells. How these Ca2+T are negatively modulated is yet poorly understood. In this work, we evaluated GlyR expression and its role on calcium signaling modulation in rat brain astrocytes. We first proved that GlyR, predominantly subunits α2 and β, was expressed in brain astrocytes and its localization was confirmed in the cytoplasm and astrocytic processes by immunohistochemistry assays. Calcium imaging experiments in cultured astrocytes showed that glycine (500 μM), a GlyR agonist, caused a concentration-dependent reduction in ATP-induced Ca2+T, an effect abolished by the GlyR antagonist, strychnine (0.8 μM), as well as by nocodazole (1 μM), known to impair GlyR anchorage to the plasma membrane. This effect was mimicked by activation of GABAAR, another Cl--permeable channel. In summary, we demonstrated that GlyR activation in astrocytes mediates an inhibitory effect upon ATP induced Ca2+T, which most probably involves changes in membrane permeability to Cl- and requires GlyR anchorage at the plasma membrane. GlyR in astrocytes may thus be part of a mechanism to modulate astrocyte-to-neuron communication.


Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1α expression in patients with glioma.
Hypoxic tissue evaluation in glioma is important for predicting treatment response and establishing antihypoxia therapy. In this preliminary study, (62)Cu-ATSM PET was used to determine its validity as a biomarker for distinguishing tumor grade and tissue hypoxia. (62)Cu-ATSM PET was performed in 22 patients with glioma, and the (62)Cu-ATSM SUV(max) and T/B ratio were semiquantitatively evaluated. (62)Cu-ATSM uptake distribution was qualitatively evaluated and compared with MR imaging findings. HIF-1α expression, a hypoxia marker, was compared with (62)Cu-ATSM uptake values. The (62)Cu-ATSM SUV(max) and T/B ratio were significantly higher in grade IV than in grade III gliomas (P = .014 and .018, respectively), whereas no significant differences were found between grade III and grade II gliomas. At a T/B ratio cutoff threshold of 1.8, (62)Cu-ATSM uptake was predictive of HIF-1α expression, with 92.3% sensitivity and 88.9% specificity. The mean T/B ratio was also significantly higher in HIF-1α-positive glioma tissue than in HIF-1α-negative tissue (P = .001). Using this optimal threshold of T/B ratio, (62)Cu-ATSM PET showed regional uptake in 61.9% (13/21) of tumors within the contrast-enhanced region on MR imaging, which was significantly correlated with presence of a necrotic component (P = .002). Our results demonstrated that (62)Cu-ATSM uptake is relatively high in grade IV gliomas and correlates with the MR imaging findings of necrosis. Moreover, the (62)Cu-ATSM T/B ratio showed significant correlation with HIF-1α expression. Thus, (62)Cu-ATSM appears to be a suitable biomarker for predicting highly malignant grades and tissue hypoxia in patients with glioma.


T follicular helper cells in human efferent lymph retain lymphoid characteristics.
T follicular helper cells (Tfh), a subset of CD4+ T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.


[Risk factor management in respect of type 2 diabetic complications: ABC management].
Type 2 diabetes (T2DM) is one of the most costly and burdensome chronic diseases in Taiwan and is a condition increasing in epidemic proportions all over the world. The symptoms of T2DM, including hyperglycemia, hypertension, and hyperlipidemia are among the highest risk factors for the development of complications with the disease. Blood sugar control alone is not enough for T2DM management. Proper HbA1C, blood pressure, and cholesterol level have been proven by many researchers to decrease T2DM morbidity and mortality. Therefore, the public and health care providers should know this latest ABC management to decrease the complications in T2DM.


Characteristics of human synovial fibroblast activation by IL-1 beta and TNF alpha.
Human synovial fibroblast cell lines (HSN), established from tissues obtained from the knee joints of arthritis patients undergoing arthoplasty, were used to investigate the effects of human interleukin-1 (IL-1) beta and tumour necrosis factor (TNF)alpha on proliferation and prostaglandin E2 (PGE2) secretion. IL-1 beta and TNF alpha were equipotent stimulators of HSN proliferation. Classical non-steroidal anti-inflammatory drugs and glucocorticoids significantly augmented this effect. In addition, IL-1 beta and TNF alpha were potent inducers of PGE2 production while exogenous PGE2 was growth inhibiting. These data suggest that the secretion of PGE2 by monokine-stimulated HSN exerts a negative feedback signal. Further examination of IL-1 beta- and TNF alpha-induced PGE2 secretion revealed IL-1 beta to be a more potent stimulator; however, this observation may be due, in part, to differences in the kinetics of induction. Rabbit anti-IL-1 beta and anti-TNF alpha specifically neutralized both proliferation and PGE2 production induced by these monokines, but anti-IL-1 beta (or anti-IL-1 alpha) did not block TNF alpha activity. It is unclear whether TNF alpha stimulates HSN to produce IL-1, but the antibody data suggest that extracellular IL-1 is not responsible for TNF alpha in vitro activity.


Retention and relapse in clinical practice.
Maintaining teeth in their corrected positions following orthodontic treatment can be extremely challenging. Teeth have a tendency to move back towards the original malocclusion as a result of periodontal, gingival, occlusal and growth related factors. However, tooth movement can also occur as a result of normal age changes. Because orthodontics is unable to predict which patients are at risk of relapse, those which will remain stable and the extent of relapse that will occur in the long-term, clinicians need to treat all patients as if they have a high potential to relapse. To reduce this risk, long term retention is advocated. This can be a significant commitment for patients, and so retention and the potential for relapse must form a key part of the informed consent process prior to orthodontic treatment. It is vital that patients are made fully aware of their responsibilities in committing to wear retainers as prescribed in order to reduce the chance of relapse. If patients are unable or unwilling to comply as prescribed, they must be prepared to accept that there will be tooth positional changes following treatment. There is currently insufficient high quality evidence regarding the best type of retention or retention regimen, and so each clinician's approach will be affected by their personal, clinical experience and expertise, and guided by their patients' expectations and circumstances.


A clinico-pathological study of non-Hodgkin's lymphomata in childhood.
In a series of 27 children with non-Hodgkin's lymphomata during a 29-year period there were 21 boys and 6 girls. Thirteen had lymphocytic lymphoma, 9 histiocytic and 5 lymphoma with a prominent starry-sky appearance. All but one had diffuse lymphoma and no case of mixed cell type lymphoma was seen. Patients with lymphocytic lymphoma had extralymphatic manifestations more often than patients with the other types, and leukaemic transformation, which was seen in 6 patients, was especially common in lymphocytic lymphoma. Patients with Burkitt-type tumours did not respond well to radiation therapy with conventional fractionation. The survival in the present series was very poor, only 3 out of 27 children still being alive. A more aggressive therapeutic approach, guided by a differentiated microscopic classification and appropriate staging procedures, may be expected to give better results.


Adjuvant Transthoracic Negative-Pressure Ventilation in Nonintubated Thoracoscopic Surgery.
To minimize the risks of barotrauma during nonintubated thoracoscopic-surgery under spontaneous ventilation, we investigated an adjuvant transthoracic negative-pressure ventilation (NPV) method in patients operated on due to severe emphysema or interstitial lung disease. In this retrospective study, NPV was employed for temporary low oxygen saturation and to achieve end-operative lung re-expansion during nonintubated lung volume reduction surgery (LVRS) for severe emphysema (30 patients, LVRS group) and in the nonintubated wedge resection of undetermined interstitial lung disease (30 patients, wedge-group). The results were compared following 1:1 propensity score matching with equivalent control groups undergoing the same procedures under spontaneous ventilation, with adjuvant positive-pressure ventilation (PPV) performed on-demand through the laryngeal mask. The primary outcomes were changes (preoperative-postoperative value) in the arterial oxygen tension/fraction of the inspired oxygen ratio (ΔPO2/FiO2;) and ΔPaCO2, and lung expansion completeness on a 24 h postoperative chest radiograph (CXR-score, 2: full or 1: incomplete). Intergroup comparisons (NPV vs. PPV) showed no differences in demographic and pulmonary function. NPV could be accomplished in all instances with no conversion to general anesthesia with intubation. In the LVRS group, NPV improved ΔPO2/FiO2 (9.3 ± 16 vs. 25.3 ± 30.5, p = 0.027) and ΔPaCO2 (-2.2 ± 3.15 mmHg vs. 0.03 ± 0.18 mmHg, p = 0.008) with no difference in the CXR score, whereas in the wedge group, both ΔPO2/FiO2 (3.1 ± 8.2 vs. 9.9 ± 13.8, p = 0.035) and the CXR score (1.9 ± 0.3 vs. 1.6 ± 0.5, p = 0.04) were better in the NPV subgroup. There was no mortality and no intergroup difference in morbidity. In this retrospective study, NITS with adjuvant transthoracic NPV resulted in better 24 h oxygenation measures than PPV in both the LVRS and wedge groups, and in better lung expansion according to the CXR score in the wedge group.


Paradoxical redistribution of pulmonary blood flow in prone and supine humans exposed to hypergravity.
We hypothesized that exposure to hypergravity in the supine and prone postures causes a redistribution of pulmonary blood flow to dependent lung regions. Four normal subjects were exposed to hypergravity by use of a human centrifuge. Regional lung perfusion was estimated by single-photon-emission computed tomography (SPECT) after administration of (99m)Tc-labeled albumin macroaggregates during normal and three times normal gravity conditions in the supine and prone postures. All images were obtained during normal gravity. Exposure to hypergravity caused a redistribution of blood flow from dependent to nondependent lung regions in all subjects in both postures. We speculate that this unexpected and paradoxical redistribution is a consequence of airway closure in dependent lung regions causing alveolar hypoxia and hypoxic vasoconstriction. Alternatively, increased vascular resistance in dependent lung regions is caused by distortion of lung parenchyma. The redistribution of blood flow is likely to attenuate rather than contribute to the arterial desaturation caused by hypergravity.


Single-Photon Interference due to Motion in an Atomic Collective Excitation.
We experimentally demonstrate the heralded generation of bichromatic single photons from an atomic collective spin excitation (CSE). The photon arrival times display collective quantum beats, a novel interference effect resulting from the relative motion of atoms in the CSE. A combination of velocity-selective excitation with strong laser dressing and the addition of a magnetic field allows for exquisite control of this collective beat phenomenon. The present experiment uses a diamond scheme with near-IR photons that can be extended to include telecommunications wavelengths or modified to allow storage and retrieval in an inverted-Y scheme.


[Wound dressings].
The wide variety of dermatologic surgical procedures has resulted in a corresponding choice of wound dressings. Considering the chemical and physical properties as well as the function of the dressings, standardized dressing techniques can be performed with relatively few materials. This saves both time and money.


Anti-inflammatory and immunomodulatory effects of Critonia aromatisans leaves: Downregulation of pro-inflammatory cytokines.
Critonia aromatisans (Asteraceae), commonly known as "Chiople", is a cultivated species that is used in Mayan traditional medicine to treat inflammation, joint pain and rheumatism. To evaluate the in vivo and in vitro anti-inflammatory and immunomodulatory properties of aqueous and organic extracts prepared from Critonia aromatisans leaves. Methanol, ethyl acetate, methylene chloride, hexanic, and aqueous extracts were obtained from the leaves of C. aromatisans. The anti-inflammatory properties of the extracts were tested in vivo to evaluate their ability to reduce the inflammatory response in the carrageenan-induced hind paw edema model in NIH mice. In addition, to explore the immunomodulatory effects of C. aromatisans, in vitro testing was performed to determine whether C. aromatisans leaf extracts are capable of decreasing macrophage production of nitric oxide (NO), tumour necrosis factor alpha (TNF-α), and cytokines IL-1β, IL-6, and cyclooxygenase 2 (COX-2) without affecting macrophage viability. Single orally administered doses (100mg/kg or 200mg/kg) of a hexanic extract of C. aromatisans leaves significantly reduced carrageenan-induced paw edema in mice (P<0.001) by 76% and 84%, respectively. The effect of the extract in this model was generally comparable to those of the standard drugs used. In the in vitro determination, the extracts reduced the amount of NO mainly at 500 and 1000μg/mL. Hexanic extract and subfractions C, D, E, and F at 50 and 100μg/mL produced the lowest concentration of mediators in culture supernatants (protein) and at the mRNA/gene level by the significant down-regulation of cytokines. These findings explain some of the anti-inflammatory activity of this species. Purification of fractions C and D allowed the complete identification of cyclocolorenone, stigmasterol and stigmasterol derivatives as some of their main components. A hexanic extract of C. aromatisans displayed anti-inflammatory effects, validating the traditional practice of Mayan communities wherein an ointment with a petrolatum base, a non-polar substance, is used to treat inflammation. Additionally, C. aromatisans showed strong in vivo and in vitro activity, and one of the mechanisms of its anti-inflammatory response was shown to be inhibition of the production of NO and pro-inflammatory cytokines. The results of this study provide a pharmacological basis for the use of C. aromatisans leaves in the treatment of inflammatory disorders. The presence of stigmasterol and cyclocolorenone could be the responsibles of the anti-inflammatory activity of this specie. Further studies should be done on the antioxidant and anti-inflammatory properties of cyclocolorenone. The results of this study provide a pharmacological basis for the use of C. aromatisans leaves in the treatment of inflammatory disorders.


COVID-19 vaccine hesitancy among pregnant women in an antenatal clinic in Durban, South Africa.
Mass administration of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most efficient intervention against the coronavirus disease 2019 (COVID-19) pandemic. Recently, vaccinations were shown to be safe and effective during pregnancy. However, vaccination rates are low in low- and middle-income countries, and vaccine hesitancy is a major limiting factor. To investigate the rate of COVID-19 vaccine hesitancy among pregnant women. A cross-sectional questionnaire-based investigation of 313 unvaccinated pregnant women attending an antenatal clinic in Durban, South Africa (SA). The questionnaire included clinical and socio-demographic data, and reasons for vaccine hesitancy were recorded and evaluated. Of 313 women participating, 126 (40.3%) were vaccinated against COVID-19, 21/313 = 6.7%; for those unvaccinated, 21/187 (13.9%) were planning to be vaccinated. However, most unvaccinated women, 174 of 187 (93%), showed COVID-19 vaccine hesitancy. The COVID-19 vaccination hesitancy among pregnant women in Durban, SA, is exceptionally high. This requires urgent attention by the relevant health authorities (both professional health organisations and the SA Department of Health) as many countries experience different waves of the variants of SARS-CoV-2 and herd immunity may not have been achieved. This study showed a high vaccine acceptance hesitancy rate among pregnant women in SA.


Social and non-social feedback stimuli lead to comparable levels of reward learning and reward responsiveness in an online probabilistic reward task.
Social stimuli seem to be processed more easily and efficiently than non-social stimuli. The current study tested whether social feedback stimuli improve reward learning in a probabilistic reward task (PRT), in which one response option is usually rewarded more often than the other via presentation of non-social reward stimuli. In a pre-registered online study with 305 participants, 75 participants were presented with a non-social feedback stimulus (a star) and information about gains, which is typically used in published PRT studies. Three other groups (with 73-82 participants each) were presented with one of three social feedback stimuli: verbal praise, an attractive happy face, or a "thumbs up"-picture. The data were analysed based on classical signal detection theory, drift diffusion modelling, and Bayesian analyses of null effects. All PRT variants yielded the expected behavioural preference for the more frequently rewarded response. There was no processing advantage of social over non-social feedback stimuli. Bayesian analyses further supported the observation that social feedback stimuli neither increased nor decreased behavioural preferences in the PRT. The current findings suggest that the PRT is a robust experimental paradigm independent of the applied feedback stimuli. They also suggest that the occurrence of a processing advantage for social feedback stimuli is dependent on the experimental task and design.


Modularity of motor output evoked by intraspinal microstimulation in cats.
We studied the forces produced at the cat's hindpaw by microstimulation of the ipsi- and contralateral lumbar spinal cord in spinal intact alpha-chloralose anesthetized (n = 3) or decerebrate (n = 3) animals. Isometric force and EMG responses were measured at 9-12 limb configurations, with the paw attached to a force transducer and with the hip and femur fixed. The active forces elicited at different limb configurations were summarized as force fields representing the sagittal plane component of the forces produced at the paw throughout the workspace. The forces varied in amplitude over time but the orientations were stable, and the pattern of an active force field was invariant through time. The active force fields divided into four distinct types, and a few of the fields showed convergence to an equilibrium point. The fields were generally produced by coactivation of the hindlimb muscles. In addition, some of the fields were consistent with known spinal reflexes and the stimulation sites producing them were in laminae where the interneurons associated with those reflexes are known to be located. Muscle activation produced by intraspinal stimulation, as assessed by intramuscular EMG activity, was modified with limb configuration, suggesting that the responses were not fixed, but were modified by position-dependent sensory feedback. The force responses may represent basic outputs of the spinal circuitry and may be related to similar spinal primitives found in the frog and rat.


Quantitative analysis of the T cell response to antigen and planar membranes containing purified Ia molecules.
Planar lipid membranes containing the purified Ia molecule E beta k:E alpha k can present a peptide antigen derived from cytochrome c to the T cell hybridoma 2B4.11. The incorporation of E beta k:E alpha k into planar membranes was linear over a 120-fold range of Ia molecule concentrations, permitting the dependence of the T cell response on the Ia molecule concentration to be examined. As the Ia molecule concentration was increased in the planar membranes, two parameters changed: less antigen was needed to stimulate the T cells, and the plateau response seen at functionally saturating concentrations of antigen increased. The antigen sensitivity was analyzed by plotting the antigen concentration (log2) required to stimulate the release of 10 U of IL 2 from the T cells as a function of the Ia molecule concentration (log2). If the T cell recognized a simple unit of one antigen molecule and one Ia molecule, this plot should have generated a straight line with a slope of -1. Surprisingly, a line with a slope of -2.04 X/divided by 1.12 was observed, suggesting that the T cell might recognize one antigen molecule and two Ia molecules. This complexity, however, resulted from changes in the maximal response achieved at different Ia molecule concentrations. A similar phenomenon was observed when the Ia molecule concentration was decreased in cultures containing splenic antigen-presenting cells (APC) by the addition of an anti-E beta k:E alpha k monoclonal antibody, or the use of [B10.A(4R) X B10.PL]F1APC. The Ia molecule concentration can therefore be limiting for T cell hybridomas in cultures containing normal APC and functionally saturating amounts of antigen. When the planar membrane data were normalized to the maximal response to eliminate the effect of the changing plateau response, the resulting plot generated a line with a slope of -1.17 X/divided by 1.11. These results suggest that the sole stimulatory signal for this T cell hybridoma consisted of a 1:1 ratio of antigen and Ia molecules.


Drug-induced lupus associated with rifabutin: a literature review.
Drug-induced lupus (DIL) is a rare adverse reaction to medications with features resembling idiopathic systemic lupus erythromatosis. Rifabutin/rifamycins have only rarely been reported as a cause of DIL, and no cases have been reported in blacks. A 55-year-old African American woman with HIV presented with severe generalized arthralgias and recurrent oral ulcers while receiving treatment for tuberculous meningitis. Arthralgias, which began in her knees after 5 weeks of antituberculous therapy, progressed to involve the joints in the ankles, wrists, and hands. She had no associated fever or rash. When she had these symptoms her antinuclear antibody (ANA) was 1:1280 homogenous pattern, antidouble stranded DNA was negative, antihistone antibody was strongly positive, anti-smith and antiribonucleoprotein (anti-RNP) were negative. Her symptoms resolved within 2 months of stopping rifabutin while continuing other antituberculous medications and her ANA titer started to decrease. We review the existing literature on this subject.


Revisiting post-ICU admission fluid balance across pediatric sepsis mortality risk strata: A secondary analyses from a prospective observational cohort study.
Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (AKI), and use of renal replacement therapy (CRRT) in pediatric septic shock. Ongoing multi-center prospective observational cohort. Thirteen pediatric ICUs in the United States (2003-2023). Six hundred and eighty-one children with septic shock. None. Cumulative percent positive fluid balance between day 1-7 (Day 1-7%PFB) was determined. Primary outcome of interest was complicated course defined as death or persistence of ≥ 2 organ dysfunctions by day 7. PERSEVERE-II biomarkers were used to assign mortality probability and categorize patients into high (n = 91), intermediate (n = 134), and low (n = 456) mortality risk strata. Cox proportional hazard regression models with adjustment for PERSEVERE-II mortality probability, presence of sepsis associated acute kidney injury (SA-AKI) on Day 3, and any use of CRRT, demonstrated that time-dependent variable Day 1-7%PFB was independently associated with increased hazard of complicated course in the cohort. Risk stratified analyses revealed that each 10% increase in Day 1-7%PFB was independently associated with increased hazard of complicated course among patients with high mortality risk strata (adj HR of 1.24 (95%CI: 1.08-1.42), p = 0.002), but not among those categorized as intermediate- or low- mortality risk. Our data demonstrate the independent influence of cumulative %PFB on the risk of complicated course. Contrary to our previous report, this risk was largely driven by patients categorized as having a high-mortality risk based on PERSEVERE-II biomarkers. Further research is necessary to determine whether this subset of patients may benefit from targeted deployment of restrictive fluid management or early initiation of de-escalation therapies upon resolution of shock.


Urinary mutagenicity on TA98 and YG1024 Salmonella typhimurium strains after a hamburger meal: influence of GSTM1 and NAT2 genotypes.
Mutagenicity on TA98 and YG1024 Salmonella typhimurium strains of pan-fried hamburger extracts and of 24 h post-meal urine from 32 non-smoking volunteers was evaluated. Each participant in the study was GSTM1 and NAT2 genotyped. After cooking the meat showed mutagenic activity (mean +/- SD) on strains TA98 and YG1024 of 114 +/- 129 and 1437 +/- 1536 net revertants/g respectively. Twenty three of 32 urine samples showed clear mutagenic activity (i.e. caused at least a doubling of the number of spontaneous revertants) on the O-acetyltransferase over-producing strain YG1024, while none of the post-meal 24 h urine samples was clearly mutagenic on strain TA98. Total 24 h post-meal YG1024-active urinary mutagens were well correlated with the levels of mutagen intake with the meal (r2 = 0.5977, F = 44.58, P < 0.01). In the group under study GSTM1 genotypes did not influence urinary mutagenicity. Highly exposed subjects (n = 15) with the NAT2-ss genotype showed significantly increased levels of urinary mutagenicity on strain YG1024 in comparison with NAT2-R subjects (mutagen intake-adjusted total 24 h mutagen excretion = 1.00 +/- 0.29 versus 0.66 +/- 0.32, Mann-Whitney U test, U = 12.5, P < 0.05). Our results suggest that the levels of urinary mutagens derived from diets rich in heterocyclic aromatic amines, which are specifically detected by the YG1024 Salmonella strain, are modulated by NAT2-dependent enzyme activity, slow acetylators having higher levels of mutagens in their urine. Subjects with the rapid acetylator genotype, who are known to be at risk for colon cancer, seem to be partially protected with respect to the risk of bladder cancer.


Non-stochastic matrix Schrödinger equation for open systems.
We propose an extension of the Schrödinger equation for a quantum system interacting with environment. This extension describes dynamics of a collection of auxiliary wavefunctions organized as a matrix m, from which the system density matrix can be reconstructed as ρ̂=mm(†). We formulate a compatibility condition, which ensures that the reconstructed density satisfies a given quantum master equation for the system density. The resulting non-stochastic evolution equation preserves positive-definiteness of the system density and is applicable to both Markovian and non-Markovian system-bath treatments. Our formalism also resolves a long-standing problem of energy loss in the time-dependent variational principle applied to mixed states of closed systems.


Anatomy podcasts for medical education.
The implementation of podcasts as a complementary educational activity increased over the past year due to the Covid-19 pandemic. Being an alternative channel for transmission of anatomical knowledge, the on-demand audio broadcasts became an intriguing medium for both students and educators. This paper presents the results of a questionnaire study on the evaluation of an audio podcast designed specifically for the first-year medical students as an innovative and optional component of the human anatomy course. The audience expressed their opinions in four categories: engagement in listening to the podcast, content and preferences, technical level and perspectives of using the podcast in further years of medical studies. Despite the non-compulsory nature of the podcast, the listenership reached the level of 45%. In the study, 1608 listeners had access to the survey and the overall response rate was 35.9%. Based on the analysis, the attitude and preferences of the listeners were demonstrated, including the preferred time of listening, length of the episodes, selection of topics, format of the broadcast, or the method of its delivery. Students also commented on the influence of the podcast on passing the final exam in anatomy and a concept of recording broadcasts in a foreign language. The presented data allowed the recognition of the needs of medical students and contributed to the improvement of the ongoing project. The paper presents the technical data and guidelines for educators willing to include this medium in the students' anatomical curriculum.


[Dynamics of operator's efficiency under the condition of long continuous vigil].
Chambered male test-subjects (n = 8) kept awake over 72 hours. Every one or two hours during the initial 67 hours they did a tracking test that took 10 to 15 minutes. The test required intense tracking of rhythmic light spots with unpredictably varying frequency and pressing the button as the frequency changed. Time of latent reaction was determined. The variable was shown to extend with the confinement and fluctuate with the period of approx. 28 hours. Average values on the first sleepless night was longer than the ones on the previous day in all subjects with personal difference ranging from 7 to 37% and averaging 21%. That is, on the first night everyone was less efficient as compared with the previous day which could be excused by fatigue and natural variations in mental efficiency known to rise in the day and reduce in the night hours.


In vitro production of platelet-binding IgG in childhood idiopathic thrombocytopenic purpura.
We studied two boys, 9 and 10 years old, respectively, who underwent splenectomy eight months and six weeks after initially presenting as "typical" cases of childhood ITP. Splenic leukocytes from each child were cultured and net synthesis rates of IgG determined. Splenic synthesis rates of IgG were five-and sevenfold greater, respectively, than in spleens of control subjects. A significant portion of the splenic culture-produced IgG from each patient demonstrated specificity for homologous and autologous platelets. Synthesis rates of IgG were determined on serial cultures of bone marrow cells from the 10-year-old boy who failed to respond to splenectomy. His initial marrow synthesis rate of IgG was five times greater than mean control values. His synthesis rate of IgG in marrow decreased to the control range in association with immunosuppressive therapy and intesive platelet transfusions. These data suggest that (1) the spleen was a production site of platelet-binding IgG in the two children, and (2) the bone marrow may have been an additional site of production in our second patient.


[Hemorrhagic hepatic complications of hepatic puncture-biopsies. Role of echography].
The authors report 7 serious haemorrhagic complications of transparietal liver biopsies and define the place of ultrasonography in the prevention of certain accidents, in the diagnosis and assessment of hepatic lesions and in follow-up of the subsequent course.


Application of the interacting particle system method to piecewise deterministic Markov processes used in reliability.
Variance reduction methods are often needed for the reliability assessment of complex industrial systems, we focus on one variance reduction method in a given context, that is, the interacting particle system (IPS) method used on piecewise deterministic Markov processes (PDMPs) for reliability assessment. The PDMPs are a very large class of processes which benefit from high modeling capacities, they can model almost any Markovian phenomenon that does not include diffusion. In reliability assessment, the PDMPs modeling industrial systems generally involve low jump rates and jump kernels favoring one safe arrival, we call such model a "concentrated PDMP." Used on such concentrated PDMPs, the IPS is inefficient and does not always provide a variance reduction. Indeed, the efficiency of the IPS method relies on simulating many different trajectories during its propagation steps, but unfortunately, concentrated PDMPs are likely to generate the same deterministic trajectories over and over. We propose an adaptation of the IPS method called IPS+M that reduces this phenomenon. The IPS+M consists in modifying the propagation steps of the IPS, by conditioning the propagation to avoid generating the same trajectories multiple times. We prove that, compared to the IPS, the IPS+M method always provides an estimator with a lower variance. We also carry out simulations on two-components systems that confirm these results.


Glycaemic Control Of Type 2 Diabetic Patients During Ramazan Fasting.
Among five main pillars of Islam Fasting is one of the key elements, all healthy adult Muslims have to observe fast from dawn till dusk during the holy month of Ramadan. According to a 2009 demographic study, Islam has 1.57 billion believers, making up 23% of the world population of 6.8 billion, and is growing by 3% per year. EPIDIAR (epidemiology of diabetes and Ramadan) study showed that 43% patients with type 1 and 79% patients with type2 diabetes observe fast during the month of Ramadan. Whereas those people who are suffering from diabetes and are fasting may be at risk of adverse outcomes and the risks may rise with longer fasting periods. Ideal management of diabetic patients who wish to fast during Ramadan needs to be done to avoid the complications. The purpose of this study was to observe the effect of fasting on glycaemic control in type 2 diabetic patients during the month of Ramadan. This was an observational cross sectional study; it was conducted at outpatient department Jinnah institute of diabetes and endocrinology Jinnah hospital Lahore during the month of Ramadan. Patients were advised to monitor blood sugar levels for two days before and after three meals (lunch, breakfast and dinner) before Ramadan and then during Ramadan blood sugar levels were monitored for four days in first Ashra before and two hours after Sehari, for four days at noon during second Ashra and then for four days pre and two hours after Iftar in last Ashra of Ramadan. Patients were educated Pre-Ramadan about glucose monitoring and drug dosage adjustments were done along with dietary counselling. Blood glucose levels two days before and during Ramadan fell within range of mean glucose level of 150-187 mg/dl showing no extreme fluctuations in blood glucose levels only one patient reported symptomatic and biochemical hypoglycaemia severe enough to break the fast at noon. We concluded that in Ramadan fasting, type 2 diabetic patients with proper education, dietary counselling and drug dosage adjustments glycaemic control can remain in safe acceptable range preventing any life-threatening complication.


Silver-Catalyzed Tandem C≡C Bond Hydroazidation/Radical Addition/Cyclization of Biphenyl Acetylene: One-Pot Synthesis of 6-Methyl Sulfonylated Phenanthridines.
A silver-catalyzed tandem carbon-carbon triple bond hydroazidation, radical addition, and cyclization of biphenyl acetylene is described under mild conditions, leading to the formation of 6-methyl sulfonylated phenanthridines in good yields. In this novel cascade reaction, most of the atoms are incorporated into the product without cleavage of the C≡C bond. Mechanistic studies suggest the reaction should proceed through an iminyl radical reactive intermediate.


Increased Number of Mast Cells in Epicardial Adipose Tissue of Cardiac Surgery Patients With Coronary Artery Disease.
Chronic inflammation of adipose tissue is associated with the pathogenesis of cardiovascular diseases. Mast cells represent an important component of the innate defense system of the organism. In our work, we quantified mast cell number in epicardial adipose tissue (EAT), subcutaneous adipose tissue (SAT), and right atrial myocardium (RA) in patients undergoing open heart surgery (n=57). Bioptic samples of EAT (n=44), SAT (n=42) and RA (n=17) were fixed by 4 % paraformaldehyde and embedded into paraffin. An anti-mast cell tryptase antibody was used for immunohistochemical detection and quantification of mast cells. We also demonstrated immunohistochemically the expression of CD117 and chymase markers. In EAT of patients with coronary artery disease (CAD), higher incidence of mast cells has been found compared to patients without CAD (3.7±2.6 vs. 2.1±1.2 cells/mm(2)). In SAT and RA, there was no difference in the number of mast cells in CAD and non-CAD patients. Mast cells in SAT, EAT and RA expressed CD117 and chymase. An increased incidence of mast cells in EAT of CAD patients may indicate the specific role of these inflammatory cells in relation to EAT and coronary arteries affected by atherosclerosis.


Trends in motorcycle helmet use in Vietnam: results from a four-year study.
Helmet use is a major risk factor for road traffic injuries and fatalities. This study sought to determine the state of helmet use in Ha Nam and Ninh Binh provinces in Vietnam, and ascertain knowledge, attitudes, and practices of helmet use over time. Observational helmet use studies, and roadside knowledge, attitudes, and practice surveys. Data were collected through observational helmet use studies at multiple sites in Ha Nam and Ninh Binh provinces over 14 rounds between June 2011 and December 2014. Six rounds of knowledge, attitude, and practice surveys were administered at gas stations between December 2011 and July 2014. Trend analysis and negative binomial regressions were used to analyze trend data. Between June 2011 and December 2014, 301,981 helmet-use observations were conducted in Ha Nam and Ninh Binh. Correct helmet use increased significantly (P < 0.01) in Ha Nam from 34.3% to 76.9% (P < 0.01), while use in Ninh Binh increased from 68.9% to 72.2% (P > 0.05). Helmet use has improved statistically significantly in Ha Nam but not in Ninh Binh. Ceiling effects may have limited the scope of improvements in Ninh Binh province.


14-3-3τ promotes surface expression of Cav2.2 (α1B) Ca2+ channels.
Surface expression of voltage-gated Ca(2+) (Cav) channels is important for their function in calcium homeostasis in the physiology of excitable cells, but whether or not and how the α1 pore-forming subunits of Cav channels are trafficked to plasma membrane in the absence of the known Cav auxiliary subunits, β and α2δ, remains mysterious. Here we showed that 14-3-3 proteins promoted functional surface expression of the Cav2.2 α1B channel in transfected tsA-201 cells in the absence of any known Cav auxiliary subunit. Both the surface to total ratio of the expressed α1B protein and the current density of voltage step-evoked Ba(2+) current were markedly suppressed by the coexpression of a 14-3-3 antagonist construct, pSCM138, but not its inactive control, pSCM174, as determined by immunofluorescence assay and whole cell voltage clamp recording, respectively. By contrast, coexpression with 14-3-3τ significantly enhanced the surface expression and current density of the Cav2.2 α1B channel. Importantly, we found that between the two previously identified 14-3-3 binding regions at the α1B C terminus, only the proximal region (amino acids 1706-1940), closer to the end of the last transmembrane domain, was retained by the endoplasmic reticulum and facilitated by 14-3-3 to traffic to plasma membrane. Additionally, we showed that the 14-3-3/Cav β subunit coregulated the surface expression of Cav2.2 channels in transfected tsA-201 cells and neurons. Altogether, our findings reveal a previously unidentified regulatory function of 14-3-3 proteins in promoting the surface expression of Cav2.2 α1B channels.


EphA2 phosphorylation at Ser897 by the Cdk1/MEK/ERK/RSK pathway regulates M-phase progression via maintenance of cortical rigidity.
Successful cell division is accomplished by the proper formation of the mitotic spindle. Here, we show that EphA2 knockdown causes mitotic errors, including a delay in M-phase progression, asymmetric spindle positioning, multipolar spindles, and cell blebs. It has been known that EphA2 is phosphorylated at Tyr588, which is triggered by the ligand binding, and at Ser897 downstream of growth factor signaling. Upon mitotic entry, EphA2 is phosphorylated at Ser897, accompanied by a reduction in Tyr588 phosphorylation. This EphA2 phosphorylation at Ser897 is inhibited by MEK/ERK and 90 kDa ribosomal S6 kinase (RSK) inhibitors and is induced by the introduction of active cyclin-dependent kinase 1 (Cdk1) and cyclin B1. EphA2 knockdown-induced M-phase delay and cell blebs are rescued by wild type EphA2 expression but not by Ser897Ala mutant. The Ras homolog gene family member G (RhoG) guanine nucleotide exchange factor Ephexin4 interacts with EphA2 in a Ser897 phosphorylation-dependent manner, and its knockdown delays M-phase progression and causes RhoG delocalization. RhoG knockdown delays M-phase progression, and EphA2 knockdown-induced M-phase delay is partially rescued by the constitutively active RhoG mutant. These results suggest that, in EphA2-expressing cells, EphA2 phosphorylation at Ser897 participates in proper M-phase progression downstream of the Cdk1/MEK/ERK/RSK pathway because of its role in maintaining cortical rigidity via Ephexin4 and RhoG and thereby regulating mitotic spindle formation.-Kaibori, Y. Saito, Y., Nakayama, Y. EphA2 phosphorylation at Ser897 by the Cdk1/MEK/ERK/RSK pathway regulates M-phase progression via maintenance of cortical rigidity.


Quantification of Interfibrillar Shear Stress in Aligned Soft Collagenous Tissues via Notch Tension Testing.
The mechanical function of soft collagenous tissues is largely determined by their hierarchical organization of collagen molecules. While collagen fibrils are believed to be discontinuous and transfer load through shearing of the interfibrillar matrix, interfibrillar shear stresses have never been quantified. Scaling traditional shear testing procedures down to the fibrillar length scale is impractical and would introduce substantial artifacts. Here, through the use of a novel microscopic variation of notch tension testing, we explicitly demonstrate the existence of interfibrillar shear stresses within tendon fascicles and provide the first measurement of their magnitude. Axial stress gradients along the sample length generated by notch tension testing were measured and used to calculate a value of 32 kPa for the interfibrillar shear stress. This estimate is comparable to the interfibrillar shear stress predicted by previous multiscale modeling of tendon fascicles, which supports the hypothesis that fibrils are discontinuous and transmit load through interfibrillar shear. This information regarding the structure-function relationships of tendon and other soft collagenous tissues is necessary to identify potential causes for tissue impairment with degeneration and provide the foundation for developing regenerative repair strategies or engineering biomaterials for tissue replacement.


Indomethacin enhances the cytotoxicity of VCR and ADR in human pulmonary adenocarcinoma cells.
The ability of anti-inflammatory agents to modulate cellular sensitivity to anticancer drugs was investigated for pulmonary carcinoma cells in vitro. We examined the drug sensitivity of two pulmonary adenocarcinoma cell lines (76-2, 77-4) in the presence of two drugs, an anticancer drug and an anti-inflammatory agent, for 72 hr by the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with 96 well plates. Anticancer drugs used for screening test were cyclophosphamide (CPM), mitomycin C (MMC), adriamycin (ADR), 5-fluorouracil (5FU), vindesine (VDS), cisplatin (CDDP), cytarabine (Ara C), methotrexate (MTX), etoposide (VP-16), and vincristine (VCR). Anti-inflammatory agents examined as modulators to anticancer drugs were aspirin, mefenamic acid, ibuprofen, sulindac, piroxicam, phenacetin, dicrofenac, ketoprofen, tolmetin and indomethacin. Screening tests showed indomethacin to be the most effective modulator, resulting in more than a 3-fold increase in cytotoxicity of VCR as compared with that produced by VCR alone. Study of each of the ten anticancer drugs in combination with indomethacin showed VCR to be the most effective anticancer drug in this combination. In 76-2 cells, the concentration of VCR producing 50% growth inhibition (IC50) for VCR alone and VCR in combination with 2 micrograms/ml indomethacin were 1.58 +/- 0.16 and 0.52 +/- 0.1 ng/ml respectively, which represents a 3-fold decrease. In 77-4 cells, the IC50 for VCR alone and VCR in combination with 2 micrograms/ml indomethacin were 2.86 +/- 0.2 and 0.52 +/- 0.11 ng/ml respectively, which represents a 3.8-fold decrease. Our studies indicate that clinically achievable concentrations of indomethacin may be useful in modulating VCR resistance in human pulmonary adenocarcinoma cells, so that combined use of VCR and indomethacin may be of potential clinical significance in the treatment of lung cancer.


Oviposition by Aedes aegypti (Diptera: Culicidae) in relation to conspecific larvae infected with internal symbiotes.
Female mosquitoes use abiotic and biotic factors, such as the presence of heavy metals or parasites, to determine the acceptability of oviposition sites. Some biotic factors can originate from mosquito larvae. When mosquito larvae are starved or infected with trematode metacercaria, they render associated water unacceptable to ovipositioning females. Internal symbiotes are common in wild mosquito populations, and I tested whether or not larvae of Aedes aegypti infected with a gregarine (Ascogregarina taiwanensis), a yeast (Candida near pseudoglaebosa), or a trichomycete (Smittium morbosum) rendered their rearing water unacceptable to oviposting mosquitoes. Infections with S. morbosum had no effect on the acceptability of the associated rearing water when compared to rearing water from uninfected larvae. However, the rearing water from larvae infected with A. taiwanensis or C. near pseudoglaebosa was more acceptable to ovipositing females than was distilled water or rearing water from uninfected larvae. Ovipositing female mosquitoes either preferred or were neutral to rearing water from larvae with gut symbiotes.


The surgical management of infections involving the cerebrum.
Infection involving the cerebrum is a true neurosurgical emergency that requires rapid diagnosis and appropriate surgical and medical intervention to achieve good clinical outcome. Because of the potential for devastating neurological sequelae, it is imperative that neurosurgeons be involved in the diagnosis and management of these serious conditions once an infection is suspected. With the advent of computed tomography and magnetic resonance imaging, it is now possible to detect an infectious process early in its course and follow the response to therapy. Although significantly more effective than in the past, antimicrobial therapy alone is insufficient to eradicate most intracranial infections, especially in the presence of compression or displacement of the cerebrum. Surgery remains an essential part of the management of intracranial infection because of its ability to provide immediate relief from pressure on neural structures and thereby result in clinical improvement. The most common infections affecting the brain, namely, cranial epidural abscess, subdural empyema, brain abscess, viral infection, tuberculosis, and neurocysticercosis, can each be associated with significant mass effect on the cerebrum that is greatly reduced through surgery. This relief, in combination with newer antimicrobial agents that have an improved ability to cross the blood brain barrier, has led to a reduction in the infection-related morbidity and mortality rates associated with intracranial infections. Combining advanced imaging and surgical techniques in the form of intraoperative magnetic resonance image-guided neurosurgery may further enhance clinical outcomes in these once uniformly fatal diseases.


[Effects of 1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone on renal fibroblast in rats].
To explore the curative effects of 1-(3-fluorophenyl)-5-methyl-2- (1H)-pyridone (FMP) on renal fibrosis in rats. The effects of FMP on the cell proliferation and Fn secretion were measured by methyl thiazolyl tetrazolium and enzyme-linked immunoabsorbent assay, respectively. FMP obviously inhibited the proliferation and Fn secretion in rat renal fibroblast 48 hours after the treatment. FMP (1 000 microg/ml) obviously inhibited the proliferation of rat renal fibroblast 24 hours after the treatment. 1-(3-Fluorophenyl) -5-methyl-2-(1H)-pyridone can obviously inhibit the proliferation of rat renal fibroblast, which may be effective for renal interstitial fibrosis prevention and treatment.


[Polyomavirus BK-associated nephropathy after kidney transplantation].
Polyomavirus BK (BKV) infection has been lately recognized as a major cause of renal allograft dysfunction. BKV-related interstitial nephropathy (PVAN) may affect 1-10% of renal allograft recipients, occurring more frequently in the first 6 months after transplantation. Progression to irreversible allograft failure has been observed in up to 45% of all cases; thanks to increased PVAN awareness and improved diagnostic techniques, the rate of graft loss has lowered, more consistently in centres with active screening and intervention programs. PVAN pathogenesis is characterized by multiple synergizing factors, among which immunodepression plays a key role. PVAN diagnosis requires the evaluation of a renal biopsy showing polyomavirus cytopathic changes and confirming BKV through an ancillary technique such as immunohistochemistry. Given the focal nature of the disease, early diagnosis may be difficult to obtain. Thus, quantification of BKV-DNA in plasma has been suggested as surrogate marker for PVAN. To date, given the lack of controlled trials, there is no consensus on a 'standard' management of PVAN. However, evidence based on reported observations suggests that a step-wise reduction of immunosuppression, preceded by pulsed steroids in case of coexistent acute rejection, may improve outcomes. Additional options may be represented by drugs with antiviral activity, such as cidofovir, leflunomide or quinolones. Application of a preventive treatment based on viremia monitoring has been recently proposed.


Markers of implantation in ectopic and high-risk early eutopic pregnancies.
This study focused on the assessment of HSP-10, HSP-27 and PSG-11 which are one of the first detectable serum pregnancy proteins. Contrary to ultrasound imaging, biochemical methods allow to clarify the pathogenesis and pathomechanism of high-risk pregnancies, fetal anomalies, and abnormal fetal implantation. Early serum concentration estimation of HSP-10, HSP-27 and PSG-11 may be very useful not only in prognosis of pregnancies of unknown localization (PUL), but also as markers of ectopic pregnancies. The aim of the study was to evaluate the expression of HSP-10, HSP-27, PSG-11 implantation proteins in ectopic and eutopic pregnancies, and their mutual correlations. The study involved 42 healthy women who were hospitalized, due to symptoms of imminent miscarriage, risk of spontaneous abortion, or the diagnosis of an ectopic pregnancy. The subjects were subdivided into two equal groups of 21 women who consented to participate in this clinical trial. Biochemical assays were performed involving PSG-11, HSP-27, and HSP-10 serum concentration. Serum concentration levels of HSP-10, HSP-27, and PSG-11 were significantly higher in pregnancies at risk of spontaneous abortion as compared to ectopic pregnancies. The results of the study indicate high value of PSG-11, HSP-27 and HSP-10 serum concentrations as predictors of correct implantation site. This may be very useful in prognosis of pregnancies of unknown localization (PUL) and early conservative/surgical ectopic pregnancies treatment if necessary to preserve maximum fertility.


Investigation of the profile of phenolic compounds in the leaves and stems of Pandiaka heudelotii using gas chromatography coupled with flame ionization detector.
The profile of phenolic compounds in the leaves and stems of Pandiaka heudelotii was investigated using gas chromatography coupled with flame ionization detector. The leaves and stems had high flavonoids and benzoic acid derivatives content, and moderate levels of lignans and hydroxycinnamates. Twenty-eight known flavonoids were detected, which consisted mainly of kaempferol (41.93% in leaves and 47.97% in stems), (+)-catechin (17.12% in leaves and 16.11% in stems), quercetin (13.83% in leaves and 9.39% in stems), luteolin (7.34% in leaves and 7.71% in stems), and artemetin (6.53% in leaves and 4.83% in stems). Of the six known hydroxycinnamates detected, chlorogenic acid (80.79% in leaves and 87.56% in stems) and caffeic acid (18.98% in leaves and 12.30% in stems) were the most abundant, while arctigenin (77.81% in leaves and 83.40% in stems) and retusin (13.82% in leaves and 10.59% in stems) were the most abundant of the nine known lignans detected. Twelve known benzoic acid derivatives were detected, consisting mainly of ellagic acid (65.44% in leaves and 72.89% in stems), p-hydroxybenzoic acid (25.10% in leaves and 18.95% in stems), and vanillic acid (8.80% in leaves and 7.30% in stems). The rich phytochemical profile of the leaves and stems is an indication of their ability to serve as sources of nutraceuticals.


The remembrance of times past: interference in temporal reference memory.
Six experiments examined human performance on a modified temporal generalization task when either 1 or 2 standard durations were encoded. In most conditions, participants were presented with a 1st standard duration (A), then judged whether a number of comparison stimuli had the same duration as A. They were then presented with a 2nd standard (B) and again judged whether other comparison stimuli had the same duration as B. Then, after a delay period of 0-45 s, further comparison stimuli were presented, and participants judged whether those stimuli had the same duration as A, without A being represented. A was either the same length as B or shorter or longer than it, so potential retroactive interference effects of B on A could be examined. After a short delay before retesting of A comparisons, the peak of the temporal generalization gradient shifted toward the shortest of the comparisons when A < B and the longest when A > B. The results suggest that certain combinations of delay and interference might render the memory of A unusable, so that a new standard is constructed on the basis of the remembered relationship between A and B, a kind of "false memory" for duration.