Distribution of the pores of epithelial basement membrane in the rat small intestine.
The distribution and diameter of the pores of epithelial basement membrane in the intestinal villi and the lymph nodules of ileal Peyer's patches were investigated in the rat small intestine by scanning electron microscopy after the removal of the overlying epithelial cells with OsO(4) maceration. In the duodenum, jejunum and ileum, the pores were mainly distributed at the upper three fourths of the villi, but were scarce around the top of the villi. The diameter of some of the pores in the upper three fourths of the villi was larger than that of those in the lower portion. The protrusion of lymphocytes and the cytoplasmic processes of macrophages were also seen at the orifices of the pores. In ileal Peyer's patches, in contrast, pores were densely distributed in the lower one third of the follicle-associated epithelium (FAE) where M cells were mainly seen. Furthermore, these pores were larger than those found in the upper two thirds. Lymphocytes or cytoplasmic processes of macrophages were frequently seen in the lower one third of FAE. These results suggest that the pores at the basement membrane correspond to the passage of the immunocompetent cells which are in contact with M cells or villous columnar epithelial cells and that the abundance of pores is a sign of aggressive interaction between the particular epithelial cells and the immunocompetent cells at the upper three fourths of intestinal villi and the lower one third of FAE in the rat small intestine.


Hybrid polarization-angle multiplexing for volume holography in gold nanoparticle-doped photopolymer.
We report on volume holographic hybrid polarization-angle multiplexing in a gold nanoparticle-doped photopolymer. When doping the gold nanoparticles, the linear photoinduced birefringence of the phenanthrenequinone-doped poly (methyl methacrylate) (PQ/PMMA) photopolymer could be increased by nearly 38%. The data pages could be recorded with the orthogonal circular polarization multiplexing, and the reconstructed images have a symbol-error rate of 3.81% and 4.46% for left circular polarization and right circular polarization state, respectively. Two biological image sets multiplexed both with the angle interval of 0.1° and with orthogonal circular polarization are reconstructed separately and simultaneously.


Output of bilirubin and pancreatic enzymes in response to different liquid test meals in man.
The output of bilirubin and pancreatic enzymes was determined after ingestion of three different liquid test meals in man. Doubling the amount of protein in a composite meal was followed by a delivery of more protein per time unit to the intestine and by a higher output of bilirubin and enzymes than was recorded after a similar meal containing less protein. The ingestion of a 15% glucose solution awoke a considerable output of bilirubin and enzymes during the first hour, thereafter it was low and decreasing. The differences in enzyme and bilirubin output corresponded to differences in quality and quantity of the emptied food components.


p65 controls NF-κB activity by regulating cellular localization of IκBβ.
NF-κB (nuclear factor κB) controls diverse cellular processes and is frequently misregulated in chronic immune diseases or cancer. The activity of NF-κB is regulated by IκB (inhibitory κB) proteins which control nuclear-cytoplasmic shuttling and DNA binding of NF-κB. In the present paper, we describe a novel role for p65 as a critical regulator of the cellular localization and functions of NF-κB and its inhibitor IκBβ. In genetically modified p65-/- cells, the localization of ectopic p65 is not solely regulated by IκBα, but is largely dependent on the NLS (nuclear localization signal) and the NES (nuclear export signal) of p65. Furthermore, unlike IκBα, IκBβ does not contribute to the nuclear export of p65. In fact, the cellular localization and degradation of IκBβ is controlled by the p65-specific NLS and NES. The results of our present study also reveal that, in addition to stimulus-induced redistribution of NF-κB, changes in the constitutive localization of p65 and IκBβ specifically modulate activation of inflammatory genes. This is a consequence of differences in the DNA-binding activity and signal responsiveness between the nuclear and cytoplasmic NF-κB-IκBβ complexes. Taken together, the findings of the present study indicate that the p65 subunit controls transcriptional competence of NF-κB by regulating the NF-κB/IκBβ pathway.


[Listeria monocytogenes meningitis in immunocompetent children: unpasteurized cheese likely cause of infection].
Listeria meningoencephalitis is a rare condition, occurring mainly in immunocompromised patients. We present two cases of Listeria monocytogenes meningoencephalitis in immunocompetent children, with successful treatment with betalactam/aminoglycoside combination. Unpasteurized cheese was postulated as the source of infection.


Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives.
A series of derivatives of 2,4-dihydroxy-3-propylacetophenone(1) were prepared and examined for their ability to block leukotriene D4 (LTD4) induced contraction of guinea pig ileum. Straight-chain carboxylic acids where the carboxyl group was separated from the acetophenone moiety by varying numbers of methylenes were evaluated, and maximum activity was obtained with the pentamethylene acid (6). Examination of ring substitution showed that the 2-propyl-3-hydroxy-4-acetyl substitution pattern was required for maximum LTD4 antagonist activity. Additional chain terminal groups were examined, and the acidic 5-tetrazolyl group separated from the acetophenone moiety by four to seven methylenes (26, 23, 27, 28) gave excellent in vitro and in vivo activities. Compound 26 (LY171883) had the best balance of in vitro and in vivo activity. It lacked bronchospastic activity at the doses administered and has been chosen for clinical evaluation.


A rare case of plastid protein-coding gene duplication in the chloroplast genome of Euglena archaeoplastidiata (Euglenophyta).
Gene duplication is an important evolutionary process that allows duplicate functions to diverge, or, in some cases, allows for new functional gains. However, in contrast to the nuclear genome, gene duplications within the chloroplast are extremely rare. Here, we present the chloroplast genome of the photosynthetic protist Euglena archaeoplastidiata. Upon annotation, it was found that the chloroplast genome contained a novel tandem direct duplication that encoded a portion of RuBisCO large subunit (rbcL) followed by a complete copy of ribosomal protein L32 (rpl32), as well as the associated intergenic sequences. Analyses of the duplicated rpl32 were inconclusive regarding selective pressures, although it was found that substitutions in the duplicated region, all non-synonymous, likely had a neutral functional effect. The duplicated region did not exhibit patterns consistent with previously described mechanisms for tandem direct duplications, and demonstrated an unknown mechanism of duplication. In addition, a comparison of this chloroplast genome to other previously characterized chloroplast genomes from the same family revealed characteristics that indicated E. archaeoplastidiata was probably more closely related to taxa in the genera Monomorphina, Cryptoglena, and Euglenaria than it was to other Euglena taxa. Taken together, the chloroplast genome of E. archaeoplastidiata demonstrated multiple characteristics unique to the euglenoid world, and has justified the longstanding curiosity regarding this enigmatic taxon.


Effects of Horticultural Therapy on Asian Older Adults: A Randomized Controlled Trial.
The effect of horticultural therapy (HT) on immune and endocrine biomarkers remains largely unknown. We designed a waitlist-control randomized controlled trial to investigate the effectiveness of HT in improving mental well-being and modulating biomarker levels. A total of 59 older adults was recruited, with 29 randomly assigned to the HT intervention and 30 to the waitlist control group. The participants attended weekly intervention sessions for the first 3 months and monthly sessions for the subsequent 3 months. Biological and psychosocial data were collected. Biomarkers included IL-1β, IL-6, sgp-130, CXCL12/SDF-1α, CCL-5/RANTES, BDNF (brain-derived neurotrophic factor), hs-CRP, cortisol and DHEA (dehydroepiandrosterone). Psychosocial measures examined cognitive functions, depression, anxiety, psychological well-being, social connectedness and satisfaction with life. A significant reduction in plasma IL-6 level (p = 0.02) was observed in the HT intervention group. For the waitlist control group, significant reductions in plasma CXCL12 (SDF-1α) (p = 0.003), CXCL5 (RANTES) (p = 0.05) and BDNF (p = 0.003) were observed. A significant improvement in social connectedness was also observed in the HT group (p = 0.01). HT, in reducing plasma IL-6, may prevent inflammatory disorders and through maintaining plasma CXCL12 (SDF-1α), may maintain hematopoietic support to the brain. HT may be applied in communal gardening to enhance the well-being of older adults.


Engineering the esaR promoter for tunable quorum sensing- dependent gene expression.
Quorum sensing (QS) systems enable bacteria to coordinate their behavior as a function of local population density and are often used in synthetic systems that require cell−cell communication. We have engineered the esaR promoter, P(esaR), which is repressed by the QS regulator E(saR). E(saR)-dependent gene expression from P(esaR) is induced by 3-oxo-hexanoyl-homoserine lactone (3OC6HSL). Here, we report a set of modified P(esaR) promoters that contain a second E(saR) binding site. We observed changes in gene expression levels, regulatory range, 3OC6HSL sensitivity, and the regulatory role of E(saR) that are dependent on the position of the second binding site. Combining the new promoters with endogenous 3OC6HSL production led to QS-dependent systems that exhibit a range of expression levels and timing. These promoters represent a new set of tools for modulating QS-dependent gene expression and may be used to tune the regulation of multiple genes in response to a single QS signal.


A positive approach to the utilization of student feedback in medical education.
Many of the problems related to the usability of student feedback in medical education are concerned with validity and reliability. In this paper the author presents a rationale and a systematic procedure for the construction, implementation, and analysis of student feedback data which will provide both valid and reliable information about specific areas of the educational process that are controllable by instructors. This information can then be combined with other factors and used for continuous improvement of the teaching/learning process.


Exosomal miR‑152‑5p/ARHGAP6/ROCK axis regulates apoptosis and fibrosis in cardiomyocytes.
Acute myocardial infarction (AMI) is a fatal cardiovascular disease with a high mortality rate. The discovery of effective biomarkers is crucial for the diagnosis and treatment of AMI. In the present study, miRNA sequencing and reverse transcription-quantitative polymerase chain reaction techniques revealed that the expression of exosome derived miR-152-5p was significantly downregulated in patients with AMI compared with healthy controls. A series of functional validation experiments were then performed using H9c2 cardiomyocytes. Following transfection of the cardiomyocytes using an miR-152-5p inhibitor, immunofluorescence staining of a-smooth muscle actin revealed a marked increase in fibrosis. Western blotting revealed that the expression levels of the apoptotic protein Bax, TNF-α and collagen-associated proteins were significantly increased, whereas those of the apoptosis-inhibiting factor Bcl-2 and vascular endothelial growth factor A were significantly decreased. Furthermore, the binding of Rho GTPase-activating protein 6 (ARHGAP6) to miR-152-5p was predicted using an online database and verified using a dual-luciferase reporter gene assay. The transfection of cardiomyocytes with miR-152-5p mimics was found to inhibit the activation of ARHGAP6 and Rho-associated coiled-coil containing kinase 2 (ROCK2). These results suggest that miR-152-5p targets ARHGAP6 through the ROCK signaling pathway to inhibit AMI, which implies that miR-152-5p may be a diagnostic indicator and potential target for treatment of myocardial infarction.


Induction of high affinity fibroblast growth factor receptor expression and proliferation in human endothelial cells by anti-HLA antibodies: a possible mechanism for transplant atherosclerosis.
The major limitation to long term survival of organ allografts is chronic rejection, which is manifested as atherosclerosis of the vessels of the transplanted organ. There is a significant association between transplant atherosclerosis and the development of Abs to the disparate HLA Ags present on the graft vasculature. We have investigated the effect of anti-HLA Abs on endothelial cells (EC) and smooth muscle cells cultured in vitro. Ab ligation of class I molecules on ECs results in increased high affinity fibroblast growth factor receptor mRNA expression, and enhanced basic fibroblast growth factor ligand binding. Ab binding to class I molecules on EC and smooth muscle cells is also accompanied by augmented cell proliferation. These results suggest that the intimal thickening observed in transplant atherosclerosis is the result of the proliferative effects of anti-HLA Abs.


Assessing the impact of electrohydrodynamic jetting on encapsulated cell viability, proliferation, and ability to self-assemble in three-dimensional structures.
In this article, we propose a systemic approach to investigate the impact of electrohydrodynamic jetting (EHDJ) encapsulation on viability, proliferation, and functionality of the encapsulated cells. EHDJ consists in applying a high-voltage electrical field between a target substrate and a jetting needle, which is fed with a suspension of cells in a polymeric solution undergoing a sol-gel transition upon contact with the target. The viability, proliferation, and self-assembling ability of SHSY5Y human neuroblastoma cell line encapsulated in 2% alginate microbeads were analyzed by confocal microscopy and DNA quantification assays. In addition, the expression of stress (HSP70B'), apoptotic (CASP3), necrotic (HMGB1), hypoxic (HYOU1, GAPDH), and adhesion (CDH2) markers was measured with reverse transcription quantitative polymerase chain reaction (qPCR). After an initial upregulation of the HSP70B' expression within 24 h, its expression decreased to the negative control level together with a decrease in the expression of CASP3. Any increase in necrotic or hypoxic marker expression was not detected, while a slight upregulation of CDH2 was observed in the first days after encapsulation, followed by its downregulation and stabilization to the control level. Furthermore, cell-laden beads started to self-assemble in three-dimensional (3D) constructs from the 3rd week after encapsulation. The results indicated that the EHDJ encapsulation method had a mild effect on cells, which after a week, fully recovered their proliferation rate and ability to self-assemble into 3D constructs.


Effect of Resveratrol on Endothelial Function in Patients with CKD and Diabetes: A Randomized Controlled Trial.
Patients with CKD and diabetes are at higher risk of developing cardiovascular disease, in part, because of impaired endothelial function. Cardioprotective compounds such as resveratrol could improve endothelial function and attenuate the cardiovascular burden in patients with CKD and diabetes. We hypothesized that resveratrol supplementation would improve endothelial function in patients with CKD and diabetes. Twenty-eight adults aged 68±7 years (84% men) with stage 3 CKD and diabetes were enrolled in a randomized, double-blind, placebo-controlled, crossover study to investigate the effects of 6-week resveratrol supplementation (400 mg/d) on endothelial function. Endothelial function was determined through brachial artery flow-mediated dilation. The mean values for eGFR and hemoglobin A 1c were 40±9 ml/min per 1.73 m 2 and 7.36%±0.72%, respectively. Compared with placebo, resveratrol supplementation increased flow-mediated dilation (ratio of geometric mean changes and 95% confidence interval for between-group comparisons, 1.43 (1.15 to 1.77); P value = 0.001). eGFR, hemoglobin A 1c , BP, and nitroglycerin-mediated dilation were unchanged with resveratrol or placebo ( P = 0.15), suggesting the observed change in flow-mediated dilation was likely independent of changes in traditional cardiovascular risk factors. Resveratrol supplementation improved endothelial function in patients with CKD and diabetes. Resveratrol and Vascular Function in CKD, NCT03597568 .


Interactive dynamic system of didactic means in medical studies.
Didactic means are an integral part of teaching also in the process of healthcare and doctoral education. They are applied not only in teaching of theoretical, but also in that of clinical subjects at medical faculties. The forms and levels of the use of didactic aids are subject to a dynamic process of transformation. They take place in form of conceptions, projects, realizations, results and effects. A part of them represent a domain of professionals, others are affected by basically non-professional teachers. The results and effects are influenced by students. The authors of this study present the didactic means used at the Faculty Medicine of Comenius University (FMCU) in Bratislava. (Tab. 1, Ref. 11.).


Incidence of hepatitis B-antigenaemia and positive alphafoetoprotein in New Zealand, Western Samoa and Tonga--(a pilot study of Polynesian liver disease).
A pilot study was carried out to determine the nature of Polynesian liver disease by a study of blood donors and liver biopsy material from natives in Samoa, Tonga and Auckland, New Zealand. The data is suggestive that the Hepatitis B carrier state and hepatoma are greater in Polynesians than in Europeans. One familial hepatoma in two Maori brothers at ages of 11 and 13 years are reported.


Effect of captopril and telmisartan on methotrexate-induced hepatotoxicity in rats: impact of oxidative stress, inflammation and apoptosis.
Methotrexate (MTX) is a commonly used antineoplastic and anti-rheumatoid drug whose efficacy is limited by its hepatotoxicity. The aim of this study was to investigate the possible protective role of captopril (100 mg/kg/day, p.o. for seven days), an angiotensin converting enzyme inhibitor, and telmisartan (10 mg/kg/day p.o. for seven days), an angiotensin II receptor blocker with peroxisome proliferative receptor gamma (PPARγ) agonism, in a model of MTX (single dose 20 mg/kg i.p. at the fifth day) induced hepatotoxicity in rats. Results of the present study revealed MTX-induced hepatotoxicity as demonstrated by increased level of liver enzymes and confirmed by histopathology. Pretreatment with captopril or telmisartan produced a significant hepatic protection manifested as a significant (p < 0.05) decrease in serum levels of alanine transferase (ALT) and aspartate transferase (AST) and alkaline phosphatase (ALP) enzymes; hepatic malondialdehyde (MDA) and total nitrites and nitrates (NOx) levels; as well as a significant increase in hepatic superoxide dismutase (SOD) activity. In addition, there was a remarkable improvement in the histopathological features and a significant reduction in the expression of COX-2, iNOS and caspase-3 enzymes as compared with the MTX group. We recommend considering captopril/Telmisartan, if tolerated and not contraindicated, as preferable antihypertensive agents in patients receiving MTX in their chemotherapy protocols.


Access to 18 F-labelled isoxazoles by ruthenium-promoted 1,3-dipolar cycloaddition of 4-[18 F]fluoro-N-hydroxybenzimidoyl chloride with alkynes.
4-[18 F]Fluoro-N-hydroxybenzimidoyl chloride (18 FBIC), an 18 F-labelled aromatic nitrile oxide, was developed as building block for Ru-promoted 1,3-dipolar cycloaddition with alkynes. 18 FBIC is obtained in a one-pot synthesis in up to 84% radiochemical yield (RCY) starting from [18 F]fluoride with 4-[18 F]fluorobenzaldehyde (18 FBA) and 4-[18 F]fluorobenzaldehyde oxime (18 FBAO) as intermediates, by reaction of 18 FBAO with N-chlorosuccinimide (NCS). 18 FBIC was found to be a suitable and stable synthon to give access to 18 F-labelled 3,4-diarylsubstituted isoxazoles by [Cp*RuCl(cod)]-catalysed 1,3-dipolar cycloaddition with various alkynes. So the radiosynthesis of a fluorine-18-labelled COX-2 inhibitor [18 F]1b, a close derivative of valdecoxib, was performed with 18 FBIC and 1-ethynyl-4-(methylsulfonyl)benzene, providing [18 F]1b in up to 40% RCY after purification in 85 minutes. The application of 18 FBIC as a building block in the synthesis of 18 F-labelled heterocycles will generally extend the portfolio of available PET radiotracers.


T-cell prolymphocytic leukaemia associated with immune checkpoint inhibitor (pembrolizumab).
We describe the case of a man in his 60s with squamous cell carcinoma of the lung with brain metastasis treated with pembrolizumab who subsequently developed T-cell prolymphocytic leukaemia. He was transferred to our hospital with worsening dyspnoea, suspected hyperviscosity syndrome and tumour lysis syndrome. He was intubated and admitted to our critical care unit. Emergent leucapheresis was started due to worsening renal function in the setting of tumour lysis and hyperviscosity syndromes. He continued to deteriorate and required continuous renal replacement therapy. Unfortunately, he eventually died from haemodynamic decompensation. There are only a few anecdotal cases pointing at a possible association between the use of immune checkpoint inhibitors and the progression or exacerbation of secondary haematological malignancies. The poor prognosis of these haematological malignancies warrants further investigation to determine if checkpoint inhibitors increase the risk of developing or propagating these potentially fatal diseases.


Illuminated curved 25-gauge vitrectomy probe for removal of subsclerotomy vitreous in vitreoretinal surgery.
Incarceration of vitreous in sclerotomy sites during pars plana vitrectomy can lead to wound-related complications similar to vitreous incarceration in cataract surgery. We describe an illuminated curved 25-gauge vitrectomy probe for removing vitreous from sclerotomy sites. Polyester tubing is used to secure a fiber optic endoilluminator (0.5 mm) with the curved 25-gauge vitrector (0.5 mm). The resultant illuminated curved vitrector (20 G) has a diameter of 1.0 mm. It facilitates complete removal of vitreous around the internal sclerotomies under direct visualization in both phakic and pseudophakic eyes. The same was confirmed with ultrasound biomicroscopy of the sclerotomy sites. Curved vitrector reduces postoperative complications related to incarcerated vitreous in phakic and pseudophakic eyes and other sclerotomy-related wound complications.


[Age and sex dependence of the diameter of the lumen of the ascending, thoracic and abdominal aorta].
The quantitative estimation of luminal diameter of 102 aortas (ascending, thoracic and abdominal aorta) from neonates to adults of 80 years showed a continuous increase with a marked change until the age of 15. From the 20th up to the 80th year we observed a further enlargement of the inner vessel-diameter of about 50%.


An in vitro model of Pseudomonas aeruginosa biofilms on viable airway epithelial cell monolayers.
Chronic rhinosinusitis (CRS) that is refractory to medical or surgical intervention may involve a particularly resistant form of infection known as a bacterial biofilm. Bacterial biofilms are three-dimensional aggregates of bacteria that often are recalcitrant to antibiotics secondary to physical barrier characteristics. To date, all studies investigating biofilms in CRS have been descriptive in either human or animal tissue. To better understand the interactions of bacterial biofilms with respiratory epithelium, we describe an in vitro model of biofilm sinusitis by establishing mature biofilms on airway epithelial air-liquid interface cultures. Airway epithelial cell cultures were grown on collagen-coated semipermeable support membranes as an air-liquid interface on tissue culture inserts. Confluent air-liquid interface cultures were inoculated with the biofilm-forming PAO-1 strain of Pseudomonas aeruginosa and compared with cultures inoculated with two mutant strains (sad-31 and sad-36) unable to form biofilms. Inoculated tissue transwells were incubated for 20 hours, allowing for biofilm growth. The semipermeable membranes were then harvested and imaged with confocal laser scanning microscopy and scanning electron microscopy. Microscopic analysis revealed the formation of biofilm-forming towers in the PAO-1 inoculated wells. The bacterial biofilms were supported by a viable airway epithelial cell surface monolayer. This study shows a reliable method for analysis of in vitro interactions of bacterial biofilms and airway epithelium. The experimental manipulation of this air-liquid interface model will help explore novel treatment approaches for bacterial biofilm-associated CRS.


Viral sexually transmitted infections and bacterial vaginosis: 2001-2004 National Health and Nutrition Examination Survey data.
Bacterial vaginosis (BV) is a common condition believed to be associated with sexually transmitted infection (STI) susceptibility. Most studies of BV and STIs have come from treatment-seeking or high-risk populations. This study examines the association between 5 viral STIs, human papilloma virus (HPV), HIV, herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), and Hepatitis C (HCV), and BV among women in the general US population. Data from the 2001 and 2003-2004 National Health and Nutrition Examination Surveys were combined. Crude and adjusted relative risks and 95% confidence intervals were estimated from logistic regression analyses for rare outcomes (<10%) and from Poisson regression with robust error variance for common outcomes. Complex survey design was taken into consideration using the survey functions in Stata. Crude analyses found an association between BV and the prevalence of all 5 STIs. After adjustment for important confounders, only HSV-1 and HSV-2 were significantly associated with the presence of BV. Moreover, crude analyses stratified by race/ethnicity suggested that associations between BV and viral STIs may not be consistent across race/ethnicity subgroups. This population-based study found that BV was significantly associated with the prevalence of HSV-1 and HSV-2 and potentially associated with HIV and HPV. Given the frequency of BV in US women, small increases in STI susceptibility may have important impacts on STI transmission.


Comparison between the refractive results of combined penetrating keratoplasty/transsclerally sutured posterior chamber lens implantation and the triple procedure.
We determined how accurately we could predict the intraocular lens (IOL) power for a combined penetrating keratoplasty and transsclerally sutured posterior chamber lens implantation procedure (PK/TS-SPCL) compared with the Triple procedure (penetrating keratoplasty, extra-capsular cataract extraction, and IOL insertion). We retrospectively evaluated the postoperative refractive results of 27 patients who had undergone PK/TS-SPCL and compared them with those of 46 patients who had undergone a Triple procedure. All patients with a final visual acuity > 20/50 who had surgery at the University of Minnesota between January 1988 and December 1993 were included in this study. The mean postoperative deviation from the predicted refractive error was 1.79 D for the Triple group and 1.81 D for the PK/TS-SPCL group (p = 0.95). Sixty-three percent of the Triple patients and 67% of the PK/TS-SPCL patients were within -2.00 D and +2.00 D of their predicted refractive error. As a group, the Triple patients had a mean postoperative keratometry reading of 44.64 compared with 45.58 for the PK/TS-SPCL patients (p = 0.12). These results indicate that our accuracy in predicting the IOL implant power in PK/ TS-SPCL is quite comparable with that obtained for the Triple procedure, and our refractive results for each group are quite similar.


Myelodysplasia following paroxysmal nocturnal haemoglobinuria: evidence for the emergence of a separate clone.
A patient with paroxysmal nocturnal haemoglobinuria (PNH) who developed a myelodysplastic syndrome (MDS) is described. After the onset of myelodysplasia the neutrophils of the patient fully expressed GPI-linked proteins. It is concluded that the myelodysplasia does not originate from transformed PNH stem cells, but represents the emergence of a separate clone arising from an injured marrow.


GWAS GUI: graphical browser for the results of whole-genome association studies with high-dimensional phenotypes.
We describe an interactive package that provides graphical overviews of the results of whole-genome association studies in datasets with rich multi-dimensional phenotypic information, such as global surveys of gene expression. Windows, Linux and Mac binaries are available from our website.


Effects of bursectomy and splenectomy of white Leghorn roosters on subsequent northern fowl mite populations.
White Leghorn roosters bursectomized at one day of age, splenectomized at 21 days of age, or bursectomized at one day of age and splenectomized at 21 days of age were infested with the northern fowl mite (NFM) at 22 to 23 weeks of age. No significant differences in NFM populations were observed in the bursectomized, splenectomized, bursectomized and splenectomized, or control roosters during the 24-week infestation period.


Early life predictors of adult depression in a community cohort of urban African Americans.
Depression among African Americans residing in urban communities is a complex, major public health problem; however, few studies identify early life risk factors for depression among urban African American men and women. To better inform prevention programming, this study uses data from the Woodlawn Study, a well-defined community cohort of urban African Americans followed from age 6 to 42 years, to determine depression prevalence through midlife and identify childhood and adolescent risk factors for adult depression separately by gender. Results indicate that lifetime depression rates do not differ significantly by gender (16.2 % of men, 18.8 % of women) in contrast to findings of a higher prevalence for women in national studies. Furthermore, rates of depression in this urban African American population are higher than those found in national samples of African Americans and more comparable to the higher rates found nationally among Whites. Regarding early predictors, for both men and women, family conflict in adolescence is a risk factor for adult depression in multivariate regression models. For women, vulnerability to depression has roots in early life, specifically, low maternal aspirations for school attainment. Females displaying more aggressive and delinquent behavior and those growing up in a female-headed household and a household with low maternal education have elevated rates of depression. Males growing up in persistent poverty, those engaging in greater delinquent behavior, and those with low parental supervision in adolescence also have elevated rates of depression. Effective prevention programming for urban African Americans must consider both individual characteristics and the family dynamic.


Regular reaction dynamics in analytical form in the vicinity of symmetrical transition states. Central barrier crossings in SN2 reactions.
When an activated complex, as defined in transition state theory (TST), has a polyhedral shape, its kinetic energy is found to be diagonal in a system of spherical polar coordinates. If, in addition, the polyhedron is characterized by a high symmetry, then its dynamics considerably simplifies. An application of this approach to the most symmetrical TS known to date, i.e., that which controls the Cl- + CH3Cl → ClCH3 + Cl- SN2 nucleophilic substitution, is presented and an analytical expression of its potential energy surface is provided. In a substantial range around the saddle point, approximate equations of motion for the two components of the reaction coordinate, i.e., the antisymmetrical stretching motion of the ClCCl core and the wagging motion of the hydrogen triad, can be derived in an analytical form. During an extensive period of time, the main component of the reaction coordinate is governed by an unexpectedly simple equation of motion that depends on a single initial condition, irrespective of the other ones and of the internal energy. Reactive trajectories are observed to form a perfectly collimated bundle characterized by undetectable dispersion, thereby giving a spectacular example of regular dynamics in an anharmonic potential. Regularity and collimation are brought about by local symmetry, which is a widespread feature of potential energy surfaces. Anharmonicity is observed to influence the dynamics only at a late stage. As energy increases, trajectories tend to fan out and to deviate from the analytical equation. For the wagging motion, chaos sets in at much lower energies.


Assessment of Glycemic Control in Nursing Home Residents with Diabetes.
To describe glycemic control in nursing home residents with diabetes and to evaluate the relevance of HbA1c in the detection of hypoglycemia risk. Diabetes treatment, geriatric assessment, blood capillary glucose (n= 24,682), and HbA1c were collected from medical charts of 236 southern France nursing home residents during a 4-month period. Glycemic control was divided into four categories: tight, fair, and moderate or severe chronic hyperglycemia using the High Blood Glucose Index or the analysis of blood glucose frequency distribution. Hypoglycemia episodes were identified by medical or biological records. Glucose control was tight in 59.3 % and fair in 19.1 % of the residents. Chronic exposure to hyperglycemia was observed in 21.6 % of the residents (severe in 9.7 % and moderate in 11.9 %). Hypoglycemia was noticed in 42/236 (17.8%), in all categories of glycemic control. Relative hypoglycemia risk was significantly (P = 0.0095) higher in residents with moderate chronic hyperglycemia compared with those with tight control. The majority of residents with hypoglycemia (39/42) or chronic hyperglycemia (45/51) were insulin-treated. The relative risk of hypoglycemia was not significantly associated with HbA1c values. Hypoglycemia risk in nursing home residents is observed in all categories of glycemic control. In tight control, the potency of antidiabetic treatment should be reduced. In chronic hyperglycemia, diet and treatment should be reevaluated in order to reduce glucose variability. HbA1c is not sufficient for hypoglycemia risk detection; capillary blood glucose monitoring is warranted for nursing homes residents with diabetes.


CpG methylation patterns in the 5' part of the nonclassical HLA-G gene in peripheral blood CD34+ cells and CD2+ lymphocytes.
A dominant goal of research focused on the nonclassical human leukocyte antigen G (HLA-G) gene is to understand the molecular mechanism involved in its limited expression. In the present report, we examined DNA methylation as a potential regulatory mechanism of HLA-G transcription in two cell types of the adult lymphomyeloid lineage: CD2+ lymphocytes express several mRNA isoforms while transcripts are undetectable in CD34+ hematopoietic cells. The methylation status of 63 CpG sites in the promoter and in the 5' CpG island was established using bisulfite-treated genomic DNA sequencing. Methylation was first analyzed by the direct sequencing of bisulfite-treated and amplified products. The general patterns of CpG methylation in the 5' part of the gene were found to be similar for CD34+ cells and CD2+ lymphocytes: the distribution of methylation was not uniform across the 63 CpG sites. In the promoter region, both CpG dinucleotides were partially or fully methylated whereas in the CpG island, several CpG sites were totally demethylated. Unexpectedly, in HLA-G positive CD2+ lymphocytes, a great number of CpG dinucleotides displayed a higher frequency of methylation relative to that found in CD34+ cells. However, the sequence analysis of cloned products revealed that the molecules have different methylation patterns which suggests that the HLA-G gene is differentially expressed in CD2+ cells. Our results suggest that methylation is not the sole mechanism that achieves the repression of HLA-G transcription in immature CD34+ cells.


Protective role of anthocyanins in plants under low nitrogen stress.
Nitrogen (N) is a major nutrient of plants but often a limiting factor for plant growth and crop yield. To adapt to N deficiency, plants have evolved adaptive responses including accumulation of anthocyanins. However, it is still unclear whether the accumulated anthocyanins are part of the components of plant tolerance under low N stress. Here, we demonstrate that low N-induced anthocyanins contribute substantially to the low N tolerance of Arabidopsis thaliana. pap1-1, a mutant defective in MYB75 (PAP1), a MYB-type transcription factor that positively regulates anthocyanin biosynthesis in Arabidopsis, was found to have significantly decreased survival rate to low N stress compared to its wild-type plants. Similarly, tt3, a mutant with severe deficiency in dihydroflavonol 4-reductase (DFR), a key enzyme in anthocyanin biosynthesis, also showed much lower survival rate under low N stress. These results indicate that anthocyanins are substantial contributors of plant tolerance to low N stress. Furthermore, a metabolomics analysis using LC-MS revealed changes in flavonoid profile in the pap1-1 and tt3 plants, which established a causal relationship between plant adaptation to low N stress and these compounds including anthocyanins. Our results showed an important role of anthocyanins rather than flavonols in conferring plant tolerance to low N stress.


Integrated phenotypic screening and activity-based protein profiling to reveal potential therapy targets of pancreatic cancer.
Pancreatic cancer has been defined as one of the most complex and challenging cancers to treat, but very few valid therapeutic targets have been identified to date. To address this issue, a 61-compound library was readily created by Ugi reaction followed by phenotypic screening, leading to the discovery of two most potent inhibitors, P21 and P26, which significantly impair BxPC-3 pancreatic cancer cell survival. A series of interacting protein hits, such as GSTO1, FAM213A, RAB6A/6B/39A and USMG5, were subsequently identified by quantitative chemoproteomics studies. The main cellular target, GSTO1, was further validated as a novel pancreatic cancer therapeutic target.


Presumptive pseudohypoaldosteronism secondary to chronic urinary tract obstruction from sloughed urinary bladder mucosa and urinary tract infection in a cat.
To describe a case of presumptive secondary pseudohypoaldosteronism (PHA) in a cat with urinary tract infection and chronic urethral obstruction. The obstruction was believed to have resulted from sloughed urinary bladder mucosa secondary to pressure necrosis. A 5-year-old, 4 kg, castrated male Siamese cat presented for vomiting and stranguria. Medical history included a perineal urethrostomy for urethral obstruction. Physical examination revealed a large, painful, nonexpressible urinary bladder. Point-of-care testing demonstrated electrolyte derangements consistent with a postrenal azotemia and metabolic acidosis. Results of urine culture was positive for bacterial growth. Diagnostic imaging revealed presence of retroperitoneal fluid, marked urinary bladder wall thickening, bilateral hydroureter, mild bilateral pyelectasia, and small nephroliths. The patient was treated for a urinary tract obstruction and infection. In the 3 weeks following initial discharge, the patient was evaluated on multiple occasions for lethargy, intermittent vomiting, inappropriate urination, and progressive polyuria and polydipsia. Although the urinary bladder was easily expressed during repeat examinations, it was persistently distended and subjectively thickened upon palpation. Repeat ultrasound of the urinary tract showed evidence of sloughed tissue in the bladder lumen, likely secondary to chronic urethral obstruction and pressure necrosis. A cystotomy was performed to remove the necrotic tissue, and a revised perineal urethrostomy was done due to a partial urethral stricture. Bladder biopsies were obtained at this time. Postoperatively, the cat was reported by the owners to be urinating normally but continued to be polyuric and polydipsic in the week following discharge. One week after surgery, the cat presented in hypovolemic shock with laboratory findings consistent with a presumptive diagnosis of secondary PHA. PHA has not been reported previously in a cat. This case report suggests that aldosterone resistance should be considered in cats with consistent laboratory findings and a history of documented obstructive uropathy and urinary tract infection.


Streptomyces montanus sp. nov., a novel actinomycete isolated from soil.
A novel actinomycete, designated strain NEAU-C151T, was isolated from soil collected from Mount Song and characterized using a polyphasic approach. Analysis of the 16S rRNA gene sequence indicated that strain NEAU-C151T belongs to the genus Streptomyces and exhibited 97.5, 97.4 and 97.4 % similarities to Streptomyces lincolnensis NRRL 2936T, Streptomyces coacervatus AS-0823T, and Streptomyces longisporus ISP 5166T, respectively. The assignment of strain NEAU-C151T to the genus Streptomyces was confirmed by chemotaxonomic data: anteiso-C15 : 0, C16 : 0, iso-C16 : 0, C16 : 1 (ω7c) and anteiso-C17 : 0 as the major cellular fatty acids; whole-cell sugars contained ribose and glucose; phospholipid profile consisted of diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), unidentified phospholipid (PL), unidentified lipids (L) and phosphatidylinositol mannoside (PIM); the menaquinones were MK-9(H4), MK-9(H6), MK-10(H2) and MK-9(H8). However, multilocus sequence analysis based on five other house-keeping genes (atpD, gyrB, recA, rpoB, and trpB), DNA-DNA relatedness and phenotypic data showed that strain NEAU-C151T could be distinguished from its closest relatives. Consequently, strain NEAU-C151T represents a novel species of the genus Streptomyces, for which the name Streptomyces montanus sp. nov. is proposed. The type strain is NEAU-C151T (=CGMCC 4.7498T=DSM 107808T).


TAUTOMERISM AND PROTONATION OF GUANOSINE.
Guanosine has been demonstrated, by infrared and nuclear magnetic resonance spectroscopy, to have a keto-amino structure in neutral aqueous solution and to undergo protonation at N(7) in acid solution.


Insulin resistance and other risk factors for coronary heart disease in elderly men. The Study of Men Born in 1913 and 1923.
We have previously shown that insulin is not a major risk factor for CHD. Our data have been re-analysed with longer follow-up and the homeostasis model assessment (HOMA) method. Prospective cohort study of 57- and 67-year-old men. Insulin resistance was estimated with the HOMA equation. Standard methods were used to measure risk factors. The endpoint (CHD) was the combination of non-fatal myocardial infarction and fatal CHD during 13 years of follow-up. The risk of CHD increased 2.5-fold in known diabetics compared with those with normal glucose tolerance, 2.2-fold among those in the highest compared with the lowest quintile of insulin resistance, and 2.4-fold among those in the highest compared with the lowest quintile of fasting insulin. Increased physical activity decreased the risk of CHD by 65%. Cholesterol was also a significant risk factor for CHD but blood pressure, obesity and smoking were not related to the incidence of CHD. Insulin resistance is a significant risk factor for CHD. Whether it is a causal risk factor remains to be proven. Regular physical activity protects against CHD.


Genome-wide association study of intracranial aneurysm identifies three new risk loci.
Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with approximately 832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 x 10(-12)), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 x 10(-9)) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 x 10(-9)). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR = 1.28, P = 1.3 x 10(-12)) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 x 10(-22)). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.


Assessment of Nonmotor Fluctuations Using a Diary in Advanced Parkinson's disease.
Since previous studies aimed to study nonmotor symptom (NMS) fluctuations in direct conjunction with motor oscillations, there are no data available on the temporal context of NMS fluctuations and motor oscillations in advanced Parkinson's disease (PD). To evaluate circadian patterns and temporal connections of NMS and motor fluctuations in PD. 15 controls, 17 non-fluctuating and 15 fluctuating PD patients completed two diaries by rating 4 key psychiatric (anxiety, depressive mood, inner restlessness, concentration/attention deficits), fatigue and 4 autonomic NMS (excessive sweating, sialorrhea, bladder urgency, dizziness) absent or present and motor function (Off, On with/without dyskinesia, and asleep) for every hour for 5 consecutive days. NMS Off state hours (hours with NMS rated as present) were less frequent compared to motor Off state hours and NMS On-Off-switches were less prevalent compared to those of the motor state. Off time and number of On-Off-switches of psychiatric NMS were moderately correlated with motor Off time and number of motor On-Off switches on the individual patient level. Changes in NMS state occurred largely independent of changes in motor states with concordance rates of only 26-43% of all NMS changes for psychiatric and 7-17% for autonomic NMS. In controls and non-fluctuating PD patients, there were no NMS state switches in concordance to motor state switches. We provide first data on the temporal context of NMS fluctuations showing similar frequencies of psychiatric NMS Off, fatigue Off and motor Off times as well as their On-Off-fluctuations, but low concordance rates of NMS with motor On-Off-state switches. We found no evidence for NMS fluctuations in non-fluctuating PD patients. Our data implicate similar fluctuation patterns of mood NMS and motor function without close timing and/or different kinetics.


Inhibition of ceramide-induced apoptosis by Bcl-2.
Ceramide, a long chain sphingolipid that is generated intracellularly upon hydrolysis of membrane-associated sphingomyelin, has recently been implicated as a second messenger-like molecule that is produced distal to ligation of the tumour necrosis factor receptor type 1 (TNFR1), as well as the related Fas (CD95/Apo-1) molecule. It is well established that ligation of TNFR1 or Fas leads to apoptosis in most cases. Furthermore, it has also recently been demonstrated that exposure to cell-permeable synthetic ceramides can result in apoptosis in many cases. These and other observations have led to the hypothesis that accumulation of intracellular ceramide may be a common element of several pathways that result in apoptosis. Here we show that exposure to synthetic ceramides triggers apoptosis in the human T lymphoblastoid cell lines, CEM and Jurkat, and that overexpression of the apoptosis-repressor protein, Bcl-2, renders these cells resistant to the apoptosis-inducing effects of ceramide, as well as to several other stimuli. Since exposure to ceramides can result in either cell proliferation, differentiation, cycle arrest, or death, the level of Bcl-2 expression in a cell may be an important factor in determining the outcome of signals that result in intracellular generation of this sphingolipid.


[Perioperative management of abdominal operation in three patients with pulmonary emphysema associated with pulmonary hypertension].
Anesthesia for abdominal operation in patients with emphysema is accompanied with a high risk of respiratory insufficiency requiring postoperative artificial ventilation. Furthermore, in patients whose pulmonary emphysema progresses and leads to pulmonary hypertension, there is the risk of developing right heart failure with postoperative respiratory insufficiency. Because perioperative circulatory drifting is massive in abdominal operation, they develop right heart failure easily during the postoperative refilling phase. Therefore, it is important to avoid right heart failure during the postoperative period in these patients. We estimate pulmonary artery pressure using echocardiography at bedside and give dopamine for diuresis during the postoperative period. We succeeded in perioperative management of abdominal operation in three patients with pulmonary emphysema associated with pulmonary hypertension.


Synthesis of Indolizines via Reaction of 2-Substitued Azaarenes with Enals by an Amine-NHC Relay Catalysis.
A metal-free catalytic strategy for the facile synthesis of biologically relevant molecular architectures indolizines and imidazopyridines has been developed. The process is promoted by amine and N-heterocyclic carbene (NHC) relay catalysis via Michael addition-[3 + 2] fusion of simple azaarenes and α,β-unsaturated aldehydes. The preparative power is demonstrated in the synthesis of anxiolytic drug saripidem via two simple one-pot operations with overall 45% yield.


In vitro suppression of macrophage spreading caused by supernatants of tumour, thymus, and lymph node cells.
Peritoneal macrophages washed out from C3Hf/Bu mice were cultivated in medium 199 supplemented with 35% foetal calf serum. If the pH of the medium was adjusted to 7.2, there were 70% spread macrophages after six hours of incubation at 37 degrees C. We investigated the effect of tumour cells on macrophage spreading. Supernatants from cell cultures of a fibro-sarcoma of C57BL mice and lymphoma of C3Hf/Bu mice were used to determine the number of spread macrophages after 6 hours of culture in these supernatants. Supernatants from cell cultures of the kidney, thymus and lymph nodes of normal C57BL or C3Hf/Bu mice and peritoneal cells of normal C3Hf/Bu mice in medium 199 alone served as control. We observed that supernatants from both allogeneic and syngeneic tumour cell cultures reduced significantly the percentage of spread macrophages in comparison with the percentage of spread macrophages found in the kidney culture supernatants. However, a similar spreading inhibition was caused also by supernatants from the thymus and lymph node cell cultures. In these experiments we confirmed the earlier observations that tumour cells can suppress the activation of macrophages, and we also pointed to the possibility that this effect is not specific only for malignant tissues.


Prokaryotic RNA Associated to Bacterial Viability Induces Polymorphonuclear Neutrophil Activation.
Polymorphonuclear neutrophils (PMN) are the first cellular line of antibacterial host defense. They sense pathogens through recognition of pathogen-associated molecular patterns (PAMPs) by innate pattern recognition receptors, such as Toll-like receptors (TLR). The aim of this study was to investigate whether PMN sense bacterial viability and explore which viability factor could be involved in this phenomenon. For this purpose, different functions were evaluated in isolated human PMN using live Escherichia coli (Ec) and heat-killed Ec (HK-Ec). We found that bacterial viability was indispensable to induce PMN activation, as measured by forward-scatter (FSC) increase, CD11b surface expression, chemotaxis, reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation. As uncapped non-polyadenylated prokaryotic mRNA has been recognized as a PAMP associated to bacterial viability by macrophages and dendritic cells, total prokaryotic RNA (pRNA) from live Ec was purified and used as a stimulus for PMN. pRNA triggered similar responses to those observed with live bacteria. No RNA could be isolated from HK-Ec, explaining the lack of effect of dead bacteria. Moreover, the supernatant of dead bacteria was able to induce PMN activation, and this was associated with the presence of pRNA in this supernatant, which is released in the killing process. The induction of bactericidal functions (ROS and NETosis) by pRNA were abolished when the supernatant of dead bacteria or isolated pRNA were treated with RNAse. Moreover, endocytosis was necessary for pRNA-induced ROS generation and NETosis, and priming was required for the induction of pRNA-induced ROS in whole blood. However, responses related to movement and degranulation (FSC increase, CD11b up-regulation, and chemotaxis) were still triggered when pRNA was digested with RNase, and were not dependent on pRNA endocytosis or PMN priming. In conclusion, our results indicate that PMN sense live bacteria through recognition of pRNA, and this sensing triggers potent bactericidal mechanisms.


A component analysis of recent fertility decline in singapore.
To aid in achieving demographic goals, since 1968 the government of Singapore has passed a series of laws designed to limit family size. Policies were instituted in 1968 to discourage couples from having more than three children; policies introduced in 1973 discouraged having more than two. Trends in fertility rates and in the numbers of abortions and sterilizations in recent years are consistent with the intent of these social policies. Decline in third and subsequent births was the most important factor in fertility decline after 1972, and the numbers of abortions and sterilizations undergone by higher parity women have increased substantially sin"e 1970. Although other factors have affected fertility in Singapore, the data suggest that the disincentives have played a role in continued fertility decline in recent years.


Whole-body positron emission tomography with 18F-fluorodeoxyglucose is an effective method to detect extra-pelvic recurrence in uterine sarcomas.
To assess the clinical use of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the post-therapy surveillance of uterine sarcoma. Eight whole-body FDG-PET studies were performed in seven women with previously treated uterine sarcoma. Conventional image studies (computed tomography) and physical examinations were performed for follow-up. All FDG-PET studies were indicated to localize suspected recurrences noted by conventional methods. The per case sensitivity of the FDG-PET studies and CT scans was 85.7% (6/7) and 100% (7/7), respectively (p = 0.174). FDG-PET was able to detect seven extrapelvic metastastic sites below the diaphragm (7/7, sensitivity: 100%), including the liver, spleen, paraaortic lymph node, spine and paracolic gutter, as well as pulmonary lesions in five patients, while the CT scan detected only three lesions (3/7, sensitivity: 42.9%; p = 0.070). FDG-PET detected only four recurrent pelvic lesions (4/6) and CT scan detected six (6/6) recurrent pelvic lesions (66.7% vs 100%, p = 0.455). The FDG-PET showed a better detection rate than the abdominal CT scan for extrapelvic metastatic lesions and a similar detection rate as well as abdominal CT scan. FDG-PET can serve as a useful detection tool for patients with uterine sarcomas because nearly 80% of recurrence involve an extrapelvic site.


Optimizing the Benefit of CNS Radiation Therapy in the Pediatric Population-PART 2: Novel Methods of Radiation Delivery.
Newer approaches in the field of radiation therapy have raised the bar in the treatment of central nervous system (CNS) malignancies, with recognized advances that have aimed to increase the therapeutic index by improving conformality of the radiation dose to the planned target volume. Beyond these advances, the continued evolution of more effective systems for delivery of radiation to the CNS may offer further benefit not only to adults but also to pediatric patients, a cohort of the population that may be more sensitive to the long-term effects of radiation. This article describes several novel irradiation techniques under investigation that hold promise in the pediatric population. These include newer approaches to intensity-modulated radiation therapy; stereotactic radiosurgery and radiation therapy; particle therapy, most notably proton therapy, which may be of particular benefit in enabling young patients to avoid radiation-related adverse effects; and radioimmunotherapy strategies that spare healthy tissue from radiotoxicity by delivering therapy directly to tumor tissue. Although emerging strategies for the delivery of radiation therapy hold promise for improved outcomes in pediatric patients, there must be rigorous long-term evaluation of consequences associated with the various techniques employed, to weigh risks, benefits, and impact on quality of life.


Uridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in mice.
Zalcitabine is an antiretroviral nucleoside analogue that exhibits long-term toxicity to hepatocytes by interfering with the replication of mitochondrial DNA (mtDNA). Uridine antagonizes this effect in vitro. In the present study we investigate the mechanisms of zalcitabine-induced hepatotoxicity in mice and explore therapeutic outcomes with oral uridine supplementation. BalbC mice (7 weeks of age, 9 mice in each group) were fed 0.36 mg/kg/d of zalcitabine (corresponding to human dosing adapted for body surface), or 13 mg/kg/d of zalcitabine. Both zalcitabine groups were treated with or without Mitocnol (0.34 g/kg/d), a dietary supplement with high bioavailability of uridine. Liver histology and mitochondrial functions were assessed after 15 weeks. One mouse exposed to high dose zalcitabine died at 19 weeks of age. Zalcitabine induced a dose dependent microvesicular steatohepatitis with abundant mitochondria. The organelles were enlarged and contained disrupted cristae. Terminal transferase dUTP nick end labeling (TUNEL) assays showed frequent hepatocyte apoptosis. mtDNA was depleted in liver tissue, cytochrome c-oxidase but not succinate dehydrogenase activities were decreased, superoxide and malondialdehyde were elevated. The expression of COX I, an mtDNA-encoded respiratory chain subunit was reduced, whereas COX IV, a nucleus-encoded subunit was preserved. Uridine supplementation normalized or attenuated all toxic abnormalities in both zalcitabine groups, but had no effects when given without zalcitabine. Uridine supplementation was without apparent side effects. Zalcitabine induces mtDNA-depletion in murine liver with consequent respiratory chain dysfunction, up-regulated synthesis of reactive oxygen species and microvesicular steatohepatitis. Uridine supplementation attenuates this mitochondrial hepatotoxicity without apparent intrinsic effects.


A revised terminology for male genitalia in Hymenoptera (Insecta), with a special emphasis on Ichneumonoidea.
Applying consistent terminology for morphological traits across different taxa is a highly pertinent task in the study of morphology and evolution. Different terminologies for the same traits can generate bias in phylogeny and prevent correct homology assessments. This situation is exacerbated in the male genitalia of Hymenoptera, and specifically in Ichneumonoidea, in which the terminology is not standardized and has not been fully aligned with the rest of Hymenoptera. In the current contribution, we review the terms used to describe the skeletal features of the male genitalia in Hymenoptera, and provide a list of authors associated with previously used terminology. We propose a unified terminology for the male genitalia that can be utilized across the order and a list of recommended terms. Further, we review and discuss the genital musculature for the superfamily Ichneumonoidea based on previous literature and novel observations and align the terms used for muscles across the literature.


Anti-inflammatory and antinociceptive effects of salbutamol on acute and chronic models of inflammation in rats: involvement of an antioxidant mechanism.
The possible role of β-2 adrenergic receptors in modulation of inflammatory and nociceptive conditions suggests that the β-2 adrenergic receptor agonist, salbutamol, may have beneficial anti-inflammatory and analgesic effects. Therefore, in this study, we induced inflammatory and nociceptive responses with carrageenan-induced paw edema or cotton-pellet-induced granuloma models, both of which result in oxidative stress. We hypothesized that salbutamol would prevent inflammatory and nociceptive responses by stimulating β-2 adrenergic receptors and the prevention of generation of ROS during the acute inflammation process in rats. Both doses of salbutamol used in the study (1 and 2 mg/kg) effectively blocked the acute inflammation and inflammatory nociception induced by carrageenan. In the cotton-pellet-induced granuloma test, both doses of salbutamol also significantly decreased the weight of granuloma tissue on the cotton pellets when compared to the control. Anti-inflammatory and analgesic effects of salbutamol were found to be comparable with those of indomethacin. Salbutamol decreased myeloperoxidase (MPO) activity and lipid peroxidation (LPO) level and increased the activity of superoxide dismutase (SOD) and level of glutathione (GSH) during the acute phase of inflammation. In conclusion, salbutamol can decrease acute and chronic inflammation, possibly through the stimulation of β-2 adrenergic receptors. This anti-inflammatory effect may be of significance in asthma treatment, where inflammation also takes part in the etiopathology. This study reveals that salbutamol has significant antioxidative effects, which at least partially explain its anti-inflammatory capabilities. These findings presented here may also shed light on the roles of β-2 adrenergic receptors in inflammatory and hyperalgesic conditions.


Serum concentrations of cross-linked N-telopeptides of type I collagen: new marker for bone resorption in hemodialysis patients.
Urinary cross-linked N-telopeptide of type I collagen (NTX) is a reliable bone resorption marker in patients with metabolic bone disease. We assessed a clinically available serum NTX assay suitable for anuric patients on hemodialysis (HD). Serum concentrations of NTX, C-terminal telopeptide of type I collagen (beta-CTX), pyridinoline (PYD), and deoxypyridinoline (DPD) were determined as bone resorption markers, and those of bone alkaline phosphatase (BAP) and intact osteocalcin (OC) as bone formation markers, in 113 male HD patients (mean age, 59.3 years; mean HD duration, 67.7 months). Each patient's bone mineral density (BMD) in the distal third of the radius was measured twice, with a 2-year interval between measurements, by dual-energy x-ray absorptiometry. Serum NTX correlated significantly with beta-CTX, PYD, DPD, BAP, and intact OC. NTX, as well as beta-CTX, PYD, DPD, BAP, and intact OC, correlated significantly with BMD at the time of measurement. NTX, beta-CTX, and DPD correlated significantly with the annual change in BMD during the 2-year period thereafter, in contrast to PYD, BAP, and intact OC. Patients in the highest quartile of serum NTX concentrations showed the fastest rate of bone loss. The sensitivity and specificity for detecting rapid bone loss were 48% and 83%, respectively, for serum NTX. Serum NTX may provide a clinically relevant serum assay to estimate bone turnover in HD patients.


Immunoregulatory activities of human immunodeficiency virus (HIV) proteins: effect of HIV recombinant and synthetic peptides on immunoglobulin synthesis and proliferative responses by normal lymphocytes.
Recombinant and synthetic peptides corresponding to envelope proteins of the human immunodeficiency virus (HIV) were examined for their effects on the activities of lymphocytes from normal donors in vitro. Although lymphocytes cultured with env-gag peptides produced significant amounts of IgG, addition of env-gag peptides to a pokeweed mitogen-induced B-cell activation system resulted in suppression of immunoglobulin synthesis by normal lymphocytes. Recombinant antigens, env-gag and env-80 dihydrofolate reductase (DHFR), produced a substantial proliferative response by peripheral blood mononuclear cells (PBMC) as determined by [3H]thymidine incorporation. PBMC precultured with HIV synthetic peptide env 578-608 also manifested significant proliferative responses as compared to control cultures. CD3+ lymphocytes precultured with recombinant HIV antigens, env-gag and env-80 DHFR, and synthetic HIV peptide, env 487-511, showed moderate but significant proliferative responses. Both recombinant antigens and synthetic peptides also produced a dose-dependent stimulatory effect on proliferation by CD3- lymphocytes. Stimulation of CD3+ and CD3- lymphocyte subpopulations induced by env-gag peptides was specifically inhibited by goat anti-env-gag polyclonal antibodies, demonstrating the specificity of the reaction. These studies demonstrate that recombinant and synthetic peptides of the HIV genome express immunoregulatory T- and B-cell epitopes. Identification of unique HIV epitopes with immunogenic and immunoregulatory activities is necessary for the development of an effective vaccine against HIV infection.


The comorbidity between bipolar disorder and ADHD in a young adult: a focus on impulsivity.
Impulsivity is a complex behavioural feature of many psychiatric disorders, in particular of risk-taking behaviour, and is an important determinant of personality. Both ADHD and bipolar disorder express features of impulsivity. The concept of having two or more simultaneous psychiatric conditions is an increasingly recognised concept in the field of psychiatry, and is important clinically for management and prognosis. Consequently, the aim of this case presentation is to report about a young patient with both bipolar II and ADHD, in order to better understand which of the possible clinical phenotypes of these psychiatric conditions exist in comorbidity, mainly focusing on impulsive features because of the relevant challenge that this psychological aspect can represent in the clinical treatment of these patients.


Influence of apolipoprotein E, smoking, and alcohol intake on carotid atherosclerosis: National Heart, Lung, and Blood Institute Family Heart Study.
Apolipoprotein E (apoE) isoforms and lifestyle factors play an important role in the development of coronary heart disease. The association of apoE and carotid atherosclerosis remains controversial. We investigated the relation of apoE, cigarette smoking, alcohol drinking, and their interaction with carotid atherosclerosis on 544 individuals free of coronary heart disease in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Atherosclerotic lesions of the carotid arteries were detected through high-resolution ultrasound. Subjects in the apoE4 group had lower blood pressure, lower high-density lipoprotein cholesterol, and higher low-density lipoprotein cholesterol. In a multivariate logistic regression model, apoE isoforms and alcohol consumption were not significantly associated with the prevalence odds of carotid atherosclerosis (P=0.94 and 0.98, respectively, for trend). In contrast, compared with those who never smoked, the prevalence odds ratios for carotid atherosclerosis were 1.7 [95% confidence interval (CI),1.1 to 2.7], 2.8 (95% CI, 1.2 to 6.2), and 1.9 (95% CI, 0.7 to 5.5) for former smokers, current smokers of 1 to 20 cigarettes per day, and current smokers of >20 cigarettes day, respectively (P=0.0018 for trend). We did not find evidence of an interaction between apoE and alcohol consumption. Our data suggested a synergistic effect between the apoE allele epsilon(4) and smoking on carotid atherosclerosis: odds ratios were 1.7 (95% CI, 0.8 to 3.6) for smoking alone, 1.0 (95% CI, 0.6 to 1.8) for epsilon4 alone, and 3.7 (95% CI, 1.1 to 3.6) for the joint presence of the apoE allele epsilon4 and smoking. Smoking but not alcohol consumption or ApoE is associated with an increased odds of carotid atherosclerosis. Our data suggest a synergistic effect between the apoE allele epsilon4 and smoking on carotid atherosclerosis.


Utility of reverse phase protein arrays: applications to signalling pathways and human body arrays.
Protein microarrays offer a new means by which to conduct quantitative profiling of disease-associated proteins. The knowledge gained may provide novel strategies for early detection, diagnosis and therapeutic intervention. A variety of sophisticated approaches, including gene arrays, sequencing consortiums and large-scale two-dimensional gel electrophoresis, continue to generate lists of proteins potentially linked to disease aetiology and progression. The challenge is to evaluate quantitatively promising lead protein candidates using matched normal and diseased cell populations. In contrast to the antibody array, the reverse phase protein microarrays (RPPA) do not require labelling of cellular protein lysates, and constitute a sensitive high throughput platform for marker screening, pathophysiology investigation and therapeutic monitoring. In this paper, examples will be provided using RPPAs in the study of the apoptotic signalling cascade and in the evaluation of the expression of organ-specific protein makers using microdissected human organ cell lysates configured as 'human body arrays'.


Agreement about acts of aggression in marriage.
Psychological and Physical Aggression scales met internal consistency and agreement standards on the Revised Conflict Tactics Scales (CTS2) in a randomly recruited sample of 453 married community couples with children. Moreover, partners agreed on the extent of psychological and physical aggression as much or more than they did on CTS2 Negotiation scale and positive behaviors assessed on the Dyadic Adjustment Scale. On the other hand, the CTS2 Sexual Coercion and Injury scales had much lower internal consistencies as measured by Cronbach's alpha, and agreement was generally very low. Men and women reported less abusive behavior and consequent injury than partners reported about them. Correction factors were provided for prevalence estimates of abusive behavior and injury when only perpetrator reports were available.


The use of a Swedish telephone medical advice service by the elderly - a population-based study.
The present study aimed to describe contact made by the elderly to Sweden's nationwide medical helpline, Healthcare Guide 1177 by Phone (HGP). Other objectives were to study potential gender differences and the association between different HGP referral levels and acute visits to hospital-based emergency departments and acute visits to primary care centres. De-identified data from recorded calls to HGP was extracted for analysis (n = 7477 for the oldest age group). Information about acute visits to emergency departments and to primary care reception was extracted from the patient administration system. Västerbotten County, Sweden. Patients over 80 years. Calling and visiting frequencies for different age groups as well as reasons for contact and individual recommendations. The utilisation rate of the telephone advice service for the oldest age group was high, with an incidence rate of 533 per 1000 person-years. Women had a 1.17 times higher incidence rate compared with men. The most common reason for contact was drug-related questions (17% of all contacts). Calls that were recommended to care by a medical specialist correlated with total emergency department visits (r = 0.30, p < 0.05) and calls that were given advice correlated with acute primary healthcare visits (r = 0.38, p = 0.005). The high utilisation of the telephone advice service by the elderly gives the telephone advice service a unique ability to function as a gatekeeper to further healthcare. Our data suggest that with the telephone advice service's present guidelines, a significant proportion of all calls are being directed to further medical help. The high frequency of drug-related questions raises concerns about the elderly's medication regimens. Key points Patients over 80 years of age had a high utilisation of the telephone medical advice service compared with other age groups. Drug-related questions were the most common reason for contact. A significant proportion of all calls made resulted in further heatlhcare contacts.


Lemierre's syndrome: how a sore throat can end in disaster.
Lemierre's syndrome is characterised by a history of recent oropharyngeal infection, clinical or radiological evidence of internal jugular vein thrombophlebitis and isolation of an anaerobic pathogen. We present a case report and review the literature.


Limited oxidative stress in common carp (Cyprinus carpio, L., 1758) exposed to a sublethal tertiary (Cu, Cd and Zn) metal mixture.
Analyzing effects of metal mixtures is important to obtain a realistic understanding of the impact of mixed stress in natural ecosystems. The impact of a one-week exposure to a sublethal metal mixture containing copper (4.8 μg/L), cadmium (2.9 μg/L) and zinc (206.8 μg/L) was evaluated in the common carp (Cyprinus carpio). To explore whether this exposure induced oxidative stress or whether defense mechanisms were sufficiently fitting to prevent oxidative stress, indicators of apoptosis (expression of caspase 9 [CASP] gene) and of oxidative stress (malondialdehyde [MDA] level and xanthine oxidase [XO] activity) were measured in liver and gills, as well as activities and gene expression of enzymes involved in antioxidant defense (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], glutathione reductase [GR] and glutathione-S-transferase [GST]). The total antioxidative capacity (T-AOC) was also quantified. No proof of oxidative stress was found in either tissue but there was indication of apoptosis in the liver. CAT, GPx, GR and GST total activities were reduced after 7 days, suggesting a potential decrease of glutathione levels and risk of increased free radicals if the exposure would have lasted longer. There were no major changes in the total activities of antioxidant enzymes in the gills, but the relative expression of the genes coding for CAT and GR were triggered, suggesting a response at the transcription level. These results indicate that C. carpio is well equipped to handle these levels of metal pollution, at least during short term exposure.


Transcutaneous electrical nerve stimulation for postoperative pain relief after arthroscopic rotator cuff repair: a prospective double-blinded randomized trial.
Arthroscopic rotator cuff repair (ARCR) can be associated with significant postoperative pain. Concern for opioid abuse has led surgeons to identify alternative, efficacious methods of postoperative analgesia. To determine whether transcutaneous electrical nerve stimulation (TENS) can have a similarly beneficial effect after shoulder procedures, we conducted a prospective double-blinded randomized trial in patients undergoing outpatient ARCR. All patients undergoing ARCR of a full-thickness rotator cuff tear by the senior authors were identified. Patients with a history of recent narcotic use or prior narcotic abuse and those under management of a pain control specialist were excluded. Patients were randomized into 2 groups, active or placebo TENS, and used the device for 4 sessions/day for 45 minutes/session for the first postoperative week. All patients received Percocet 5/325 mg (oxycodone/acetaminophen) for use as rescue pain pills. One-week narcotic consumption and visual analog scale pain scores were compared between groups. The final analysis included 37 patients (21 active,16 placebo). Baseline and procedural differences were not different between groups. At 1 week postoperatively, patients in the active group had significantly lower pain scores (3.6 ± 2.1 vs. 5.8 ± 1.2; P= .008). Postoperative Percocet consumption during the initial 48 hours (12.8 ± 4.7 vs. 17.2 ± 6.3; P = .020) and during the first week (25.2 ± 9.9 vs. 33.8 ± 14.3; P = .037) was also significantly lower in the active group. Results from this prospective double-blinded randomized trial demonstrate that compared with placebo TENS, active TENS can result in significantly less pain and reduced opioid use in the immediate postoperative period after ARCR, suggesting that TENS may be potentially useful in a multimodal approach to managing postoperative pain.


Identification of brief presentations of facial expressions of affects in schizophrenics.
Two experiments were designed to test information extraction capacity from briefly shown photographs depicting simple familiar objects and facial/affective stimuli. Photographs were presented tachistoscopically at six exposure times, 1 sec, 200 msec, 40 msec, 20 msec, 4 msec, 2 msec, to chronic schizophrenic patients, general medical patients, and nonpatient control subjects. Experiment 1 was conducted using the number of correct responses (true scores) and experiment 2 using the number of trials taken (error scores) to identify the tazget stimuli, as the dependent measures. In experiment 1, schizophrenics did not differ from general medical patients but both were inferior to nonpatient controls in identifying brief visual stimuli. However, in experiment 2, schizophrenics required significantly more trials than general medical patients, who in turn required significantly more trials than nonpatient controls in identifying brief visual stimuli.


Within-Match Performance Dynamics - Momentary Strength in Handball.
Handball is an Olympic team sport characterized by changes of ball possession, where teams either play on offense or defense. In this paper, we model momentary strength in handball as scoring probabilities based on a double moving average. In this cross-sectional observational study, the aim was to describe the dynamics of momentary strength in handball from both theoretical and practical perspectives. Momentary strength can be used to further characterize the nuances of the sport by identifying different phases in a match. The momentary strength model was applied to the 2019 International Handball Federation (IHF) Men's World Championship. Ninety-six games were analyzed. The results showed that momentary strength could be used to better understand the dynamic interaction process between two teams. The Spearman correlation between the teams' median momentary strength and their final ranks at the Championship was -0.830. Virtually each team faced phases in its matches with a momentary scoring probability lower than 0.10 and with 4 exceptions also higher than 0.90. Twelve out of the 24 teams showed phases with a momentary scoring probability of exactly 0 as well as exactly 1.


Different reconstitution of peripheral blood lymphocytes and dendritic cells in liver and kidney transplant patients.
T cells and dendritic cells are responsible for immune alloreactivity or tolerance after transplantation. In this study, we compared the levels of circulating T, B, and NK lymphocytes, as well as monocytes, plasmacytoid dendritic cells, and myeloid dendritic cells, in adult patients undergoing a liver transplant or kidney transplant. Our findings show that candidates for liver transplant had significantly lower levels of circulating T, B, and dendritic cells than candidates for kidney transplant. Nevertheless, liver transplant patients showed a greater T-cell recovery, despite the use of thymoglobulin, as compared with kidney transplant patients who were induced with Daclizumab. In four kidney transplant patients with allograft rejection we observed a dramatic drop of circulating T and dendritic cells at the time of rejection, and while myeloid dendritic cells and CD4(+) and CD8(+) cells rapidly recovered after 1 month, plasmacytoid dendritic cells and CD4(+)CD25(+) T-cell numbers remained significantly lower than in patients without rejection. Future studies will evaluate the monitoring of circulating CD4(+)CD25(+) T cells and myeloid dendritic cell:plasmacytoid dendritic cell ratio as potential biomarkers for rejection or, alternatively, for withdrawal of immune suppression.


Electroencephalographic findings in relation to diagnostic constructs in psychiatry.
A group of 759 patients with final DSM-I and -II diagnoses of schizophrenia was identified among a cohort of 1494 adults who were hospitalized between 1965 and 1972. Admission EEG recordings were done in each patient during waking, activation procedures, drowsiness, and sleep. All cases were reclassified according to the Feighner et al. criteria, and relationships between the EEG, reassigned diagnosis, and outcome were examined. One-third of the schizophrenics were rediagnosed as having affective, organic, or other disorders. EEG abnormalities predicted diagnostic change and relatively favorable prognosis. Mean alpha frequencies were slower in schizophrenics than in patients with other DSM I-II disorders, and less in patients with Feighner et al. diagnoses of schizophrenia than in some rediagnosed categories. In 1980-82, matched samples from the original cohort with affective, schizophrenic, and mixed Feighner et al. diagnoses were followed and evaluated blindly with the SADS-L. RDC follow-up diagnoses were significantly correlated with the index EEG findings in terms of higher alpha average frequencies proportional to the amount of affective psychopathology. A subgroup of high functioning individuals within the RDC schizophrenic category was identified with affective symptomatology early in the course of illness, normal EEGs, and high alpha average frequencies. Patients with a consistent diagnosis of schizophrenia according to the three nosologic systems were shown to function better in some areas if the index EEG was abnormal. Discriminant function analysis established that DSM-I and -II categories possessed the greatest long-term predictive accuracy which was enhanced by the EEG diagnosis and alpha average to a level of more than 50%. The Feighner et al. and RDC diagnostic systems were not as relevant for prediction of long-term follow-up status.


Analysis of the chloroacetanilide herbicides in water using SPME with CAR/PDMS and GC/ECD.
The solid-phase microextraction (SPME) technique using a 75 mm film of carboxen/polydimethylsiloxane was applied to the analysis of chloroacetanilide herbicides (acetochlor, alachlor, butachlor, metolachlor, and propachlor) residues. The feasibility of SPME with gas chromatography electron capture detection analysis has been evaluated. The effects of experimental parameters such as magnetic stirring, salt addition, humic acid addition, pH value, and extraction time, as well as desorption temperature and time, were investigated. Analytical parameters such as linearity, repeatability and limit of detection were also evaluated. The inhibition of humic acid to the extraction of chloroacetanilide herbicides was observed. A standard addition method for calibration was recommended to reduce deviations caused by matrix interferences. The proposed method provided a simple and rapid analytical procedure for chloroacetanilide herbicides in water with limits of detection 0.002-0.065 microg/L for deionized water, and 0.005-0.22 microg/L for farm water. The relative standard deviations (n = 5) for analyses of farm water were 7-20% for 5 [corrected] microg/L chloroacetanilide herbicides. This application was illustrated by the analysis of sample collected from farm water in the Chung-hwa area, Taiwan.


Involved field radiation therapy after surgical resection of solitary brain metastases--mature results.
Whole brain radiation therapy (WBRT) reduces local recurrence in patients after surgical resection of brain metastases without improving overall survival. Involved field radiation therapy (IFRT) has been used at our center to avoid delayed neurotoxicity associated with WBRT in well-selected patients with surgically resected single brain metastases. The purpose of this study was to evaluate the long-term outcomes of these patients. Thirty-three consecutive patients with single brain metastases from a known primary tumor were treated with gross total resection followed by IFRT between 2006 and 2011. The postoperative surgical bed was treated to 40.05 Gy in 15 fractions of 2.67 Gy with conformal radiation therapy. Patients received serial MRIs and neurological exams in follow-up. Surgery, WBRT, or stereotactic radiosurgery was performed as salvage treatment when necessary. The median follow-up was 16 months (range: 2-65 months). Local control, distant brain recurrence-free survival, and overall survival at 12 and 24 months were 90.3% and 85.8%, 60.7% and 51.4%, and 65.6% and 61.5%, respectively. Overall, 5 (15%) patients developed recurrence at the resection cavity, and 13 (39%) patients experienced recurrence at a new intracranial site. Two patients received WBRT, 8 stereotactic radiosurgery, 2 surgery, and 2 both chemotherapy and IFRT as salvage. Four patients died from CNS disease progression. For patients with newly diagnosed single brain metastases treated with surgical resection, postoperative IFRT to the resection cavity achieves reasonable rates of local control and is an excellent alternative to WBRT.


Comparison of hemostatic matrix and standard hemostasis in patients undergoing primary TKA.
Bleeding after total knee arthroplasty increases the risk of pain, delayed rehabilitation, blood transfusion, and transfusion-associated complications. The authors compared pre- and postoperative decreases in hemoglobin as a surrogate for blood loss in consecutive patients treated at a single institution by the same surgeon (J.L.C.) using conventional hemostatic methods (electrocautery, suturing, or manual compression) or a gelatin and thrombin-based hemostatic matrix during total knee arthroplasty. Data were collected retrospectively by chart review. The population comprised 165 controls and 184 patients treated with hemostatic matrix. Median age was 66 years (range, 28-89 years); 66% were women. The arithmetic mean ± SD for the maximal postoperative decrease in hemoglobin was 3.18 ± 0.94 g/dL for controls and 2.19 ± 0.83 g/dL for the hemostatic matrix group. Least squares means estimates of the group difference (controls-hemostatic matrix) in the maximal decrease in hemoglobin was 0.96 g/dL (95% confidence interval, 0.77-1.14 mg/dL; P<.0001). Statistically significant covariate effects were observed for preoperative hemoglobin level (P<.0001) and body mass index (P=.0029). Transfusions were infrequent in both groups. The frequency of acceptable range of motion was high (control, 88%; hemostatic matrix, 84%). In both groups, overall mean tourniquet time was approximately 1 hour, and the most common length of stay was 3 to 5 days. No serious complications related to the hemostatic agent were observed. These data demonstrate that the use of a flowable hemostatic matrix results in less reduction in hemoglobin than the use of conventional hemostatic methods in patient undergoing total knee arthroplasty.


microRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin.
microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play important roles in tumor initiation and progression. Recently, we examined the global miRNA expression profile of esophageal squamous cell carcinoma (ESCC) and demonstrated that miR-92a was highly expressed in tumor tissues. In this study, we found that the up-regulation of miR-92a was significantly correlated with the status of lymph node metastasis and TNM stage in 107 ESCC patients. Moreover, the up-regulation of miR-92a was associated with poor survival of ESCC patients and might be used as an independent prognostic factor. Next, we investigated the role and mechanism of miR-92a in ESCC cells, and found that miR-92a modulated the migration and invasion but not apoptosis and proliferation of ESCC cells in vitro. We further demonstrated that miR-92a directly targeted the CDH1 3'-UTR and repressed the expression of CDH1, a tumor metastasis suppressor. In addition, restoring of miR-92a-resistant CDH1 expression in miR-92a-overexpression cells recovered the pro-metastasis activity of miR-92a. Taken together, we demonstrated that miR-92a promotes ESCC cell migration and invasion at least partially via suppression of CDH1 expression, and patients with up-regulated miR-92a are prone to lymph node metastasis and thus have poor prognosis.


Upregulation of the axonal growth and the expression of substance P and its NK1 receptor in human allergic contact dermatitis.
Nerve fibers and sensory neuropeptides substance P and calcitonin gene-related peptide (CGRP) have been reported to be involved in allergic contact dermatitis (ACD). In the present study, we investigated the general innervation (using antibody against protein gene product 9.5, PGP 9.5), axonal growth (using antibody against growth associated protein, GAP-43), CGRP, and substance P with its receptor neurokinin 1 (NK1), in positive epicutaneous reactions to nickel sulphate from nickel-allergic patients, at the peak of inflammation, 72 hr after challenge with the antigen. There was an increased (p < 0.01) number of GAP-43 positive fibers in the eczematous compared with control skin, indicating an increased axonal growth already at 72 hr postchallenge. Double staining revealed a coexpression of CGRP and GAP-43 on dermal nerve fibers. There was no difference in the number of substance P and CGRP positive nerve fibers between eczematous and control skin. However, semiquantification analyses showed an increased expression of substance P positive inflammatory cells, being CD3, CD4, or CD8 positive, and NK1R positive inflammatory cells, being tryptase or CD3 positive. These results indicate a contribution of regenerating nerve fibers and substance P to the contact allergic reaction.


Electrocardiographic Evaluation in Athletes and Use of the Seattle Criteria to Improve Specificity.
The screening of athletes for cardiovascular disease prior to participation can be challenging. Sustained training often leads to anatomical changes in the heart that can translate into electrocardiographic (ECG) abnormalities. This can lead to a high false-positive rate that excludes healthy participants or results in costly workups. The Seattle Criteria applied to ECG interpretation has resulted in improved specificity without sacrificing sensitivity. At the Houston Methodist DeBakey Heart & Vascular Center in Houston, we have had much success using this tool to screen thousands of athletes ranging across all age groups and levels of expertise-from the middle school level to the professional athlete.


Open science and human genetic data: recommendations on South Africa's Draft National Open Science Policy.
The Draft National Open Science Policy, which was shared by the South African government with stakeholders in 2022, is an encouraging step forward as it aims to promote the practice of open science in South Africa through a system of incentives. Since South Africa is constitutionally committed to be an open and democratic society, this approach is preferable to the approach of state control that characterizes the Draft National Policy on Data and Cloud-another data-related policy initiative by the South African government. However, there is room for improvement in the Draft National Open Science Policy. In particular, it should: (a) rely on the right to freedom of scientific research to strengthen the policy; (b) rectify the omission of ownership from its policy analysis; and (c) retain a clear differentiation between human and non-human genetic data. This will ensure that the final policy is clearly anchored in the South African Constitution, and that the principle of "as open as possible, as closed as necessary" can be applied to human genetic data in a legally well informed and accountable way.


[Protective immune responses induced by a recombinant Listeria monocytogenes delivering HPV16 E7].
To investigate specific immune responses elicited by a recombinant Listeria monocytogenes strain LM4 deltahly::E7 and assess protective effect in C57BL/6 mice. C57BL/6 mice were intraperitoneally immunized with LM4 deltahly:: E7 at 1-week intervals. After the second immunization, cellular immunity elicited by this recombinant L. monocytogenes strain was analyzed via an ELISPOT assay, Cytotoxic T lymphocytes (CTL) measurement assay and analysis of effector T cells proportion in the splenocytes. Also, the serum antibodies against HPV16 E7 protein were determined in an ELISA assay. Finally, protective effect was assessed against the challenge with TC-1 tumor cells. The immune responses elicited by LM4 deltahly::E7 were biased towards Th1 type in the ELISPOT assay. Also, LM4 deltahly::E7 was able to induce E7-specific CTL activity, with average specific lysis of 72%, which was highly significant difference compared with the controls (P<0.01). Moreover, the proportion of effector T cells in the spleens were increased in mice immunized with recombinant L. monocytogenes strain (P<0.05). The titer of E7-specific antibodies in mice immunized with LM4 delta hly::E7 was 1:400 in the ELISA assay. Furthermore, immunization with LM deltahly::E7 protected all mice against the lethal tumor cell challenge. The data suggest that attenuated Listeria monocytogenes delivering HPV16 E7 antigen could induce both E7-specific cell mediated immunity and humoral immunity, and had a protective effect against challenge with TC-1 tumor cells.


[Protective effects of cordycepin on renal proximal tubular cells injury induced by lipopolysaccharide].
To investigate the protective effect and potential mechanism of cordycepin on renal proximal tubular cells injury induced by lipopolysaccharide (LPS). Renal proximal tubular cells NRK-52E were incubated on a cell culture plated at a density of 1×105/mL for experiment, then divided into control group (Ctrl group), LPS group (cells were stimulated with 1 mg/L LPS), 10 μmol/L or 20 μmol/L cordycep in intervention groups (LPS+C 10 group and LPS+C 20 group). Cell viability was measured using cell counting kit-8 (CCK-8) reagent. The level of intracellular reactive oxygen species (ROS) was detected by 2',7'-dichlorofluorescin diacetate (DCFH-DA) staining. The protein expressions of inflammatory factors intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), interleukin-1β (IL-1β), and nuclear factor-κB (NF-κB) were detected by Western blotting. Compared with the Ctrl group, LPS significantly inhibited NRK-52E cell viability, increased intracellular ROS, and up-regulated the expressions of ICAM-1, VCAM-1, IL-1β and NF-κB. Compared with LPS group, after treated with 10 μmol/L or 20 μmol/L cordycepin, NRK-52E cell viability was significantly increased (Ctrl group as 1: 0.717±0.017, 0.916±0.036 vs. 0.554±0.046) and intracellular ROS level was significantly decreased (Ctrl group as 1: 1.527±0.165, 1.098±0.168 vs. 2.543±0.127), meanwhile the expressions of ICAM-1, VCAM-1, IL-1β and NF-κB were significantly down-regulated [Ctrl group as 1, ICAM-1/GAPDH: 2.364±0.097, 1.561±0.074 vs. 3.101±0.121; VCAM-1/GAPDH: 2.866±0.135, 1.920±0.098 vs. 4.170±0.119; IL-1β/GAPDH: 2.358±0.107, 1.563±0.179 vs. 3.301±0.210; phosphorylation NF-κB p65 (NF-κB p-p65)/GAPDH: 2.559±0.166, 1.596±0.148 vs. 3.183±0.098], the differences were statistically significant (all P < 0.05). Compared with the LPS+C 10 group, the cell activity of LPS+C 20 group was more significant (0.916±0.036 vs. 0.717±0.017, P < 0.01), and the expressions of ICAM-1, VCAM-1, IL-1β, NF-κB were down-regulated more significantly (ICAM-1/GAPDH: 1.561±0.074 vs. 2.364±0.097, VCAM-1/GAPDH: 1.920±0.098 vs. 2.866±0.135, IL-1β/GAPDH: 1.563±0.179 vs. 2.358±0.107, NF-κB p-p65/GAPDH: 1.596±0.148 vs. 2.559±0.166, all P < 0.05). Cordycepin could significantly increase the survival rate of NRK-52E cells, reduce intracellular ROS level, and inhibit inflammation, and the anti-inflammation effect can be related with NF-κB pathway.


Raloxifene Has No Efficacy in Reducing the High Bone Turnover and the Risk of Spontaneous Vertebral Fractures after Denosumab Discontinuation.
At denosumab discontinuation, an antiresorptive agent is prescribed to reduce the high bone turnover, the rapid bone loss, and the risk of spontaneous vertebral fractures. We report the case of a woman treated with aromatase inhibitors and denosumab for 5 years. Raloxifene was then prescribed to prevent the rebound effect. Raloxifene was ineffective to reduce the high bone turnover and to avoid spontaneous clinical vertebral fractures. We believe that among the antiresorptive treatments, the most powerful bisphosphonates should be favored, and their administration adapted according to the serial follow-up of bone markers.