[The expression of interferon-lambda1 in CHO cell].
To construct the eukaryotic expression vector PCI-dhfr-lambda1 and PCI-dhfr-SP163-lambda1 which linked the enhancer SP163 with interferon lambda1. Then express the interferon lambda1 in CHO (dhfr-) cells. Using PCR method to introduce the restriction enzyme sites and through the fusion PCR binding the enhancer with the interferon Lambda1. After sequenced, lambda1 and SP163-lambda1 was inserted into PCI-dhfr forming the expression vector PCI-dhfr-lambda1 and PCI-dhfr-SP163-lambda1 which was constructed successfully confirming by sequencing. Then the expressing vectors were transfected into CHO (dhfr-) cells using liposome transfection method and interferon lambda1 protein was assayed with indirect immunofluorescence and Western Blot. Using cytopathic effect inhibition evaluated the antiviral activity of interferon lambda1. Successfully constructing the eukaryotic expression vectors of interferon lambda and the vectors could express interferon lambda1. The result of immunofluorescence showed the enhancer developed the expression of interferon lambda1. Detecting the interferon lambda1 in CHO (dhfr-) cells after transfecting 48 hour using Western Blot. The cytopathic effect inhibition showed the expressed interferon lambda1 has the antiviral activity. Successfully expressed the interferon lambda1 in CHO (dhfr-) cells and the protein possesses antiviral activity, which may supply a valuable basis for building the stable cell line of interferon lambda1.


Vaginal microbiota and its role in HIV transmission and infection.
The urogenital tract appears to be the only niche of the human body that shows clear differences in microbiota between men and women. The female reproductive tract has special features in terms of immunological organization, an epithelial barrier, microbiota, and influence by sex hormones such as estrogen. While the upper genital tract is regarded as free of microorganisms, the vagina is colonized by bacteria dominated by Lactobacillus species, although their numbers vary considerably during life. Bacterial vaginosis is a common pathology characterized by dysbiosis, which increases the susceptibility for HIV infection and transmission. On the other hand, HIV infections are often characterized by a disturbed vaginal microbiota. The endogenous vaginal microbiota may protect against HIV by direct production of antiviral compounds, through blocking of adhesion and transmission by ligands such as lectins, and/or by stimulation of immune responses. The potential role of probiotics in the prevention of HIV infections and associated symptoms, by introducing them to the vaginal and gastrointestinal tract (GIT), is also discussed. Of note, the GIT is a site of considerable HIV replication and CD4(+) T-cell destruction, resulting in both local and systemic inflammation. Finally, genetically engineered lactobacilli show promise as new microbicidal agents against HIV.


The third permanent molar eruption in Kenyan Africans and Asians.
Data on third permanent molar eruption was obtained from a cross-sectional study of 1343 African and 1092 Asian students aged 13-23 years attending various schools in Nairobi and the University of Nairobi, Kenya. Africans are significantly ahead of the Asians in third molar emergence. As seen from the median age of eruption, in Africans mandibular molars emerge at 17.6-18.3 years followed by the maxillary at 18.5-18.9 years, while in the Asians mandibular molars emerge at 19.9-20.3 years and maxillary at 20.7-21.0 years. African females appear to be earlier than the males in median age of eruption by 0.3-0.4 years, while the Asian females tend to be later than the males by about 0.3 years, but these differences are not significant. Third molar emergence starts earlier in Africans at 13 years of age, and by 18.5 years 50% of Africans have all four molars present. In the Asians, third molar emergence begins at about 15 years and by 21.5 years 50% have all four molars present.


Properties of cadmium-binding proteins in rat testes. Characteristics unlike metallothionein.
Since the exposure of rats to cadmium causes zinc to accumulate in metallothionein in liver and kidney but not in a similar protein in the testes, the properties of the low-Mr cadmium-binding proteins were investigated in rat testes. Weanling rats that had been given dietary cadmium for 6 weeks were injected with 109CdCl2 and subsequently killed, and the 109Cd-labelled low-Mr proteins from testes were purified. The pooled low-Mr cadmium-containing fractions from the gel-filtration (Sephadex G-75) columns were eluted through DEAE-Sephacel columns, yielding two peaks. Each of the individual peaks from this Sephacel column was further purified by rechromatography on DEAE-Sephacel and on Bio-Gel P-10 columns. Amino acid analysis of the two purified proteins revealed a low cysteine (about 3%) content, with aspartate, glutamate and glycine as the predominant amino acids. Thus these low-Mr cadmium-binding proteins induced by cadmium in rat testes do not appear to be metallothionein.


Human marrow stromal cells downsize the stem cell fraction of lung cancers by fibroblast growth factor 10.
The functional interplay between cancer cells and marrow stromal cells (MSCs) has attracted a great deal of interest due to the MSC tropism for tumors but remains to be fully elucidated. In this study, we investigated human MSC-secreted paracrine factors that appear to have critical functions in cancer stem cell subpopulations. We show that MSC-conditioned medium reduced the cancer stem cell-enriched subpopulation, which was detected as a side population and quiescent (G0) cell cycle fraction in human lung cancer cells by virtue of fibroblast growth factor 10 (FGF10). This reduction of the stem cell-enriched fraction was also observed in lung cancer cells supplemented with recombinant human FGF10 protein. Moreover, supplementary FGF10 attenuated the expression of stemness genes encoding transcription factors, such as OCT3/4 and SOX2, and crippled the self-renewal capacity of lung cancer cells, as evidenced by the impaired formation of floating spheres in the suspension culture. We finally confirmed the therapeutic potential of the FGF10 treatment, which rendered lung cancer cells prone to a chemotherapeutic agent, probably due to the reduced cancer stem cell subpopulation. Collectively, these results add further clarification to the molecular mechanisms underlying MSC-mediated cancer cell kinetics, facilitating the development of future therapies.


[Dosimetric control in interstitial gamma-therapy of malignant vaginal tumors].
Dosimetric studies were performed by means of a specially designed phantom schematically simulating the anatomy of the female pelvis, to investigate into the dose distribution of interstitial gamma-therapy. Measurements were done during the simulation of tumor irradiation in 4 regions of the vagina: in the anterior and posterior walls, in the lower and upper thirds. The urinary bladder posterior wall received the largest dose during irradiation of the anterior vaginal wall, whereas the anterior rectal wall during irradiation of the posterior vaginal wall. In comparing the calculated and experimental dosimetric data one can mark their coincidence within 20%. The authors also provide the results of a study of the radiation-hygienic working conditions of the staff responsible for administering interstitial radiation therapy.


Acute haemodynamic comparison of amrinone and pirbuterol in chronic heart failure. Additional effects of isosorbide dinitrate.
A randomised, within patient comparison was made in patients with severe chronic heart failure, to study the acute haemodynamic effects of oral agents which have inotropic and vasodilator properties. A non-glycosidic non-adrenergic positive inotropic agent with vasodilator properties (amrinone) was compared with a beta-agonist which has vasodilator and positive inotropic effects (pirbuterol). To assess whether combined treatment with a venodilator might be advantageous, the effect of adding isosorbide dinitrate was studied. Oral amrinone or pirbuterol were given in random order to each of 13 patients, on successive days, and oral isosorbide dinitrate was added after two-and-a-half hours. Control values before amrinone or pirbuterol were similar, and both drugs increased cardiac index while reducing left ventricular filling pressure, right atrial pressure, and systemic vascular resistance. Heart rate and blood pressure were unchanged. The magnitude of the changes caused by amrinone and pirbuterol were not significantly different. The addition of isosorbide dinitrate caused further falls in left ventricular filling pressure and right atrial pressures, and a fall in heart rate with each drug. Other measurements remained unchanged. Although amrinone and pirbuterol have different pharmacological properties, their acute haemodynamic effects in patients with chronic heart failure are indistinguishable.


Electrothermally-assisted capsular shift.
The marriage of biomedical instrumentation and patient care has once again proven itself successful. The ETAC is a new procedure with various potential applications. Despite its embryonic stage, this procedure is being used by a handful of shoulder surgeons who are cautiously pursuing new and improved ways to prevent the common and debilitating diagnosis of shoulder instability. Follow-up thus far is short, and the current literature lacks studies that compare the time-honored conventional standard of open stabilization to this new procedure. However, those surgeons who have been using this device are optimistic about its role in the future repair of shoulder injuries.


Effect of captopril on proliferation of aortic smooth muscle cells.
To study the effect of captopril (Cap) on proliferation of smooth muscle cells (SMC). Proliferation of cultured porcine aortic SMC was promoted by hyperlipidemic sera (HLS). Cap (0.2 mg.L-1) remarkably reduced [3H]thymidine ([3H]TdR) incorporation, inhibited DNA synthesis and proliferation of SMC, and lessened morphological changes caused by HLS. After administration of Cap, malondialdehyde (MDA) content and plasminogen activator inhibitor (PAI) activity were reduced, 6-keto-PGF1 alpha and cAMP contents were obviously increased (P < 0.05-0.01). Cap inhibited the proliferation of SMC, associated with MDA, PAI, 6-keto-PGF1 alpha and cAMP.


35S and 3H-proline incorporation in rats deficient in essential fatty acids.
The effects of essential fatty acid (EFA) deficiency on connective tissue metabolism were studied in rats deficient in EFA and prostaglandins (PG). In chronic EFA deficiency, 3H-proline fixation, a measure of protein synthesis, was markedly reduced in the stomach, liver, adrenal, kidney, spleen, heart, and small intestine. Collagen rich tissues, such as lung, aorta, and cartilage also demonstrated reduced 3H-proline incorporation. 35S uptake, a measure of glycosaminoglycan synthesis, was inhibited in the lung, kidney, spleen, aorta, small intestine, and cartilage. Shorter periods of EFA deficiency resulted in similar diminished 35S incorporation. However, corn oil supplements largely corrected these metabolic defects. PGE1 injections stimulated 35S uptake in the mucus secreting tissues of the stomach and intestine. Comments are presented suggesting that the anti-PG actions of steroids and non-steroidal anti-inflammatory drugs contribute to ulcer formation during drug therapy.


Autocrine FGF-2 is responsible for the cell density-dependent susceptibility to apoptosis of HUVEC : A role of a calpain inhibitor-sensitive mechanism.
To elucidate the factors affecting endothelial susceptibility to apoptosis, we studied the effects of cell density on endothelial cell apoptosis induced by deprivation of serum and fibroblast growth factor-2 (FGF-2/basic FGF). On deprivation, more cells became apoptotic in a dense culture (5 x 10(2) cells/mm(2)) than in a sparse culture (1 x 10(2) cells/mm(2)) of human umbilical vein endothelial cells. FGF-2, hepatocyte growth factor, and vascular endothelial cell growth factor, but not insulin-like growth factor-I, decreased apoptosis in the dense culture to a level similar in the sparse culture. An anti-FGF-2 antibody significantly increased the apoptosis in the sparse culture, suggesting that the sparse culture was resistant to apoptosis because of the greater autocrine production of FGF-2. Western blot analysis and metabolic labeling revealed that the sparse culture has, in fact, more FGF-2 than the dense culture. The steady state level of mRNA for FGF-2 was not significantly different between the dense and sparse cultures. Among a panel of inhibitors for 2 major cytoplasmic proteolytic enzymes, calpain inhibitors increased FGF-2 in the dense culture, but proteasome inhibitors did not. Our findings demonstrate that cell density affects endothelial survival by regulating autocrine FGF-2 production through a calpain inhibitor-sensitive mechanism.


Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly.
Treatment for acromegaly patients with long-acting somatotropin release-inhibiting factor (LA-SRIF) often does not result in complete normalization of IGF-1. Addition of pegvisomant (PEGV), a GH receptor antagonist, could improve this; however, the literature has not described long-term follow-up. To assess long-term efficacy and safety of this combined treatment in the largest current single-center cohort of patients, from 2004-2013. Acromegaly patients were treated for at least 6 months with a high-dose LA-SRIF. To patients with persistently elevated IGF-1 levels (>1.2 × upper limit of normal) or poor quality of life, PEGV was added as one weekly injection. The patients (n = 141) were treated with PEGV and LA-SRIFs for a median period of 4.9 years (range, 0.5-9.2). Efficacy, defined as the lowest measured IGF-1 level during treatment, was 97.0%. The median PEGV dose to achieve this efficacy was 80 mg weekly (interquartile range, 60-120 mg). Combination treatment-related adverse events were recorded in 26 subjects (18.4%). Pituitary tumor size increase was observed in one patient. Injection-site reactions were observed in four subjects. In 19 patients (13.5%), transiently elevated liver transaminases of more than three times the upper limit of normal were observed, of which 83% occurred within the first year of combination treatment. Eight patients died, at a mean age of 71 years; none of them were considered treatment-related. The combination treatment with LA-SRIFs and PEGV was effective in 97% of the patients, it appears to be a safe medical treatment and it reduces the required dose of PEGV.


[Television cytophotometer based on the principle of summation selected on given levels of optical density].
A method of cytophotometry and the apparatus for its realization are described. The object with heterogenous distribution of the dye stuff is represented as a set of areas with different optical density with following summation of these areas. The apparatus is assembled on the whole of the industrial serial instruments. The identify of measuring results obtained with a two-wave cytophotometer and with the one described here is shown.


[Implication of the anxiety and depression in eating disorders of young obese].
the goals of the present study were: 1) to compare the levels of anxiety, depression, and eating disorders in young patients assisted at a children's hospital for obesity; 2) to determine whether anxiety and depression explain the symptoms of the eating disorders; and 3) to know which of these symptoms better discriminate the young people with different degrees of obesity. Descriptive, cross-sectional study with a sample comprised by 281 youngsters (56% girls) aged 11-17 years. The BMI percentiles were calculated by using the WHO growth tables. Two study groups were created: severe obesity and overweight/light-moderate obesity. The following questionnaires were used: Eating Disorders Inventory-2 (EDI-2), depression questionnaire (DQ), and Status-Trait Anxiety Questionnaire (STAI). The youngsters with obesity showed more psychological problems than youngsters with overweight/light-moderate obesity, 12% had anxiety, and 11% depression. In both groups, the behaviours related with eating disorders were partially explained by the presence of symptoms of anxiety and depression. Dissatisfaction with the body and high anxiety trait increased the risk for perpetuating the obesity and were the two symptoms that better discriminated the patients with or without severe obesity. Obesity prevention programmes should include body dissatisfaction and the anxiety trait into the assessment and management protocols, and prevent anxiety getting fixed as a personality trait.


[Syndromes 15. Robin sequence].
Robin sequence (RS) is a congenital anomaly that includes micrognathia, U-shaped cleft palate, and upper airway obstruction. More than 80% of children with RS have other malformations as a result of associated congenital anomalies. This report briefly reviews some multidisciplinary aspects, including etiopathology, diagnosis and treatment.


Ozone Exposure During Implantation Increases Serum Bioactivity in HTR-8/SVneo Trophoblasts.
Implantation is a sensitive window in reproductive development during which disruptions may increase the risk of adverse pregnancy outcomes including intrauterine growth restriction. Ozone exposure during implantation in rats reduces fetal weight near the end of gestation, potentially though impaired trophoblast migration and invasion and altered implantation. The current study characterized changes in ventilation, pulmonary injury, and circulating factors including hormonal, inflammatory, and metabolic markers related to exposure to ozone (0.4-1.2 ppm) for 4-h on gestation days 5 and 6 (window of implantation) in Long-Evans dams. To determine the effects of this exposure on trophoblast function, placental-derived, first trimester, HTR-8/SVneo cells were exposed to serum from air- or ozone (0.8 ppm×4 h)-exposed dams and examined for impacts on metabolic capacity, wound-closure, and invasion. Peri-implantation exposure to ozone induced ventilatory dysfunction and lung vascular leakage in pregnant rats, with little effect on most of the circulating markers measured. However, ozone inhalation induced a significant reduction in several serum cytokines (interferon-γ, interleukin-6, and interleukin-13). Treatment of HTR-8/SVneo trophoblasts with serum from ozone-exposed dams for 16-h downregulated metabolic capacity, wound-closure, and invasion through a Matrigel membrane compared with both air-serum and fetal bovine serum-treated cells. Ozone-serum treated cells increased the release of a critical inhibitor of invasion and angiogenesis (soluble fms-like receptor 1; sFlt1) compared with air-serum treatment. Together, our data suggest that circulating factors in the serum of pregnant rats exposed to ozone during implantation receptivity can hinder critical processes of implantation (eg, invasion and migration) and impair trophoblast metabolic capacity.


Nanoscopic cylindrical dual concentric and lengthwise block brush terpolymers as covalent preassembled high-resolution and high-sensitivity negative-tone photoresist materials.
We describe a high-resolution, high-sensitivity negative-tone photoresist technique that relies on bottom-up preassembly of differential polymer components within cylindrical polymer brush architectures that are designed to align vertically on a substrate and allow for top-down single-molecule line-width imaging. By applying cylindrical diblock brush terpolymers (DBTs) with a high degree of control over the synthetic chemistry, we achieved large areas of vertical alignment of the polymers within thin films without the need for supramolecular assembly processes, as required for linear block copolymer lithography. The specially designed chemical compositions and tuned concentric and lengthwise dimensions of the DBTs enabled high-sensitivity electron-beam lithography of patterns with widths of only a few DBTs (sub-30 nm line-width resolution). The high sensitivity of the brush polymer resists further facilitated the generation of latent images without postexposure baking, providing a practical approach for controlling acid reaction/diffusion processes in photolithography.


Weight changes, medical complications, and performance during an Ironman triathlon.
Subjects exercising without fluid ingestion in desert heat terminated exercise when the total loss in body weight exceeded 7%. It is not known if athletes competing in cooler conditions with free access to fluid terminate exercise at similar levels of weight loss. To determine any associations between percentage weight losses during a 224 km Ironman triathlon, serum sodium concentrations and rectal temperatures after the race, and prevalence of medical diagnoses. Athletes competing in the 2000 and 2001 South African Ironman triathlon were weighed on the day of registration and again immediately before and immediately after the race. Blood pressure and serum sodium concentrations were measured at registration and immediately after the race. Rectal temperatures were also measured after the race, at which time all athletes were medically examined. Athletes were assigned to one of three groups according to percentage weight loss during the race. Body weight was significantly (p<0.0001) reduced after the race in all three groups. Serum sodium concentrations were significantly (p<0.001) higher in athletes with the greatest percentage weight loss. Rectal temperatures were the same in all groups, with only a weak inverse association between temperature and percentage weight loss. There were no significant differences in diagnostic indices of high weight loss or incidence of medical diagnoses between groups. Large changes in body weight during a triathlon were not associated with a greater prevalence of medical complications or higher rectal temperatures but were associated with higher serum sodium concentrations.


Speciation history of three closely related pines Pinus mugo (T.), P. uliginosa (N.) and P. sylvestris (L.).
Nucleotide polymorphisms at genomic regions including 17 nuclear loci, two chloroplast and one mitochondrial DNA fragments were used to study the speciation history of three pine species: dwarf mountain pine (Pinus mugo), peat-bog pine (P. uliginosa) and Scots pine (P. sylvestris). We set out to investigate three specific speciation scenarios: (I) P. uliginosa is a homoploid hybrid between the other two, (II) the species have evolved without gene flow after divergence and (III) there has been substantial gene flow between the species since their divergence. Overall, the genetic data suggest that P. mugo and P. uliginosa share the same gene pool (average net divergence of 0.0001) and that the phenotypic differences (e.g. growth form) are most likely due to very limited areas of the genome. P. mugo and P. uliginosa are more diverged from P. sylvestris than from each other (average net divergence of 0.0027 and 0.0026, respectively). The nucleotide patterns can best be explained by the divergence with migration speciation scenario, although the hybrid speciation scenario with small genomic contribution from P. sylvestris cannot be completely ruled out. We suggest that the large amount of shared polymorphisms between the pine taxa and the lack of monophyly at all loci studied between P. sylvestris and P. mugo-P. uliginosa can largely be explained by relatively recent speciation history and large effective population sizes but also by interspecific gene flow. These closely related pine taxa form an excellent system for searching for loci involved in adaptive variation as they are differentiated in phenotype and ecology but have very similar genetic background.


The influence of concentration on specific ion effects at the silica/water interface.
Second harmonic generation spectroscopy is a useful tool for monitoring changes in interfacial potential at buried insulator/liquid interfaces. Here we apply this technique to the silica/aqueous interface and monitor the changes in interfacial potential while varying the pH in the presence of different alkali halides at 0.1M concentration. Within the pH range explored, the bimodal distribution of acidic sites on planar silica is clearly observed, corresponding to two types of acidic SiOH groups. Comparing these data with previous work at 0.5M sheds light on whether the presence of the ions stabilizes the charged or neutral state of the surface sites. For the alkali chlorides, with the exception of NaCl, we observe that the presence of the alkali chlorides stabilize the less acidic site in the protonated (SiOH) rather than deprotonated (SiO(-)) form. This unusual influence of the cation is attributed to the combination of interactions at the interface between water, surface sites and the electrolyte. Overall, we observe that the influence of the alkali ion on the ratio of the two types of sites and their effective acid dissociation constants is minor at 0.1M, unlike that observed at 0.5M. In contrast, the influence of the anion on the cooperative dissociation of surface sites and their relative distribution is little affected upon decreasing the concentration, which indicates that these specific anion effects are prevalent in nature.


The additive effect of dorzolamide hydrochloride (Trusopt) and a morning dose of bimatoprost (Lumigan) on intraocular pressure and retrobulbar blood flow in patients with primary open-angle glaucoma.
To assess the additive effect of dorzolamide hydrochloride 2% on the diurnal intraocular pressure (IOP) curve and retrobulbar haemodynamics in patients with primary open-angle glaucoma (POAG) treated with morning-dosed bimatoprost 0.03%. Twenty-five patients with POAG were evaluated in a prospective, single-masked study. After a 1 week run-in period with bimatoprost all patients were treated with bimatoprost dosed once in the morning for 1 month, after which dorzolamide was added twice daily for 2 months. Goldmann applanation IOP, arterial blood pressure (ABP) and heart rate were measured every 2 h for 24 h and diurnal ocular perfusion pressure (OPP) was calculated. Colour Doppler imaging (CDI) of the ophthalmic artery (OA) and the central retinal artery (CRA) was recorded five times daily. All measurements were taken after the two phases of treatment and were compared. The mean baseline IOP was 14.8 ± 3.5 mm Hg. Mean IOP following bimatoprost monotherapy (12.8 ± 2.9 mm Hg) and after 2 months of dorzolamide adjunctive therapy (12.2 ± 2.6 mm Hg) were not statistically significantly different (p=0.544). Only at the 4:00 h time point was IOP significantly reduced using the bimatoprost/dorzolamide combined treatment (p=0.013). The 24 h IOP fluctuations were lower when dorzolamide was added (6.0 ± 2.3 mm Hg vs 4.6 ± 1.5 Hg, p=0.0016). Repeated analysis of variance detected a significant decrease of vascular resistance in the OA (p=0.0167) with adjunctive dorzolamide treatment. The addition of dorzolamide to morning-dosed bimatoprost had an additive hypotensive effect only on the night-time IOP curve at 4:00 h and resulted in a lower IOP fluctuation. Dorzolamide added to bimatoprost may reduce vascular resistance in the OA.


Identification of the HNSC88 Molecular Signature for Predicting Subtypes of Head and Neck Cancer.
Head and neck squamous cell carcinoma (HNSC) exhibits genetic heterogeneity in etiologies, tumor sites, and biological processes, which significantly impact therapeutic strategies and prognosis. While the influence of human papillomavirus on clinical outcomes is established, the molecular subtypes determining additional treatment options for HNSC remain unclear and inconsistent. This study aims to identify distinct HNSC molecular subtypes to enhance diagnosis and prognosis accuracy. In this study, we collected three HNSC microarrays (n = 306) from the Gene Expression Omnibus (GEO), and HNSC RNA-Seq data (n = 566) from The Cancer Genome Atlas (TCGA) to identify differentially expressed genes (DEGs) and validate our results. Two scoring methods, representative score (RS) and perturbative score (PS), were developed for DEGs to summarize their possible activation functions and influence in tumorigenesis. Based on the RS and PS scoring, we selected candidate genes to cluster TCGA samples for the identification of molecular subtypes in HNSC. We have identified 289 up-regulated DEGs and selected 88 genes (called HNSC88) using the RS and PS scoring methods. Based on HNSC88 and TCGA samples, we determined three HNSC subtypes, including one HPV-associated subtype, and two HPV-negative subtypes. One of the HPV-negative subtypes showed a relationship to smoking behavior, while the other exhibited high expression in tumor immune response. The Kaplan-Meier method was used to compare overall survival among the three subtypes. The HPV-associated subtype showed a better prognosis compared to the other two HPV-negative subtypes (log rank, p = 0.0092 and 0.0001; hazard ratio, 1.36 and 1.39). Additionally, within the HPV-negative group, the smoking-related subgroup exhibited worse prognosis compared to the subgroup with high expression in immune response (log rank, p = 0.039; hazard ratio, 1.53). The HNSC88 not only enables the identification of HPV-associated subtypes, but also proposes two potential HPV-negative subtypes with distinct prognoses and molecular signatures. This study provides valuable strategies for summarizing the roles and influences of genes in tumorigenesis for identifying molecular signatures and subtypes of HNSC.


Beyond just-in-time: the UCLA Medical Center experience.
This article is a narrative description of how and why the UCLA Medical Center arrived at the point of a vendor-managed supply distribution program. The article outlines a historical perspective of supply distribution and places UCLA in that framework. It goes on to summarize the UCLA Medical Center model both for stock and nonstock distribution. A new program overview outlines the Owens & Minor commitment to UCLA, and there is a short discussion of AXIOMM, the UCLA Medical Center computer purchasing program.


The anti-inflammatory activity of curcumin protects the genital mucosal epithelial barrier from disruption and blocks replication of HIV-1 and HSV-2.
Inflammation is a known mechanism that facilitates HIV acquisition and the spread of infection. In this study, we evaluated whether curcumin, a potent and safe anti-inflammatory compound, could be used to abrogate inflammatory processes that facilitate HIV-1 acquisition in the female genital tract (FGT) and contribute to HIV amplification. Primary, human genital epithelial cells (GECs) were pretreated with curcumin and exposed to HIV-1 or HIV glycoprotein 120 (gp120), both of which have been shown to disrupt epithelial tight junction proteins, including ZO-1 and occludin. Pre-treatment with curcumin prevented disruption of the mucosal barrier by maintaining ZO-1 and occludin expression and maintained trans-epithelial electric resistance across the genital epithelium. Curcumin pre-treatment also abrogated the gp120-mediated upregulation of the proinflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6, which mediate barrier disruption, as well as the chemokines IL-8, RANTES and interferon gamma-induced protein-10 (IP-10), which are capable of recruiting HIV target cells to the FGT. GECs treated with curcumin and exposed to the sexually transmitted co-infecting microbes HSV-1, HSV-2 and Neisseria gonorrhoeae were unable to elicit innate inflammatory responses that indirectly induced activation of the HIV promoter and curcumin blocked Toll-like receptor (TLR)-mediated induction of HIV replication in chronically infected T-cells. Finally, curcumin treatment resulted in significantly decreased HIV-1 and HSV-2 replication in chronically infected T-cells and primary GECs, respectively. All together, our results suggest that the use of anti-inflammatory compounds such as curcumin may offer a viable alternative for the prevention and/or control of HIV replication in the FGT.


The human endolymphatic sac. An ultrastructural study.
In observing the fine structure of the human endolymphatic sac (ES) by transmission electron microscopy, we defined the cytologic characteristics of the epithelial lining of the various portions of the sac and identified five types of epithelial cells with presumably somewhat different functions. The morphologic findings may suggest that the human ES is involved in endolymph resorption and phagocytosis. In addition, there are indications that in humans the sac may be involved in pressure regulation in the internal ear. The ES has a possible role in the turnover of macular statoconia.


Advantages of online SPE coupled with UPLC/MS/MS for determining the fate of pesticides and pharmaceutical compounds.
Laboratory experimentation is essential for our understanding of the fate and behaviour of pollutants. Many analytical techniques exist, but they all have disadvantages either in terms of sensitivity or of selectivity. The number of samples that can be analysed, the low volume of samples available during the experiment and the need to identify different degradates are all obstacles that new techniques are able to overcome. The work presented here summarizes progress in the field of metrology as concerns online solid phase extraction technology coupled with liquid chromatography followed by tandem mass spectrometry detection. Recently developed analytical techniques were validated for both 18 pesticides and their degradates and 17 pharmaceuticals and their degradates. Limits of quantification from 20 to 70 ng L(-1) for pharmaceuticals and from 15 to 25 ng L(-1) for pesticides and metabolites have been obtained, with linearity range up to 1 μg L(-1). The limits of quantification of a few nanograms per litre, the possibility of working on less than 1 mL of sample and the simultaneous quantification of the target products and their transformation products are all advantages that are demonstrated by two environmental applications. The first application concerns the evaluation of ecotoxicological effects of pesticides on aquatic organisms exposed in mesocosms. The second application aims to determine the adsorption constants of pharmaceutical molecules on soils and river sediments. For both applications, the robustness, range of linearity and limit of quantification of the developed analytical methods satisfy the requirements for laboratory experiments conducted under controlled conditions. Specific constraints generated by this type of experiment (adding CaCl2 for the adsorption study and filtration of the water coming from the mesocosms) were not found to limit the use of online SPE. These two preliminary studies show that new experimental fields are possible thanks to online solid phase extraction coupled with liquid chromatography.


Psychophysical measures of central auditory dysfunction in multiple sclerosis: neurophysiological and neuroanatomical correlates.
Central auditory function was assessed in 15 patients with multiple sclerosis (MS) to determine whether the demyelinating lesions resulted in disruption of temporal processing. Auditory evoked potential (AEP) recordings included all three latency regions: Auditory brain stem responses (ABRs), midlatency responses (MLRs), and long-latency responses (LLRs). Two psychophysical tasks thought to involve temporal processing were used: a monaural-processing task (gap-detection) and a binaural-processing task (masking level difference; MLD). Further, AEP abnormalities and psychophysical performance deficits were related to lesion location, based on magnetic resonance imaging (MRI) scans. Reduced MLDs were seen in six MS subjects. Abnormal MLDs were always accompanied by abnormal ABRs and MLRs, and compared to subjects with normal MLDs, the subjects with abnormal MLDs were more likely to have bilateral abnormalities in the AEPs. Further, MLR indices of abnormal binaural interaction appeared to be specifically related to the psychophysical measure of binaural processing. The MRI data of these patients indicated widespread involvement of the auditory pathway. MS subjects with abnormal MRI signals restricted to levels caudal to the lateral lemniscus did not have abnormal MLDs. Gap-detection thresholds were more resistant to the effects of the demyelinating lesions; only two subjects had abnormal gap-detection thresholds. These subjects had extensive AEP abnormalities (bilaterally, in all three latency regions). The gap-detection thresholds were most specifically related to abnormalities of the LLRs. In addition, the subjects with elevated gap-detection thresholds were the only ones with a prolonged interval between the ABRs and MLRs. Thus, efficient neural conduction between the upper brain stem and auditory cortex appears to be crucial for normal monaural temporal processing. The results indicate that demyelinating lesions can cause deficits in temporal processing in the central auditory pathway. However, auditory temporal processing is not a unitary phenomenon since abnormalities at different levels of the auditory system disrupt different types of temporal processing. Finally, abnormal psychophysical performance was not seen in all subjects with AEP and MRI evidence of involvement of the auditory pathway; rather, these psychophysical measures appeared to be sensitive to disruption only in specific portions of the auditory system.


[Comparison of the cost-effectiveness of the most common diagnostic methods for coronary artery disease].
The cost-effectiveness of medical procedures is becoming a crucial factor besides their efficacy in clinical decision-making. We performed a cost-effectiveness analysis of the most common diagnostic modalities used in assessing coronary artery disease (CAD). A decision tree model for determining the cost-effectiveness in CAD diagnosis was applied to the situation in Germany to calculate the cost-effectiveness of exercise ECG (ExECG), stress echocardiography (ECHO), myocardial scintigraphy (SPECT), and coronary angiography (ANGIO). The cost-effectiveness was defined as direct and induced costs per correctly identified patient. A sensitivity analysis was performed varying the predictive accuracies, the complication-related costs, and costs and complication rates of ANGIO. The costs per correctly identified patient decreased in a hyperbolic fashion as the pretest likelihood of CAD increased due to the higher incidence of positive findings. For a pretest likelihood between 10 and 40%, ExECG and ECHO were most cost effective with costs per CAD patient of 5,880 - 2,500 EUR and 6,410 - 2,280 EUR, respectively. The combination of ExECG und ECHO (application of the second modality in case the first one was nondiagnostic) further improved the cost-effectiveness up to a pretest likelihood of 35%. For a pretest likelihood of 50% or greater, ANGIO costing 1,880 - 940 EUR per correct diagnosis was most cost-effective. Sensitivity analysis revealed no significant changes demonstrating the robustness of the model. ANGIO is the most cost-effective procedure for a pretest likelihood of 50% or greater. At lower pretest likelihoods, ExECG, ECHO and the combined ExECG/ECHO strategy based on economic considerations are the preferred modalities for diagnosis of CAD.


Cyclin-dependent kinase regulation of the replication functions of polyomavirus large T antigen.
The amino-terminal portion of polyomavirus (Py) large T antigen (T Ag) contains two phosphorylation sites, at T187 and T278, which are potential substrates for cyclin-dependent kinases (CDKs). Our experiments were designed to test whether either or both of these sites are involved in the origin DNA (ori DNA) replication function of Py T Ag. Mutations were generated in Py T Ag whereby either or both threonines were replaced with alanine, generating T187A, T278A, and double-mutants (DM [T187A T278A]) mutant T Ags. We found that the Py ori DNA replication functions of T278A and DM, but not T187A, mutant T Ags were abolished both in vivo and in vitro. Consistent with this finding, it was shown that the ori DNA binding and unwinding activities of mutant T278A Py T Ag were greatly impaired. Moreover, whereas wild-type Py T Ag is an efficient substrate for phosphorylation by cyclin A-CDK2 and cyclin B-cdc2 complexes, it is phosphorylated poorly by a cyclin E-CDK2 complex. In contrast to mutant T187A, which behaved similarly to the wild-type protein, T278A was only weakly phosphorylated by cyclin B-cdc2. These data thus suggest that T278 is an important site on Py T Ag for phosphorylation by CDKs and that loss of this site leads to its various defects in mediating ori DNA replication. S- and G2-phase-specific CDKs, but not a G1-specific CDK, can phosphorylate wild-type T Ag, which suggests yet another reason why DNA tumor viruses require actively cycling host cells.


Development of heart failure in chronic hypertensive Dahl rats: focus on heart failure with preserved ejection fraction.
The impact of hypertension on left ventricular (LV) structure, pump function, and heart failure in Dahl salt-sensitive rats is poorly characterized but hypothesized to yield insights into the pathophysiology of heart failure with normal or preserved ejection fraction. Eighty Dahl salt-sensitive rats were fed either a high-salt (HS) or low-salt (LS, controls) diet starting at age 7 weeks. Ventricular properties were measured by echocardiography, hemodynamics and end-systolic and end-diastolic pressure-volume relationships (ESPVR and EDPVR, respectively). Compared with LS controls, HS rats developed severe hypertension and LV hypertrophy. At week 12, HS rats developed passive diastolic dysfunction (leftward/upward shifted EDPVR, increased chamber stiffness) with reductions in end-diastolic volume. However, the ESPVR also shifted upward (enhanced end-systolic function) so that overall pump function was enhanced compared with LS, and there was no change in end-diastolic pressure (EDP). At 16 and 20 weeks, HS hearts enlarged so that end-diastolic volumes and EDPVRs became similar to the respective age-matched LS controls. Concomitantly, the ESPVRs and overall pump function curves also moved toward controls, and ejection fraction declined. Despite normal or enhanced overall pump function at these times, EDP and wet lung weight increased, indicative of development of heart failure. In the Dahl salt-sensitive rat, which pathophysiologically retains salt and water, the development of heart failure (increased EDP and wet lung weight) is dissociated from changes in passive diastolic and active systolic properties. These observations suggest that a volume overload sate plays an important pathophysiological role in development of heart failure despite preserved overall ventricular pump function in this model of chronic hypertension.


Autoimmune disorders in patients affected by celiac sprue and inflammatory bowel disease.
Although clinically different, celiac sprue and inflammatory bowel disease are characterized by chronic intestinal inflammation and associated extraintestinal manifestations. To assess and compare the presence of autoimmune disorders in patients affected by celiac sprue and inflammatory bowel disease referred to a single tertiary centre. From October 2005 to January 2006, a total of 297 consecutive outpatients were enrolled in this cross-sectional study. Diagnoses of celiac sprue and inflammatory bowel disease were based on standard criteria. Data were recorded using an operator-assisted questionnaire: 18 autoimmune diseases, when adequately confirmed, were considered. Clinical characteristics of our patients are in conformity with those of the literature. The prevalence of associated autoimmune diseases was 25.6%, 21.1%, and 10% in patients affected by celiac sprue, Crohn's disease, and ulcerative colitis. Between the prevalence in celiac sprue and Crohn's disease there was no difference, whereas a significant difference was present between these two diseases and ulcerative colitis. The most frequent disorder in all three groups was Hashimoto's thyroiditis. Celiac sprue and Crohn's disease show similar prevalence of associated autoimmune disease, higher than the prevalence in ulcerative colitis. The two diseases share the same pathogenic immunologic response and altered intestinal permeability.


Inferring online and offline processing of visual feedback in target-directed movements from kinematic data.
Vision plays an important role in the planning and execution of target-directed aiming movements. In this review, we highlight the limitations that exist in detecting visual regulation of limb trajectories from traditional kinematic analyses such as the identification of discontinuities in velocity and acceleration. Alternative kinematic analyses that involve examining variability in limb trajectories to infer visual control processes are evaluated. The basic assumption underlying these methods is that noise exists in the neuromotor system that subsequently leads to variability in motor output. This leads to systematic relations in limb trajectory variability at different stages of the movement that are altered when trajectories are modified during movement execution. Hence, by examining the variability in limb trajectories and correlations of kinematic variables throughout movement for vision and no vision conditions, the contribution of visual feedback in the planning and control of movement can be determined.


T cell-independent modulation of experimental autoimmune encephalomyelitis in ADAP-deficient mice.
The adhesion- and degranulation-promoting adaptor protein (ADAP), expressed in T cells, myeloid cells, and platelets, is known to regulate receptor-mediated inside-out signaling leading to integrin activation and adhesion. In this study, we demonstrate that, upon induction of active experimental autoimmune encephalomyelitis (EAE) by immunization with the myelin oligodendrocyte glycoprotein35-55 peptide, ADAP-deficient mice developed a significantly milder clinical course of EAE and showed markedly less inflammatory infiltrates in the CNS than wild-type mice. Moreover, ADAP-deficient recipients failed to induce EAE after adoptive transfer of myelin oligodendrocyte glycoprotein-specific TCR-transgenic T cells (2D2 T cells). In addition, ex vivo fully activated 2D2 T cells induced significantly less severe EAE in ADAP-deficient recipients. The ameliorated disease in the absence of ADAP was not due to expansion or deletion of a particular T cell subset but rather because of a strong reduction of all inflammatory leukocyte populations invading the CNS. Monitoring the adoptively transferred 2D2 T cells over time demonstrated that they accumulated within the lymph nodes of ADAP-deficient hosts. Importantly, transfer of complete wild-type bone marrow or even bone marrow of 2D2 TCR-transgenic mice was unable to reconstitute EAE in the ADAP-deficient animals, indicating that the milder EAE was dependent on (a) radio-resistant nonhematopoietic cell population(s). Two-photon microscopy of lymph node explants revealed that adoptively transferred lymphocytes accumulated at lymphatic vessels in the lymph nodes of ADAP-deficient mice. Thus, our data identify a T cell-independent mechanism of EAE modulation in ADAP-deficient mice.


DCW11, down-regulated gene 11 in CW-type cytoplasmic male sterile rice, encoding mitochondrial protein phosphatase 2c is related to cytoplasmic male sterility.
Causes of cytoplasmic male sterility (CMS) in plants have been studied for two decades, and mitochondrial chimeric genes have been predicted to induce CMS. However, it is unclear what happens after CMS-associated proteins accumulate in mitochondria. In our previous study of microarray analysis, we found that 140 genes are aberrantly regulated in anthers of CW-type CMS of rice (Oryza sativa L.). In the present study, we investigated DCW11, one of the down-regulated genes in CW-CMS encoding a protein phosphatase 2C (PP2C). DCW11 mRNA was preferentially expressed in anthers, with the highest expression in mature pollen. As predicted by the N-terminal sequence, DCW11 signal peptide-green fluorescent protein (GFP) fusion protein was localized in mitochondria. Knockdown of DCW11 in wild-type rice by RNA interference caused a major loss of seed-set fertility, without visible defect in pollen development. Since this knockdown phenotype resembled that of CW-CMS, we concluded that the down-regulation of DCW11 is correlated with CW-CMS. This idea was supported by the up-regulation of alternative oxidase 1a (AOX1a), which is known to be regulated by mitochondrial retrograde signaling, in DCW11 knockdown lines. Down-regulation of DCW11 and up-regulation of AOX1a were also observed in two other types of rice CMS. Our result indicates that DCW11 could play a role as a mitochondrial signal transduction mediator in pollen germination.


[Character changes in epilepsy?].
There are no personality structures which are typical of epilepsies in the sense of a change in character that can be seen in cross and especially in longitudinal sections. Reported changes of character due to epilepsies cannot be exactly defined reproducibly for the forms of fits to be differentiated and cannot, therefore, be used operationally. There is no doubt, however, that several causal factors must be considered to be responsible for the manifestation of certain frequently observed peculiarities and characteristics, respectively. In addition to organic, psychodynamic, and socio-situational causes, long-time antiepileptic medication is an essential factor of changes in character due to diseases characterized by fits. A better understanding has now been obtained of the importance of this particular factor, and this allows to conclude that there can only be epileptic functioning and reacting.


Sorafenib, a multikinase inhibitor, is effective in vitro against non-Hodgkin lymphoma and synergizes with the mTOR inhibitor rapamycin.
Non-Hodgkin lymphoma (NHL) represents a heterogenous group of neoplasias originating from lymphoid cells. Increased angiogenesis and expression of Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR) have been found to be associated with NHL disease progression. Increase in VEGF and other cytokines stimulate signaling cascades, including the Ras/Raf/Mek/Erk pathway, resulting in increased proliferation and decreased apoptosis. Here, we report the in vitro antilymphoma activity of sorafenib, an inhibitor of VEGFR and Raf kinase. Sorafenib induced potent cytotoxicity in NHL cell lines and patient samples. This induction of cytotoxicity was associated with a corresponding increase in apoptotic cell death. Mechanism of action of sorafenib was investigated in follicular (DoHH2) and Burkitt lymphoma (Raji) cell lines. pStat3, pAkt, Mcl1, and Xiap were downregulated in both cell lines, whereas pErk decreased in Raji but not in DoHH2 cells following sorafenib treatment. IL6 was unable to prevent sorafenib induced repression of pStat3, pAkt, Mcl1, and Bcl-Xl. Sorafenib in combination with an mTORC1 inhibitor rapamycin demonstrated synergy in inducing cytotoxicity in NHL cells. Sorafenib/rapamycin combination resulted in downregulation of pAkt, pmTOR, p-p70S6K, p4EBP1, pGSK3β, Mcl1, and Bcl-Xl. On the basis of our results, a clinical trial is underway using sorafenib with everolimus in NHL patients.


The Great Reset. Restratification for lives, livelihoods, and the planet.
In reviewing the Great Reset, an initiative launched by the World Economic Forum (WEF) in response to the global coronavirus crisis, this perspective article considers the scenario of an epochal transition from capitalism to "restorism". To facilitate the observation of underlying trends and assumptions, a systems-theoretical framework is developed for the observation of both this Great Reset scenario and those scenarios that are by implication excluded by the WEF vision. It is thus shown that the "shared goals" advocated by the WEF would converge to a transition from a modern pluralist to a "new-normative" order stratified to the primacy of individual, institutional, and planetary health. In discussing sociological implications of this transition, a vision emerges of a new digitally enhanced medieval era where health plays the role once played by religion. In this restorist scenario of a neo-medieval world health society, the emergence of new social strata corresponding to different levels of purity, infection, or pollution would be a probable consequence. The paper concludes that idea of deliberately caused great resets and other control illusions nurtured by the WEF initiative are barely smarter than and spur what the UN Secretary-General refers to as "wild conspiracy theories".


Localisation of ventricular septal defects by simultaneous display of superimposed colour Doppler and cross sectional echocardiographic images.
Precise non-invasive localisation of the site of a small ventricular septal defect was attempted using a new technique that simultaneously combines conventional cross sectional echocardiography with a Doppler system by superimposing the colour coded direction and velocity of blood flow directly on to real time ultrasound images. Twenty three patients with unoperated ventricular septal defects and a further eight after surgical closure were studied; 12 children with normal hearts served as controls. A colour coded blood flow jet entering the right ventricle during systole was identified in all 23 unoperated patients, in 11 of whom the defect was too small to be visualised by conventional cross sectional echocardiography. The colour Doppler technique precisely located 19 perimembranous and five trabecular defects (one patient had two defects). Five of the postoperative patients were without clinical evidence of a significant shunt but had pansystolic murmurs. In each of these five, trans-septal shunt blood flow as demonstrated by colour Doppler images whereas in only three of these patients was the residual defect large enough to be visualised by conventional cross sectional echocardiography. Three postoperative patients had no murmurs and showed no residual shunt on colour Doppler images. This was confirmed at cardiac catheterisation. There were no false positive results among the controls. This technique is useful for the more accurate diagnosis and location of ventricular septal defects and may help in assessing their natural or surgical closure.


Contemporary issues in HIM. Software engineering--what does it mean to you?
There have been significant advances in the way we develop software in the last two decades. Many companies are using the new process oriented approach to software development. Companies that use the new techniques and tools have reported improvements in both productivity and quality, but there are still companies developing software the way we did 30 years ago. If you saw the movie Jurassic Park, you saw the perfect way not to develop software. The programmer in the movie was the only person who knew the details of the system. No processes were followed, and there was no documentation. This was an absolutely perfect prescription for failure. Some of you are probably familiar with the term hacker which describes a person who spends hours sitting at a terminal hacking out code. Hackers have created some outstanding software products, but with today's complex systems, most companies are trying to get away from their dependence on hackers. They are instead turning to the process-oriented approach. When selecting software vendors, don't just look at the functionality of a product. Try to determine how the vendor develops software, and determine if you are dealing with hackers or a process-driven company. In the long run, you should get better, more reliable products from the latter.


The morphological basis of the arm-to-wing transition.
Human-powered flight has fascinated scientists, artists, and physicians for centuries. This history includes Abbas Ibn Firnas, a Spanish inventor who attempted the first well-documented human flight; Leonardo da Vinci and his flying machines; the Turkish inventor Hezarfen Ahmed Celebi; and the modern aeronautical pioneer Otto Lilienthal. These historic figures held in common their attempts to construct wings from man-made materials, and though their human-powered attempts at flight never came to fruition, the ideas and creative elements contained within their flying machines were essential to modern aeronautics. Since the time of these early pioneers, flight has continued to captivate humans, and recently, in a departure from creating wings from artificial elements, there has been discussion of using reconstructive surgery to fabricate human wings from human arms. This article is a descriptive study of how one might attempt such a reconstruction and in doing so calls upon essential evidence in the evolution of flight, an understanding of which is paramount to constructing human wings from arms. This includes a brief analysis and exploration of the anatomy of the 150-million-year-old fossil Archaeopteryx lithographica, with particular emphasis on the skeletal organization of this primitive bird's wing and wrist. Additionally, certain elements of the reconstruction must be drawn from an analysis of modern birds including a description of the specialized shoulder of the European starling, Sturnus vulgaris. With this anatomic description in tow, basic calculations regarding wing loading and allometry suggest that human wings would likely be nonfunctional. However, with the proper reconstructive balance between primitive (Archaeopteryx) and modern (Sturnus), and in attempting to integrate a careful analysis of bird anatomy with modern surgical techniques, the newly constructed human wings could function as cosmetic features simulating, for example, the nonfunctional wings of flightless birds.


Di (2-Ethylhexyl) Phthalate and Its Role in Developing Cholestasis: An In Vitro Study on Different Liver Cell Types.
Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in many polyvinylchloride medical devices and is washed out easily. Thereby critically ill infants can become exposed to DEHP concentrations significantly exceeding the recommended threshold. We suspect DEHP to play an important role in the development of intestinal failure-associated liver disease. The aim of this study was therefore to determine the direct influence of DEHP on different liver cell types. HepG2, human upcyte hepatocytes, primary murine hepatocytes, LX-2, human upcyte hepatic stellate cells, and liver organoids were cultured with DEHP (0.5-500 μmol/L) and parameters including cytotoxicity, cell-cell interactions, and expression of metabolizing enzymes were investigated. DEHP modulated the expression of xenobiotic metabolizing enzymes, reduced the formation of bile canaliculi and cell polarity, and inhibited Cyp-activity in hepatocytes. DEHP had a toxic effect on LX-2 and induced the fibrogenic activation of hepatic stellate cells. The mode of action of DEHP was different in monolayer cultures compared to 3D-liver organoids, which were more sensitive to DEHP. This study suggests that DEHP modulates expression and activity of drug-detoxifying liver enzymes in humans at a clinically relevant concentration. Furthermore, it may contribute to the development of cholestasis and fibrosis. These findings strongly support the opinion, that there is a significant potential for serious adverse effects of DEHP derived from medical devices on human health, especially in very young infants with immature livers.


Sleep homeostasis and cortical synchronization: II. A local field potential study of sleep slow waves in the rat.
Sleep slow-wave activity (SWA, EEG power between 0.5 and 4.0 Hz) decreases homeostatically in the course of non-rapid eye movement sleep (NREM) sleep. According to a recent hypothesis, the homeostatic decrease of sleep SWA is due to a progressive decrease in the strength of corticocortical connections. This hypothesis was evaluated in a large-scale thalamocortical model, which showed that a decrease in synaptic strength, implemented through a reduction of postsynaptic currents, resulted in lower sleep SWA in simulated local field potentials (LFP). The decrease in SWA was associated with a decreased proportion of high-amplitude slow waves, a decreased slope of the slow waves, and an increase in the number of multipeak waves. Here we tested the model predictions by obtaining LFP recordings from the rat cerebral cortex and comparing conditions of high homeostatic sleep pressure (early sleep) and low homeostatic sleep pressure (late sleep). Intracortical LFP recordings during baseline sleep and after 6 hours of sleep deprivation. Basic sleep research laboratory. WKY adult male rats. N/A. Early sleep (sleep at the beginning of the major sleep phase, sleep immediately after sleep deprivation) was associated with (1) high SWA, (2) many large slow waves, (3) steep slope of slow waves, and (4) rare occurrence of multipeak waves. By contrast, late sleep (sleep at the end of the major sleep phase, sleep several hours after the end of sleep deprivation) was associated with (1) low SWA, (2) few high-amplitude slow waves, (3) reduced slope of slow waves, and (4) more frequent multipeak waves. In rats, changes in sleep SWA are associated with changes in the amplitude and slope of slow waves, and in the number of multi-peak waves. Such changes in slow-wave parameters are compatible with the hypothesis that average synaptic strength decreases in the course of sleep.


History of physical or sexual abuse and participation in 12-step self-help groups.
Although 12-step groups are an important resource for managing substance use problems, their efficacy for patients with a physical or sexual abuse history is unknown. In the present study, patients with a history of physical or sexual (n = 122) or no (n = 143) abuse were interviewed at entry to outpatient substance use treatment at the Veterans Administration. After adjusting for baseline substance use, physical or sexual abuse was associated with more attendance at and involvement in 12-step groups. Participation in 12-step groups predicted abstinence at one year, regardless of abuse history. Limitations and implications are discussed.


Diffracted-light contrast enhancement: a re-examination of oblique illumination.
A re-examination and modification of the very old oblique illumination technique has resulted in a method for contrast enhancement in microscopes, diffracted-light contrast (DLC), which provides high-contrast, high-resolution images of unstained biological material. The technique, which utilizes the diffracted light from the edge of a small, opaque plate, provides shadowcast images similar to those obtained by Nomarski DIC, anaxial illumination, modulation contrast, or single-sideband microscopy; however, it requires only a single additional component, which can be added to any bright field microscope. The contrast and three-dimensionality of the final image can be controlled by inserting differently shaped edges. Any bright field condenser will work with the technique and, consequently, it is a technique that may be especially useful with relatively basic, inexpensive laboratory and teaching microscopes although the image produced on a research grade microscope is of very high quality, comparable to that obtained with DIC.


An Oral Pressure Conversion Ratio as a Predictor of Vocal Efficiency.
Voice production is an inefficient process in terms of energy expended versus acoustic energy produced. A traditional efficiency measure, glottal efficiency, relates acoustic power radiated from the mouth to aerodynamic power produced in the trachea. This efficiency ranges between 0.0001% and 1.0%. It involves lung pressure and hence would appear to be a useful effort measure for a given acoustic output. Difficulty in the combined measurement of lung pressure and tracheal airflow, however, has impeded clinical application of glottal efficiency. This article uses the large data base from Schutte (1980) and a few new measurements to validate a pressure conversion ratio (PCR) as a substitute for glottal efficiency. PCR has the potential for wide application because of low cost and ease of use in clinics and vocal studios.


Implementation of childhood obesity prevention and control policies in the United States and Latin America: Lessons for cross-border research and practice.
Progress has been made in the development and widespread implementation of effective interventions to address childhood obesity, yet important challenges remain. To understand how the United States and Latin American countries achieved success in implementing obesity policies and programs (PAPs) and identify improvement opportunities using implementation science principles. We identified three comparative case studies: (1) front-of-food package labeling (Mexico and Chile); (2) Open Streets/play streets (Colombia and the United States); and (3) the Baby-Friendly Hospital Initiative (Brazil and the United States). Information from multiple sources (e.g., scientific and gray literature and key informant interviews) was synthesized to describe barriers, facilitators, and progress of PAPs across RE-AIM framework dimensions. Evidence-based advocacy along with political will and evidence of scalability and impact were key for successful launch and implementation of all PAPs. Diverse adaptations of PAP design and implementation had to be done across contexts. Stronger process and impact monitoring and evaluation systems that track equity indicators are needed to maximize the population benefits of these PAPs. Implementation science offers an important contribution toward addressing knowledge gaps, enhancing obesity policy dialogue, and producing transferable lessons across the Americas and, therefore, should be used for research and evaluation during PAP development and throughout the implementation and maintenance phases.


Global and depth resolved phosphorus magnetic resonance spectroscopy to predict outcome after birth asphyxia.
Twelve normal and 32 asphyxiated neonates were studied using global and depth resolved phosphorus magnetic resonance spectroscopy (31PMRS). Eight of the asphyxiated group died or survived with major neurodevelopmental abnormalities. A global phosphocreatinine/inorganic phosphate (PCr/Pi) ratio below the range of values from normal infants predicted adverse outcome after asphyxia with a positive predictive value of 64%, sensitivity 88%, and specificity 83%. Corresponding values for global inorganic orthophosphate/adenosine triphosphate (Pi/ATP) ratios were positive predictive value 88%, sensitivity 96%, and specificity 88%. Spatially localised MRS data, obtained using phase modulated rotating frame imaging, showed cerebral energy metabolism to be more abnormal in deep than superficial regions after birth asphyxia. However, in this population of full term infants none of the regional metabolite concentrations were superior to global data for prediction of outcome.


Effectiveness of a web-based health risk assessment with individually-tailored feedback on lifestyle behaviour: study protocol.
Physical inactivity, unhealthy dietary habits, smoking and high alcohol consumption are recognized risk factors for cardiovascular disease and cancer. Web-based health risk assessments with tailored feedback seem promising in promoting a healthy lifestyle. This study evaluates the effectiveness of a web-based health risk assessment with individually-tailored feedback on lifestyle behaviour, conducted in a worksite setting. The web-based health risk assessment starts with a questionnaire covering socio-demographic variables, family and personal medical history, lifestyle behaviour and psychological variables. Prognostic models are used to estimate individual cardiovascular risks. In case of high risk further biometric and laboratory evaluation is advised. All participants receive individually-tailored feedback on their responses to the health risk assessment questionnaire. The study uses a quasi-experimental design with a waiting list control group. Data are collected at baseline (T0) and after six months (T1). Within each company, clusters of employees are allocated to either the intervention or the control group. Primary outcome is lifestyle behaviour, expressed as the sum of five indicators namely physical activity, nutrition, smoking behaviour, alcohol consumption, and symptoms of burnout. Multilevel regression analysis will be used to answer the main research question and to correct for clustering effects. Baseline differences between the intervention and control group in the distribution of characteristics with a potential effect on lifestyle change will be taken into account in further analyses using propensity scores. This study will increase insight into the effectiveness of health risk assessments with tailored feedback and into conditions that may modify the effectiveness. This information can be used to design effective interventions for lifestyle behaviour change among employees. Dutch Trial Register NTR8148.


What Do District Health Managers in Ghana Use Their Working Time for? A Case Study of Three Districts.
Ineffective district health management potentially impacts on health system performance and service delivery. However, little is known about district health managing practices and time allocation in resource-constrained health systems. Therefore, a time use study was conducted in order to understand current time use practices of district health managers in Ghana. All 21 district health managers working in three districts of the Eastern Region were included in the study and followed for a period of three months. Daily retrospective interviews about their time use were conducted, covering 1182 person-days of observation. Total time use of the sample population was assessed as well as time use stratified by managerial position. Differences of time use over time were also evaluated. District health managers used most of their working time for data management (16.6%), attending workshops (12.3%), financial management (8.7%), training of staff (7.1%), drug and supply management (5.0%), and travelling (9.6%). The study found significant variations of time use across the managerial cadres as well as high weekly variations of time use impulsed mainly by a national vertical program. District health managers in Ghana use substantial amounts of their working time in only few activities and vertical programs greatly influence their time use. Our findings suggest that efficiency gains are possible for district health managers. However, these are unlikely to be achieved without improvements within the general health system, as inefficiencies seem to be largely caused by external factors.


Human CD43+ B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally in healthy individuals.
CD20(+)CD27(+)CD43(+) B (CD43(+) B) cells have been newly defined among PBMCs and proposed to be human B1 cells. However, it is controversial as to whether they are orthologs of murine B1 cells and how they are related to other B-cell populations, particularly CD20(+)CD27(+)CD43(-) memory B cells and CD20(low)CD27(high)CD43(high) plasmablasts. Our objective is to identify phenotypically the position of CD43(+) B cells among peripheral B-lineage cell compartments in healthy donors, with reference to B-cell subsets from patients with systemic lupus erythematosus (SLE). We found that CD43(+) B cells among PBMCs from healthy subjects were indistinguishable phenotypically from memory B cells in terms of surface markers, and spontaneous in vitro Ig and IL-10 secretion capability, but quite different from plasmablasts. However, a moderate correlation was found in the frequency of CD43(+) B cells with that of plasmablasts in healthy donors but not in SLE patients. An in vitro differentiation experiment indicated that CD43(+) B cells give rise to plasmablasts more efficiently than do memory B cells, suggesting that they are more closely related to plasmablasts developmentally than are memory B cells, which is also supported by quantitative PCR analysis of mRNA expression of B-cell and plasma cell signature genes. Thus, we conclude that, in healthy individuals, CD43(+) B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally, although the developmental origin of CD43(+) B cells is not necessarily the same as that of plasmablasts.


Cytoreductive surgery and perioperative intraperitoneal chemotherapy in recurrent ovarian cancer: 18 years of experience.
To identify the clinical and pathological factors associated with relapse in women who had undergone secondary cytoreductive surgery due to locally advanced recurrent ovarian cancer. Women with locally advanced recurrent ovarian cancer who had undergone cytoreduction between 2000 and 2018 were included in this study. Demographic, clinical and biochemical intraoperative findings were recorded for each woman. All factors were assessed in order to identify which correlated with the outcomes of interest (i.e. disease relapse, mortality and morbidity). In total, 181 women who had undergone secondary cytoreduction were analysed. The hospital mortality rate was 1.7 % (n = 3) and the morbidity rate was 32.1 % (n = 58). Recurrence was recorded in 101 (55.8 %) women. Infiltration of large bowel lymph nodes was a negative prognostic indicator of morbidity (p = 0.029). A prior surgical score of 1 (PSS-1) [odds ratio (OR) 0.465] and complete cytoreduction (OR 0.518) were found to be significant independent predictors for disease relapse. Median overall survival was greater for patients with PSS-1 (151.3 vs 59.4 vs 44.1 months; p = 0.049) and patients with complete cytoreduction (137.6 vs 36.2 vs 10.0 vs 27.4 months; p < 0.001). Complete cytoreduction and PSS-1 are associated with reduced disease relapse and increased overall survival. Infiltration of large bowel lymph nodes is associated with increased morbidity.


Interactive drivers of activity in a free-ranging estuarine predator.
Animal activity patterns evolve as an optimal balance between energy use, energy acquisition, and predation risk, so understanding how animals partition activity relative to extrinsic environmental fluctuations is central to understanding their ecology, biology and physiology. Here we use accelerometry to examine the degree to which activity patterns of an estuarine teleost predator are driven by a series of rhythmic and arrhythmic environmental fluctuations. We implanted free-ranging bream Acanthopagrus australis with acoustic transmitters that measured bi-axial acceleration and pressure (depth), and simultaneously monitored a series of environmental variables (photosynthetically active radiation, tidal height, temperature, turbidity, and lunar phase) for a period of approximately four months. Linear modeling showed an interaction between fish activity, light level and tidal height; with activity rates also negatively correlated with fish depth. These patterns highlight the relatively-complex trade-offs that are required to persist in highly variable environments. This study demonstrates how novel acoustic sensor tags can reveal interactive links between environmental cycles and animal behavior.


Integrative Analysis of Machine Learning and Molecule Docking Simulations for Ischemic Stroke Diagnosis and Therapy.
Due to the narrow therapeutic window and high mortality of ischemic stroke, it is of great significance to investigate its diagnosis and therapy. We employed weighted gene coexpression network analysis (WGCNA) to ascertain gene modules related to stroke and used the maSigPro R package to seek the time-dependent genes in the progression of stroke. Three machine learning algorithms were further employed to identify the feature genes of stroke. A nomogram model was built and applied to evaluate the stroke patients. We analyzed single-cell RNA sequencing (scRNA-seq) data to discern microglia subclusters in ischemic stroke. The RNA velocity, pseudo time, and gene set enrichment analysis (GSEA) were performed to investigate the relationship of microglia subclusters. Connectivity map (CMap) analysis and molecule docking were used to screen a therapeutic agent for stroke. A nomogram model based on the feature genes showed a clinical net benefit and enabled an accurate evaluation of stroke patients. The RNA velocity and pseudo time analysis showed that microglia subcluster 0 would develop toward subcluster 2 within 24 h from stroke onset. The GSEA showed that the function of microglia subcluster 0 was opposite to that of subcluster 2. AZ_628, which screened from CMap analysis, was found to have lower binding energy with Mmp12, Lgals3, Fam20c, Capg, Pkm2, Sdc4, and Itga5 in microglia subcluster 2 and maybe a therapeutic agent for the poor development of microglia subcluster 2 after stroke. Our study presents a nomogram model for stroke diagnosis and provides a potential molecule agent for stroke therapy.


Visualization of materials using the confocal laser scanning microscopy technique.
The development of materials science always benefits from advanced characterizations. Currently, imaging techniques are of great technological importance in both fundamental and applied research on materials. In comparison to conventional visualization methods, confocal laser scanning microscopy (CLSM) is non-invasive, with macroscale and high-contrast scanning, a simple and fast sample preparation procedure as well as easy operation. In addition, CLSM allows rapid acquisition of longitudinal and cross-sectional images at any position in a material. Therefore, the CLSM-based visualization technique could provide direct and model-independent insight into material characterizations. This review summarizes the recent applications of CLSM in materials science. The current CLSM approaches for the visualization of surface structures, internal structures, spatial structures and reaction processes are discussed in detail. Finally, we provide our thoughts and predictions on the future development of CLSM in materials science. The purpose of this review is to guide researchers to build a suitable CLSM approach for material characterizations, and to open viable opportunities and inspirations for the development of new strategies aiming at the preparation of advanced materials. We hope that this review will be useful for a wide range of research communities of materials science, chemistry, and engineering.


Magnetoencephalography reveals slowing of resting peak oscillatory frequency in children born very preterm.
Resting cortical activity is characterized by a distinct spectral peak in the alpha frequency range. Slowing of this oscillatory peak toward the upper theta-band has been associated with a variety of neurological and neuropsychiatric conditions and has been attributed to altered thalamocortical dynamics. Children born very preterm exhibit altered development of thalamocortical systems. To test the hypothesis that peak oscillatory frequency is slowed in children born very preterm, we recorded resting magnetoencephalography (MEG) from school age children born very preterm (≤ 32 wk gestation) without major intellectual or neurological impairment and age-matched full-term controls. Very preterm children exhibit a slowing of peak frequency toward the theta-band over bilateral frontal cortex, together with reduced alpha-band power over bilateral frontal and temporal cortex, suggesting that mildly dysrhythmic thalamocortical interactions may contribute to altered spontaneous cortical activity in children born very preterm.


Cooperative role of NF-{kappa}B and poly(ADP-ribose) polymerase 1 (PARP-1) in the TNF-induced inhibition of PHEX expression in osteoblasts.
Reduced bone mass is a common complication in chronic inflammatory diseases, although the mechanisms are not completely understood. The PHEX gene encodes a zinc endopeptidase expressed in osteoblasts and contributes to bone mineralization. The aim of this study was to determine the molecular mechanism involved in TNF-mediated down-regulation of Phex gene transcription. We demonstrate down-regulation of the Phex gene in two models of colitis: naive T-cell transfer and in gnotobiotic IL-10(-/-) mice. In vitro, TNF decreased expression of Phex in UMR106 cells and did not require de novo synthesis of a transrepressor. Transfecting UMR-106 cells with a series of deletion constructs of the proximal Phex promoter identified a region located within -74 nucleotides containing NF-κB and AP-1 binding sites. After TNF treatment, the RelA/p50 NF-κB complex interacted with two cis-elements at positions -70/-66 and -29/-25 nucleotides in the proximal Phex promoter. Inhibition of NF-κB signaling increased the basal level of Phex transcription and abrogated the effects of TNF, whereas overexpression of RelA mimicked the effect of TNF. We identified poly(ADP-ribose) polymerase 1 (PARP-1) binding immediately upstream of the NF-κB sites and showed that TNF induced poly(ADP-ribosyl)ation of RelA when bound to the Phex promoter. TNF-mediated Phex down-regulation was completely abrogated in vitro by PARP-1 inhibitor and overexpression of poly(ADP-ribose) glucohydrolase (PARG) and in vivo in PARP-1(-/-) mice. Our results suggest that NF-κB signaling and PARP-1 enzymatic activity cooperatively contribute to the constitutive and inducible suppression of Phex. The described phenomenon likely contributes to the loss of bone mass density in chronic inflammatory diseases, such as inflammatory bowel disease.


Successful management of cervico-isthmic pregnancy delivered at term.
A 29-year-old woman was diagnosed with a cervico-isthmic pregnancy based on ultrasound findings at 8 weeks of gestation. At 30 weeks of gestation, placenta previa was confirmed. During cesarean section at 37 weeks, the placenta did not spontaneously detach from the uterus; therefore, we decided to leave it in the uterus to avoid major hemorrhage. Blood loss was 775 mL and a healthy infant was delivered. After the operation, weekly methotrexate injection was initiated. Shortly after the eighth course of injection, massive vaginal bleeding suddenly occurred and bilateral uterine artery embolization was performed to control it. After the procedure, the retained placental tissue was removed and the patient was discharged with good general condition. Although a cervico-isthmic pregnancy constitutes a high-risk pregnancy, fertility-sparing management without a hysterectomy or blood transfusion was possible by not removing the placenta manually during the operation.


Two-dimensional characterization of prostatic acid phosphatase, prostatic specific antigen and prostate binding protein in expressed prostatic fluid.
Specimens of pooled prostatic fluid, collected by rectal massage from men under 50 years of age with no apparent prostatic disorders, were subjected to two-dimensional gel electrophoresis to study the composition of its proteins. In a preliminary study, a total of 57 major protein groups were detected. In the present study, we attempted to identify, in the two-dimensional gels, those that are related to prostate-associated proteins, i.e., prostatic acid phosphatase (PAP), prostatic specific antigen (PSA), and prostate binding protein (PBP). Individual proteins were recognized by the procedure of Western Blot using specific antisera with peroxidase-antiperoxidase as the staining reagent. Each protein spot in the two-dimensional gel was expressed, along the abscissa, by its isoelectric point (pI) and, along the ordinate, by the molecular weight (MW). PAP consisted of a train of more than ten protein spots that occupied an area in the gel from pI 7.0, MW 45,000 to pI 6.0, MW 50,000. Four protein spots with a MW of 34,000 and a pI range of 8.2-8.8 were identified as PSA. PBP was observed as having three protein spots that were located at pI 5.6-6.6 with a single MW of 15,000. For PAP and PSA, additional protein spots with lower MWs also stained positively with the specific antisera, suggestive of the presence of degradative products of these proteins. Following the removal of the serum-related proteins by an extensive absorption with anti-human serum antibody by affinity chromatography, the prostatic fluid contained 27 major groups of non-serum proteins. These non-serum proteins in the prostatic fluid included PAP, PSA, PBP, and their related smaller molecular species. These results indicate that the prostatic fluid contains PAP, PSA, PBP and that their presence and the patterns of their distribution in the two-dimensional gels should be considered as the characteristic property of the prostatic secretions.


Vitamin E analogues as anticancer agents: lessons from studies with alpha-tocopheryl succinate.
The new millennium has witnessed considerable decrease in a number of previously fatal pathologies, largely due to the advancement in molecular medicine and modern approaches to treatment. In spite of this success, neoplastic disease remains a serious problem due to several reasons. These include an exceedingly high variability of cancer cells even within the same type of tumour. Cancer cells, albeit of clonal origin, mutate so that they escape established treatments, resulting in the fatal outcome of current therapies. Moreover, there are types of cancer, such as mesotheliomas, that cannot be treated at present. A novel group of clinically interesting anticancer drugs has been a recent focus in the literature that hold substantial promise as selective anticancer drugs. These compounds, epitomised by alpha-tocopheryl succinate, comprise redox-silent analogues of vitamin E that have been shown to suppress several types of cancer in animal models, including breast, colon and lung cancer as well as mesotheliomas and melanomas, while being nontoxic to normal cells and tissues. It is now proven that the strong anticancer effect of vitamin E analogues stems from their propensity to induce selective apoptosis in malignant cells. The results point to the novel group of vitamin E analogues as promising agents applicable to different types of tumours.


Alteration of Airway Reactivity and Reduction of Ryanodine Receptor Expression by Cigarette Smoke in Mice.
Small airways are a major site of airflow limitation in chronic obstructive pulmonary disease (COPD). Despite the detrimental effects of long-term smoking in COPD, the effects of acute cigarette smoke (CS) exposure on small airway reactivity have not been fully elucidated. Balb/C mice were exposed to room air (sham) or CS for 4 days to cause airway inflammation. Changes in small airway lumen area in response to contractile agents were measured in lung slices in situ using phase-contrast microscopy. Separate slices were pharmacologically maintained at constant intracellular Ca(2+) using caffeine/ryanodine before contractile measurements. Gene and protein analysis of contractile signaling pathways were performed on separate lungs. Monophasic contraction to serotonin became biphasic after CS exposure, whereas contraction to methacholine was unaltered. This altered pattern of contraction was normalized by caffeine/ryanodine. Expression of contractile agonist-specific receptors was unaltered; however, all isoforms of the ryanodine receptor were down-regulated. This is the first study to show that acute CS exposure selectively alters small airway contraction to serotonin and down-regulates ryanodine receptors involved in maintaining Ca(2+) oscillations in airway smooth muscle. Understanding the contribution of ryanodine receptors to altered airway reactivity may inform the development of novel treatment strategies for COPD.


A phylogeny for the Drosophila montium species group: A model clade for comparative analyses.
The Drosophila montium species group is a clade of 94 named species, closely related to the model species D. melanogaster. The montium species group is distributed over a broad geographic range throughout Asia, Africa, and Australasia. Species of this group possess a wide range of morphologies, mating behaviors, and endosymbiont associations, making this clade useful for comparative analyses. We use genomic data from 42 available species to estimate the phylogeny and relative divergence times within the montium species group, and its relative divergence time from D. melanogaster. To assess the robustness of our phylogenetic inferences, we use 3 non-overlapping sets of 20 single-copy coding sequences and analyze all 60 genes with both Bayesian and maximum likelihood methods. Our analyses support monophyly of the group. Apart from the uncertain placement of a single species, D. baimaii, our analyses also support the monophyly of all seven subgroups proposed within the montium group. Our phylograms and relative chronograms provide a highly resolved species tree, with discordance restricted to estimates of relatively short branches deep in the tree. In contrast, age estimates for the montium crown group, relative to its divergence from D. melanogaster, depend critically on prior assumptions concerning variation in rates of molecular evolution across branches, and hence have not been reliably determined. We discuss methodological issues that limit phylogenetic resolution - even when complete genome sequences are available - as well as the utility of the current phylogeny for understanding the evolutionary and biogeographic history of this clade.


Dermal suture only versus layered closure: A randomized, split wound comparative effectiveness trial.
Layered closure of cutaneous wounds is a commonly used surgical practice. However, there are studies that suggest the additional layer of epidermal sutures might not be necessary. To compare scar outcomes between the single-layer deep-dermal suture technique and the conventional layered suture technique for primary closure of cutaneous wounds. A total of 49 patients were enrolled in a prospective, randomized, evaluator-blinded, split scar study to compare the conventional bilayered closure technique with the single-layer deep-dermal suturing technique for primary closure of wounds. The primary outcome measure was mean sum Patient and Observer Scar Assessment Scale (POSAS) score at 3 and 12 months. At the 3-month follow-up, there was a statistically significant difference in the mean total POSAS scores for both the blinded observer and patients, indicating a preference for the side with the standard layered closure. However, at the 12-month follow-up, this difference was lost, with the exception of scar color, which was significantly more noticeable on the wound side closed with only dermal sutures. Single-center study. Three months after surgery, the layered closure technique resulted in a slightly better scar outcome than the single-layered closure containing only dermal sutures. At 12-months' follow-up, this difference diminished, with scars for both sides appearing similar.


Age-adjusted nonparametric detection of differential DNA methylation with case-control designs.
DNA methylation profiles differ among disease types and, therefore, can be used in disease diagnosis. In addition, large-scale whole genome DNA methylation data offer tremendous potential in understanding the role of DNA methylation in normal development and function. However, due to the unique feature of the methylation data, powerful and robust statistical methods are very limited in this area. In this paper, we proposed and examined a new statistical method to detect differentially methylated loci for case control designs that is fully nonparametric and does not depend on any assumption for the underlying distribution of the data. Moreover, the proposed method adjusts for the age effect that has been shown to be highly correlated with DNA methylation profiles. Using simulation studies and a real data application, we have demonstrated the advantages of our method over existing commonly used methods. Compared to existing methods, our method improved the detection power for differentially methylated loci for case control designs and controlled the type I error well. Its applications are not limited to methylation data; it can be extended to many other case-control studies.


Biofunctionalization of polydioxythiophene derivatives for biomedical applications.
The polydioxythiophenes PEDOT and more recently ProDOT have emerged as champion materials in the field of organic bioelectronics, both in the domain of biosensing and also for integration with living cells (both in vitro and in vivo). Although polydioxythiophenes in their pristine forms have shown great promise for bioelectronics, in order to broaden the spectrum of applications, a biofunctionalization step is essential. In this review we summarise the methods that have been used thus far to biofunctionalize polydioxythiophenes in an effort to improve the biotic/abiotic interface. We provide an introduction to this class of materials, focusing particularly on the different methods of synthesis (chemical oxidative polymerization, vapor phase polymerization or direct electrochemical polymerization) and discuss the implications of synthesis on biofunctionalization. Rather than provide an exhaustive review, we chose to highlight key examples of biofunctionalization techniques for polydioxythiophenes for specific biomedical applications. Finally, we conclude with a brief discussion of the importance of biofunctionalization methods in future bioelectronics applications, and some ideas for future directions in this field.


[The ALANAM statement on public health policy].
The ALANAM (Association of Latin American National Academies of Medicine) statement on public health policy, issued following its 19th Congress, held October 28–30, 2010, in Santiago, Chile, declares that cardiovascular diseases, cancer, accidents and violence are the leading causes of death in the region, while in several of its member nations, emergent and re-emergent infectious diseases, malnutrition, and mother-child illnesses remain prevalent. The statement calls attention to the lack of functioning water supply and sewage systems in many villages and rural areas. After describing the social causes of the present state of public health in Latin America (poverty levels reaching upwards of 44% of the total population, or some 110 million people), it calls on governments, first, to spare no efforts in the task of eradicating extreme poverty in the short-term, and poverty in the long-term. Second, considering that about 15 million 3-to-6 year-olds have no access to education, it recommends extending educational services to these children, and to improve the quality of existing pre-school and primary education. Third, the statement calls for universal health care coverage and for equal access to good quality medical care for everyone, and for programs aimed at promoting healthy personal habits and self-care. In this regard, it also recommends that disease prevention programs be sustained over time, that national sanitary objectives be defined, and that its results be periodically reviewed. Fourth, it recommends that primary health care be extended to everyone, and that it be enhanced by improving coverage and coordination with secondary and tertiary level health care institutions. The statement lays special stress on the need for adopting public health policies aimed at lowering the cost of medicines; to this end, it calls for the creation of an official list of generic drugs. The statement ends by calling on governments to support public health research as a necessary step in tackling with greater efficiency the health problems still prevalent in the region.


IMU-Based Classification of Parkinson's Disease From Gait: A Sensitivity Analysis on Sensor Location and Feature Selection.
Inertial measurement units (IMUs) have a long-lasting popularity in a variety of industrial applications from navigation systems to guidance and robotics. Their use in clinical practice is now becoming more common, thanks to miniaturization and the ability to integrate on-board computational and decision-support features. IMU-based gait analysis is a paradigm of this evolving process, and in this study its use for the assessment of Parkinson's disease (PD) is comprehensively analyzed. Data coming from 25 individuals with different levels of PD symptoms severity and an equal number of age-matched healthy individuals were included into a set of 6 different machine learning (ML) techniques, processing 18 different configurations of gait parameters taken from 8 IMU sensors. Classification accuracy was calculated for each configuration and ML technique, adding two meta-classifiers based on the results obtained from all individual techniques through majority of voting, with two different weighting schemes. Average classification accuracy ranged between 63% and 80% among classifiers and increased up to 96% for one meta-classifier configuration. Configurations based on a statistical preselection process showed the highest average classification accuracy. When reducing the number of sensors, features based on the joint range of motion were more accurate than those based on spatio-temporal parameters. In particular, best results were obtained with the knee range of motion, calculated with four IMUs, placed bilaterally. The obtained findings provide data-driven evidence on which combination of sensor configurations and classification methods to be used during IMU-based gait analysis to grade the severity level of PD.