In-vitro hepatotoxicity of three dichlorobenzene isomers in human liver slices.
1 The cytotoxicity of dichlorobenzenes in cultured rat liver slices has previously been shown to be strain specific and biotransformation related. 2 In order to extrapolate animal models to humans, the dichlorobenzenes were incubated with human liver slices to try to clarify their hepatotoxic potential in man. 3 The degree of hepatotoxicity observed with the dichlorobenzenes depended on whether Waymouth's or Krebs-Henseleit was used as the incubation medium. 4 All three dichlorobenzenes (1 mM) produced no significant differences from control when incubated in Waymouth's medium. However, in the Krebs-Henseleit buffer there was a substantial increase in cytotoxicity. 5 In both incubation mediums the dichlorobenzene isomers exhibited the following rank order 1,3-DCB greater than 1,2-DCB greater than 1,4-DCB. 6 1,2-dichlorobenzene hepatotoxicity was blocked by metyrapone, 1,3-dichlorobenzene toxicity was blocked by SKF 525-A and neither one of these inhibitors could block the 1,4-dichlorobenzene cytotoxicity. 7 The use of human liver tissues to evaluate potential toxicants merits consideration since the hepatotoxicity of xenobiotics and drugs in man is the ultimate question.


Super-resolution imaging of C-type lectin spatial rearrangement within the dendritic cell plasma membrane at fungal microbe contact sites.
Dendritic cells express DC-SIGN and CD206, C-type lectins (CTLs) that bind a variety of pathogens and may facilitate pathogen uptake for subsequent antigen presentation. Both proteins form punctate membrane nanodomains (∼80 nm) on naïve cells. We analyzed the spatiotemporal distribution of CTLs following host-fungal particle contact using confocal microscopy and three distinct methods of cluster identification and measurement of receptor clusters in super-resolution datasets: DBSCAN, Pair Correlation and a custom implementation of the Getis spatial statistic. Quantitative analysis of confocal and super-resolution images demonstrated that CTL nanodomains become concentrated in the contact site relative to non-contact membrane after the first hour of exposure and established that this recruitment is sustained out to 4 h. DC-SIGN nanodomains in fungal contact sites exhibit a 70% area increase and a 38% decrease in interdomain separation. Contact site CD206 nanodomains possess 90% greater area and 42% lower interdomain separation relative to non-contact regions. Contact site CTL clusters appear as disk-shaped domains of approximately 150-175 nm in diameter. The increase in length scale of CTL nanostructure in contact sites suggests that the smaller nanodomains on resting membranes may merge during fungal recognition, or that they become packed closely enough to achieve sub-resolution inter-domain edge separations of <30 nm. This study provides evidence of local receptor spatial rearrangements on the nanoscale that occur in the plasma membrane upon pathogen binding and may direct important signaling interactions required to recognize and respond to the presence of a relatively large pathogen.


Early and Intermediate-Term Outcome of Balloon Aortic Valvuloplasty in Children With Aortic Stenosis and Left Ventricular Dysfunction at Tertiary Care Hospital.
Background Left ventricular (LV) dysfunction in patients with aortic valve stenosis (AVS) is seen in two scenarios: in neonates and in elderly patients. Neonatal AVS may present as a congestive cardiac failure (CCF), while older children rarely present with CCF if they have not been diagnosed early. Only a few reports of LV dysfunction with AVS have been described in the literature. However, there is a paucity of data regarding the safety and effectiveness of balloon aortic valvuloplasty (BAV) in children with AVS with LV dysfunction. Therefore, the aim of this study was to evaluate outcomes to establish the safety and effectiveness of BAV in children with AVS and LV dysfunction in improving LV function and survival. Methods A total of 160 BAVs were performed from 2004 to 2017; of these, 41 (25.6%) patients had LV dysfunction. We reviewed these cases, and data were obtained on clinical features, echocardiographic parameters including LV ejection fraction (LVEF) and LV dimensions, LV posterior wall, interventricular septal thickness, pressure gradient across the valve, aortic valve morphology and annulus and aortic insufficiency (AI), and angiographic parameters such as aortic and LV pressures, AI and annulus size, and balloon size. Echocardiography was done before the procedure, one day after intervention, at three months, at six months, and on regular follow-up. Mortality during and after the procedure and at follow-up was reported. Results Children who had undergone BAV for AVS and LV dysfunction within the age range of six to 192 months showed a significant reduction in peak-to-peak pressure gradient (PPG) from 73.5 ± 30 mmHg to 26.7 ± 6.7 mmHg and improvement in LVEF from 32.8 ± 11% to 54.3 ± 12.7% after 24 hours. Instantaneous gradient on echocardiography after three months showed PPG was 29.8 ± 7.7 mmHg and mean LVEF was 63 ± 8.6%. Mean LV end-diastolic pressure was 20.8 ± 4.7 mmHg and decreased to 13 ± 2.4 mmHg. Four patients died, all of whom had severe LV dysfunction - one died during the procedure and three died within six to 20 hours after successful BAV. On average follow-up of 6.4 ± 3.8 years, with a range of three months to 13 years, there was no mortality, pressure gradient increased to 40 ± 16.3 mmHg (range, 20 to 90 mmHg), and three had BAV after one, four, and six years, respectively. There was an increase in AI from mild to moderate in five patients, but they did not require any intervention. Four patients had aortic valve replacement (AVR) with two patients having an increase in pressure gradient and AI after eight and 13 years, respectively. One patient had AI (+3) after BAV had AVR after three years, and one patient who had a very thick and dysplastic aortic valve with LVEF of 20% and pulmonary hypertension (PH) had AVR after six months. Conclusion Patients with AVS who develop LV dysfunction deteriorate and die soon without treatment. Our data suggest that BAV in children with aortic stenosis and LV dysfunction is safe and effective in the normalization of LV function.


miR-205 in situ expression and localization in head and neck tumors - a tissue array study.
microRNAs are small non-coding RNA that control gene expression by mRNA degradation or translational inhibition. These molecules are known to play essential roles in many biological and physiological processes. miR-205 may be differentially expressed in head and neck cancers; however, there are conflicting data and localization of expression has yet to be determined. miR-205 expression was investigated in 48 cases of inflammatory, benign and malignant tumor tissue array of the neck, oronasopharynx, larynx and salivary glands by Locked Nucleic Acid in situ hybridization (LNA-ISH) technology. miR-205 expression was significantly differentially expressed across all of the inflammatory, benign and malignant tumor tissues of the neck. A significant increase in miR-205 staining intensity (p<0.05) was observed from inflammation to benign and malignant tumors in head and neck tissue array, suggesting that miR-205 could be a biomarker to differentiate between cancer and non-cancer tissues. LNA-ISH revealed that miR-205 exhibited significant differential cytoplasmic and nuclear staining among inflammation, benign and malignant tumors of head and neck. miR-205 was not only exclusively expressed in squamous epithelial malignancy. This study offers information and a basis for a comprehensive study of the role of miR-205 that may be useful as a biomarker and/or therapeutic target in head and neck tumors.


Tropilaelaps mercedesae parasitism changes behavior and gene expression in honey bee workers.
Tropilaelaps mercedesae is one of the most problematic honey bee parasites and has become more threatening to the beekeeping industry. Tropilaelaps can easily parasitize immature honey bees (larvae and pupae) and have both lethal and sublethal effects on the individual worker bees. Our study for the first time experimentally assessed the effects of T. mercedesae on olfactory learning, flight ability, homing ability as well as transcriptional changes in parasitized adult honey bees. T. mercedesae infestation had negative impacts on olfactory associated function, flight ability, and homing rate. The volume of the mushroom body significantly increased in infested honey bees, which may be correlated to the lower sucrose responsiveness as well as lower learning ability in the infested bees. The gene expression involved in immune systems and carbohydrate transport and metabolism were significantly different between infested bees and non-infested bees. Moreover, genes function in cell adhesion play an essential role in olfactory sensory in honey bees. Our findings provide a comprehensive understanding of European honey bees in response to T. mercedesae infestation, and could be used to further investigate the complex molecular mechanisms in honey bees under parasitic stress.


Venlafaxine and nefazodone, two pharmacologically distinct antidepressants.
Venlafaxine, a phenylethylamine, and nefazodone, a phenylpiperazine compound, are the newest antidepressants to receive approval of the Food and Drug Administration and to be marketed in the United States. Both strongly inhibit serotonin (5-HT) reuptake; venlafaxine also inhibits norepinephrine reuptake, and nefazodone also exhibits 5-HT2-receptor antagonism. Venlafaxine inhibits the cytochrome P-450 2D6 isozyme to a lesser extent than the selective serotonin reuptake inhibitors (SSRIs) and is 27% protein bound. Structurally, the drugs are unrelated to SSRIs and have some clinically important differences in side effect profiles. Nausea, headache, somnolence, and dry mouth are the most frequently reported side effects with both. Sustained hypertension was reported by a limited number of venlafaxine-treated patients.


[A three dimensional fractal simulation of the lung bronchial tree].
The lungs are naturally irregular and asymmetrical organ in anatomy. The conducting bronchial trees in the lungs display complex self-similar structure. We have established the host mesh coordinates of the right lung on the basis of the anatomical data from the literature. A three-dimensional fractal model of the conducting airways was set up by calculating the coordinates of the mass centers of the divided blocks, searching the branch direction and determining branch lengths with the use of the drawing tool OpenGL. Specific data of the lengths at various grades, branching angles, and capillary diameters were obtained. As a result, the computed data were identical with those of the existing statistical data. The fractal covering dimensionality obtained in the computation of this model was 2.19, which is very close to the ideal dimensionality, 2.17, from the literature. The present model has laid the foundation for further research of the gas diffusion and transfer performance in the lungs using the fractal concept, and furthermore, it helps to save the computer memories and fastening the graphic transfer.


Potential impact of EUS-FNA staging of proximal lymph nodes in patients with distal esophageal carcinoma.
Distal esophageal carcinomas can be resected using transthoracic esophagectomy or transhiatal esophagectomy. Accurate diagnosis of subcarinal and supracarinal lymph-node metastases is important for selecting the surgical strategy. The impact of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) on the preoperative diagnosis of subcarinal and supracarinal lymph-node metastases in patients with distal esophageal carcinoma was therefore investigated. Patients with a resectable distal esophageal carcinoma and subcarinal and/or supracarinal lymph nodes visualized on preoperative EUS were prospectively included. The lymph nodes were sampled using EUS-FNA, and if they were found to have metastases, transthoracic resection was offered; by contrast, patients without metastases were offered a transhiatal resection. Lymph-node metastases were found with EUS-FNA in 11 of the 48 patients included (23 %). Thirteen patients had suspicious nodes on EUS, in four of whom (31 %) the diagnosis was changed into nonmalignant nodes with FNA. Thirty-five patients had nonsuspicious nodes on EUS, in three of whom (9 %) the FNA procedure revealed malignant cells. EUS with the addition of the FNA procedure has a significant impact on decision-making in patients with esophageal carcinoma in whom transhiatal esophagectomy would otherwise be planned.


Exploring effects of different antioxidants on dexamethasone-induced lipid peroxidation using common laboratory markers.
As a part of our ongoing effort to explore drug-induced lipid peroxidation in relation to drug-induced toxicity, our recent observations on lipid peroxidation induction potential of dexamethasone, a commonly used glucocorticoid compound in inflammatory and allergic conditions, has been presented considering lipid peroxidation a possible mediator of toxicity. An attempt was made to see the suppressive actions of some conventional antioxidant compounds, viz, ascorbic acid, alpha-tocopherol and probucol on dexamethasone-induced lipid peroxidation. It was found from the study that dexamethasone increased malondialdehyde content vis-a-vas decreased the level of reduced glutathione significantly in the liver homogenate. This suggests that dexamethasone caused a significant extent of lipid peroxidation which may be related to the toxic potential of the drug. It was further found all of the above antioxidants could suppress dexamethasone-induced lipid peroxidation to the significant extent.


Impact on bacterial community in midguts of the Asian corn borer larvae by transgenic Trichoderma strain overexpressing a heterologous chit42 gene with chitin-binding domain.
This paper is the first report of the impact on the bacterial community in the midgut of the Asian corn borer (Ostrinia furnacalis) by the chitinase from the transgenic Trichoderma strain. In this study, we detected a change of the bacterial community in the midgut of the fourth instar larvae by using a culture-independent method. Results suggested that Proteobacteria and Firmicutes were the most highly represented phyla, being present in all the midgut bacterial communities. The observed species richness was simple, ranging from four to five of all the 16S rRNA clone libraries. When using Trichoderma fermentation liquids as additives, the percentages of the dominant flora in the total bacterial community in larval midgut changed significantly. The community of the genus Ochrobactrum in the midgut decreased significantly when the larvae were fed with the fermentation liquids of the transgenic Trichoderma strain Mc4. However, the Enterococcus community increased and then occupied the vacated niche of the Ochrobactrum members. Furthermore, the Shannon-Wiener (H) and the Simpson (1-D) indexes of the larval midgut bacterial library treated by feeding fermentation liquids of the transgenic Trichoderma strain Mc4 was the lowest compared with the culture medium, fermentation liquids of the wild type strain T30, and the sterile artificial diet. The Enterococcus sp. strain was isolated and characterized from the healthy larvae midgut of the Asian corn borer. An infection study of the Asian corn borer larvae using Enterococcus sp. ACB-1 revealed that a correlation existed between the increased Enterococcus community in the larval midgut and larval mortality. These results demonstrated that the transgenic Trichoderma strain could affect the composition of the midgut bacterial community. The change of the midgut bacterial community might be viewed as one of the factors resulting in the increased mortality of the Asian corn borer larvae.


Bovine granulosa cells produce basic fibroblast growth factor.
Cultured bovine granulosa cells express the gene encoding basic fibroblast growth factor (bFGF). The bFGF gene is transcribed into 7.0- and 3.7-kilobase mRNA transcripts which are apparently translated into 16,000 mol wt bFGF-like growth factor. The granulosa cell-derived bFGF is bioactive, i.e. it can stimulate the proliferation of capillary endothelial or granulosa cells. This mitogenic effect is prevented by specific neutralizing anti-bFGF antibodies. Our results indicate that bFGF derived from granulosa cells can act as both autocrine and paracrine growth factor, and they further suggest that the factor may be involved in the development of the rich vasculature of the theca interna of the follicle.


Handling of New Drug Safety Information in the Dutch Hospital Setting: A Mixed Methods Approach.
The implementation of new drug safety information and Direct Healthcare Professional Communications (DHPCs) in hospitals is important for patient safety. The aim of this study was to gain insight into which procedures and practices are in place to handle new drug safety information and particularly DHPCs in the Dutch hospital setting. We first conducted focus groups including medical specialists and hospital pharmacists, focusing on handling of drug safety information at the individual and organisational level. A survey was then developed and distributed among hospital pharmacists in all Dutch hospitals to quantify the existence of specific procedures and committees to handle drug safety information and DHPCs. Eleven specialists and 14 pharmacists from six hospitals participated in focus groups. Drug safety information was usually considered before drugs were included in formularies or treatment protocols. Furthermore, drug safety information was consulted in response to patients experiencing adverse events. DHPCs were mostly dealt with by individual professionals. DHPCs could lead to actions but this was very uncommon. Completed surveys were received from 40 (53%) of the hospitals. In 32 (80%), the hospital pharmacy had procedures to deal with new drug safety information, whereas in 11 (28%) a hospital-wide procedure was in place. Drug safety was considered in committees concerning drug formulary decisions (69%) and antibiotic policies (63%). DHPCs were assessed by a hospital pharmacist in 50% of the hospitals. Drug safety information was used for evaluation of new treatments and in response to adverse events. Assessment of whether a DHPC requires action was primarily an individual task.


Gut Microbiome Alterations in Patients With Visceral Obesity Based on Quantitative Computed Tomography.
The gut microbiota is crucial in the pathogenesis of obesity. Abdominal obesity is known to significantly increase the risk of metabolic syndrome and cardiovascular disease, so further study is needed to investigate the changes of intestinal microorganisms in patients with excessive visceral fat. In our study, 41 people (n = 41) with normal body mass index (BMI) (18.5 ≤ BMI < 23.9) were included and divided into the low visceral fat area (L-VFA) group (n = 23, VFA < 100 cm2) and the high visceral fat area (H-VFA) group (n = 18, VFA ≥ 100 cm2). Several clinical indicators of the H-VFA group were significantly higher than those of the L-VFA group, including the waist circumference (WC), the fasting blood glucose (FBG), the triglyceride (TG), the total cholesterol (TC), the low-density lipoprotein cholesterol (LDL), the serum uric acid (SUA), the white blood cell count (WBC), the blood neutrophil count (NEC), and the blood lymphocyte count (LYC). Using whole-genome shotgun sequencing, we found that the types of the intestinal microbiota of H-VFA patients were different from those of the L-VFA patients, with 18 bacteria enriched in the H-VFA group and nine bacteria in the L-VFA group. A total of 16 species of gut microbes showed a strong correlation with VFA, and Escherichia coli has the strongest correlation, followed by Mitsuokella unclassified, Bifidobacterium longum, Escherichia unclassified, Ruminococcus torques, Dialister succinatiphilus, Eubacterium hallii, and Ruminococcus gnavus. Compared to the VFA, only two species show a strong correlation with BMI and WC. Further functional genetic studies suggested that the degradation of short-chain fatty acids (SCFAs) and the generation of lipopolysaccharide (LPS) might be related to visceral fat accumulation. Together, visceral fat was more closely correlated with the gut microbiome compared with BMI and WC. It suggested an intrinsic connection between the gut microbiome and visceral fat and its related metabolic disorders. Specific microbial species and pathways associated with visceral fat accumulation might contribute to new targeted therapies for visceral fat and its metabolic disorders.


Size-Dependent Diffusion of Dextrans in Excised Porcine Corneal Stroma.
Delivery of therapeutic agents to the eye requires efficient transport through cellular and extracellular barriers. We evaluated the rate of diffusive transport in excised porcine corneal stroma using fluorescently labeled dextran molecules with hydrodynamic radii ranging from 1.3 to 34 nm. Fluorescence correlation spectroscopy (FCS) was used to measure diffusion coefficients of dextran molecules in the excised porcine corneal stroma. The preferential sensitivity of FCS to diffusion along two dimensions was used to differentially probe diffusion along the directions parallel to and perpendicular to the collagen lamellae of the corneal stroma. In order to develop an understanding of how size affects diffusion in cornea, diffusion coefficients in cornea were compared to diffusion coefficients measured in a simple buffer solution. Dextran molecules diffuse more slowly in cornea as compared to buffer solution. The reduction in diffusion coefficient is modest however (67% smaller), and is uniform over the range of sizes that we measured. This indicates that, for dextrans in the 1.3 to 34 nm range, the diffusion landscape of corneal stroma can be represented as a simple liquid with a viscosity approximately 1.5 times that of water. Diffusion coefficients measured parallel vs. perpendicular to the collagen lamellae were indistinguishable. This indicates that diffusion in the corneal stroma is not highly anisotropic. Our results support the notion that the corneal stroma is highly permeable and isotropic to transport of hydrophilic molecules and particles with hydrodynamic radii up to at least 34 nm.


Distinct roles of different fragments of PDCD4 in regulating the metastatic behavior of B16 melanoma cells.
Melanoma is an aggressive cutaneous malignancy. In this study, we demonstrated that the levels of the programmed cell death 4 (PDCD4) protein and mRNA were lower in tumor tissues compared with normal tissues. In order to further investigate the effects of PDCD4 and its fragments in B16 melanoma cells, we established B16 clones with expression of different PDCD4 fragments. Intact PDCD4, PDCD4∆164‑469 and PDCD4∆327-440 expression, respectively, decreased proliferation and migration and increased apoptosis in B16 cells in vitro. We found that intact PDCD4, PDCD4∆164-469 or PDCD4∆327-440 can inhibit the activity of MMP-2 and the expression of CXCR4. However, PDCD4∆164-275 showed no effects on B16 cells. These results may prove helpful for the development of novel therapies for melanoma treatment.


Evaluation of the pathogenesis of skeletal changes in ovariectomized rats.
Young adult ovariectomized rats were used to investigate the pathogenesis of ovarian hormone deficiency osteopenia, uncomplicated by other forms of age-related bone loss. It was observed that the femurs of ovariectomized rats were less dense with less hydroxyproline and less calcium (Ca) and phosphorus per unit volume of bone than those of age-matched controls. Compared to animals killed at the beginning of the study to serve as baseline controls, ovariectomized rats and their age-matched controls had increased periosteal and cortical areas, but in contrast to the age-matched controls, ovariectomized rats had markedly increased medullary area and the ratio of their cortical area to periosteal area was decreased (P less than 0.02). When the changes in cross-sectional areas were expressed as percent of the baseline levels, the medullary area was increased 32% in ovariectomized rats, and only 14% in the age-matched controls; the net increase in cortical area was 17% for the controls and 11% for the ovariectomized rats and there was only 3% difference between the increases in their periosteal areas. Furthermore, ovariectomy caused a marked decrease in serum calcitonin and Ca levels but not in PTH levels. As expected, PTH administration increased serum Ca in all rats, but the rise was greater in ovariectomized calcitonin-deficient rats than in rats that were only ovariectomized or only thyroidectomized. Whereas these findings support the concept of increased sensitivity of bone to PTH in ovarian hormone deficiency osteopenia, the decrease in serum Ca in ovariectomized rats indicates that other factors may be involved as well.


[Rational use of medications in the treatment of urinary infections].
MAIN: to encourage the rational use of medication in the treatment of uncomplicated acute cystitis (UAC). SECONDARY: to find the most common germs in our area and their sensitivity to medication, the most common anti-microbials used and patients age, and to evaluate the savings made through a policy of rational use of medication.Design. Retrospective, descriptive, observational study. La Solana Health Centre jointly with the biochemistry laboratory of the Talavera Area. Probabilistic randomised sampling of clinical histories of women between 20 and 80 with episodes of UAC (349 in all) between 01/10/95 and 01/10/00. First, the laboratory evaluated 591 urine cultures of complicated/uncomplicated UTI from 01/01/00 to 01/10/00, with study of the germs involved and their sensitivities. 373 positives were isolated: E. coli (78.3%), which had the greatest sensitivity to amoxycillin/clavulanic acid, fosfomycin, nitrofurantoin and cefixime; Proteus (7.2%) and Streptococcus D (5.8%). Second, clinical records were analysed for the following: antibiotics (norfloxacine and cyprofloxacine, the most common); length of treatment (average of 6.52.34 days); age of patient (greater number in under-65s). E. coli is the most common germ in UTI and is highly sensitive to amoxy/clavulanic acid, nitrofurantoin, fosfomycin and cefixime. Resistance to cyprofloxacine and norfloxacine are starting to be significant. In UAC the three-day model should be encouraged for young women; and 7 days is recommended for the over-65s. More rational use of medication would increase efficacy and suppose a considerable economic saving in our area.


The glutaredoxin/glutathione system modulates NF-kappaB activity by glutathionylation of p65 in cinnamaldehyde-treated endothelial cells.
Reversible protein glutathionylation is an important posttranslational modification that provides protection against oxidation. In endothelial cells (ECs), cinnamaldehyde is an electrophilic compound that can increase the intracellular glutathione (GSH) levels or reactive oxygen species (ROS) production depending on the treatment duration. ECs treated with GSH and H(2)O(2) show increased sulfhydryl modifications of the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), which are responsible for NF-kappaB inactivation, and also a block in TNF-alpha-induced p65 nuclear translocation and inter-cellular adhesion molecule-1 (ICAM-1) expression. In our current study, we find that cinnamaldehyde induces p65 glutathionylation and inhibits TNF-alpha-induced p65 nuclear translocation and ICAM-1 expression within 12 h of treatment. Our analyses also reveal that p65 glutathionylation is suppressed by a GSH synthesis inhibitor, buthionine sulfoximine (BSO), and we further observed that the inhibitory effects of p65 nuclear translocation and ICAM-1 expression are also suppressed by BSO. NF-E2-related factor-2 small interfering RNA (siRNA) molecules not only inhibit glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) induction and increases in GSH but also abolish cinnamaldehyde-induced p65 glutathionylation and its inhibitory effects. The gene expression and activity of glutaredoxin-1 (Grx-1), which catalyzes the formation of protein-glutathione mixed disulfides (protein-SSG), were also found to be increased after cinnamaldehyde treatment. A knock down of endogenous Grx-1 by siRNA or pretreatment with an inhibitor of Grx-1 activity, CdCl(2), abolishes p65-SSG formation. In addition, Grx-1 siRNA blocks the inhibition of p65 nuclear translocation and ICAM-1 expression, suggesting that this enzyme is involved in the cinnamaldehyde-mediated NF-kappaB inhibition. Our current results thus indicate that the GSH/Grx-1-dependent glutathionylation of p65 is likely to be responsible for cinnamaldehyde-mediated NF-kappaB inactivation and for the enhanced inhibitory effects of cinnamaldehyde upon TNF-alpha-treated ECs.


Subcutaneous IgG in the Myositis Spectrum Disorders.
The efficacy of subcutaneous immunoglobulin is reported in several neurological disorders and, more recently, its use has been extended to other inflammatory diseases, such as the idiopathic inflammatory myopathies, including polymyositis and dermatomyositis. Due to the rarity of these disorders, the role of immunoglobulin, administered intravenously or subcutaneously, remains unclear and poorly investigated. We report our experience about the use of subcutaneous immunoglobulin in myositis spectrum disorders, from idiopathic inflammatory myopathies to more complex conditions, such as overlap and cancer-associated myositis or pregnancy.


Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection.
CD4 T cells provide protection against cytomegalovirus (CMV) and other persistent viruses, and the ability to quantify and characterize epitope-specific responses is essential to gain a more precise understanding of their effector roles in this regard. Here, we report the first two I-A(d)-restricted CD4 T cell responses specific for mouse CMV (MCMV) epitopes and use a major histocompatibility complex class II (MHC-II) tetramer to characterize their phenotypes and functions. We demonstrate that MCMV-specific CD4 T cells can express high levels of granzyme B and kill target cells in an epitope- and organ-specific manner. In addition, CD4 T cell epitope vaccination of immunocompetent mice reduced MCMV replication in the same organs where CD4 cytotoxic T lymphocyte (CTL) activity was observed. Together, our studies show that MCMV epitope-specific CD4 T cells have the potential to mediate antiviral defense by multiple effector mechanisms in vivo. CD4 T cells mediate immune protection by using their T cell receptors to recognize specific portions of viral proteins, called epitopes, that are presented by major histocompatibility complex class II (MHC-II) molecules on the surfaces of professional antigen-presenting cells (APCs). In this study, we discovered the first two epitopes derived from mouse cytomegalovirus (MCMV) that are recognized by CD4 T cells in BALB/c mice, a mouse strain commonly used to study the pathogenesis of this virus infection. Here, we report the sequences of these epitopes, characterize the CD4 T cells that recognize them to fight off MCMV infection, and show that we can use the epitopes to vaccinate mice and protect against MCMV.


Scoring of Side-Chain Packings: An Analysis of Weight Factors and Molecular Dynamics Structures.
The protein side-chain packing problem (PSCPP) is a central task in computational protein design. The problem is usually modeled as a combinatorial optimization problem, which consists of searching for a set of rotamers, from a given rotamer library, that minimizes a scoring function (SF). The SF is a weighted sum of terms, that can be decomposed in physics-based and knowledge-based terms. Although there are many methods to obtain approximate solutions for this problem, all of them have similar performances and there has not been a significant improvement in recent years. Studies on protein structure prediction and protein design revealed the limitations of current SFs to achieve further improvements for these two problems. In the same line, a recent work reported a similar result for the PSCPP. In this work, we ask whether or not this negative result regarding further improvements in performance is due to (i) an incorrect weighting of the SFs terms or (ii) the constrained conformation resulting from the protein crystallization process. To analyze these questions, we (i) model the PSCPP as a bi-objective combinatorial optimization problem, optimizing, at the same time, the two most important terms of two SFs of state-of-the-art algorithms and (ii) performed a preprocessing relaxation of the crystal structure through molecular dynamics to simulate the protein in the solvent and evaluated the performance of these two state-of-the-art SFs under these conditions. Our results indicate that (i) no matter what combination of weight factors we use the current SFs will not lead to better performances and (ii) the evaluated SFs will not be able to improve performance on relaxed structures. Furthermore, the experiments revealed that the SFs and the methods are biased toward crystallized structures.


Diagnosis and development of screening items for migraine in neurological practice in Taiwan.
The objectives of this study were to: (1) survey migraine diagnoses among neurological outpatients in Taiwan; (2) compare neurologists' migraine diagnoses with the International Classification of Headache Disorders 2nd Edition (ICHD-2) criteria; and (3) evaluate the diagnostic ability of screening items on a patient migraine questionnaire. This prospective study surveyed patients who consulted neurologists for the first time with a chief complaint of headache, excluding those experiencing headaches for > or = 15 days/month. Each neurologist interviewed a maximum of 10 patients. Patients were asked to complete a self-administered questionnaire and their physicians completed another questionnaire. The physicians were asked if patients could be diagnosed with migraine. In addition, a diagnosis of ICHD-2 migraine was made by the physician's questionnaire through a computer-generated algorithm. In this study, migraine without aura (code 1.1) or migraine with aura (code 1.2) were designated as "strict migraine", and the combination of strict migraine and ICHD-2 probable migraine (code 1.6) as "any migraine". Among 755 patients who were eligible for analysis, 537 (71%) were diagnosed as having "any migraine", 363 (48%) with "strict migraine", and 451 (60%) with physician-diagnosed migraine. Among the 537 patients diagnosed as having "any migraine", 308 patients (57%) had not been diagnosed by any physician before. A moderate agreement (kappa statistic around 0.5) was found between the physicians' diagnoses and ICHD-2 "strict migraine" or "any migraine". In patients with ICHD-2 probable migraine (n = 174), only 52% were diagnosed with migraine by our physicians. Nausea was the best single item for predicting migraine diagnosis, while any combination of two items among nausea/vomiting, moderate or severe pain and photophobia, provided the optimum screening tool. Migraine was the most common headache diagnosis in the neurologists' clinics. Probable migraine was not completely adopted as a migraine spectrum among neurologists. In contrast to ID Migraine(TM), moderate or severe headache intensity replaced headache-related disability as one screening item for migraine in Taiwan.


The tomato plastidic fructokinase SlFRK3 plays a role in xylem development.
Plants have two kinds of fructokinases (FRKs) that catalyze the key step of fructose phosphorylation, cytosolic and plastidic. The major cytosolic tomato FRK, SlFRK2, is essential for the development of xylem vessels. In order to study the role of SlFRK3, which encodes the only plastidic FRK, we generated transgenic tomato (Solanum lycopersicon) plants with RNAi suppression of SlFRK3 as well as plants expressing beta-glucoronidase (GUS) under the SlFRK3 promoter. GUS staining indicated SlFRK3 expression in vascular tissues of the leaves and stems, including cambium, differentiating xylem, young xylem fibers and phloem companion cells. Suppression of SlFRK3 reduced the stem xylem area, stem and root water conductance, and whole-plant transpiration, with minor effects on plant development. However, suppression of SlFRK3 accompanied by partial suppression of SlFRK2 induced significant growth-inhibition effects, including the wilting of mature leaves. Grafting experiments revealed that these growth effects are imposed primarily by the leaves, whose petioles had unlignified, thin-walled xylem fibers with collapsed parenchyma cells around the vessels. A cross between the SlFRK2-antisense and SlFRK3-RNAi lines exhibited similar wilting and anatomical effects, confirming that these effects are the result of the combined suppression of SlFRK3 and SlFRK2. These results demonstrate a role of the plastidic SlFRK3 in xylem development and hydraulic conductance.


Estimating Childhood Stunting and Overweight Trends in the European Region from Sparse Longitudinal Data.
Monitoring countries' progress toward the achievement of their nutrition targets is an important task, but data sparsity makes monitoring trends challenging. Childhood stunting and overweight data in the European region over the last 30 y have had low coverage and frequency, with most data only covering a portion of the complete age interval of 0-59 mo. We implemented a statistical method to extract useful information on child malnutrition trends from sparse longitudinal data for these indicators. Heteroscedastic penalized longitudinal mixed models were used to accommodate data sparsity and predict region-wide, country-level trends over time. We leveraged prevalence estimates stratified by sex and partial age intervals (i.e., intervals that do not cover the complete 0-59 mo), which expanded the available data (for stunting: from 84 sources and 428 prevalence estimates to 99 sources and 1786 estimates), improving the robustness of our analysis. Results indicated a generally decreasing trend in stunting and a stable, slightly diminishing rate for overweight, with large differences in trends between low- and middle-income countries compared with high-income countries. No differences were found between age groups and between sexes. Cross-validation results indicated that both stunting and overweight models were robust in estimating the indicators for our data (root mean squared error: 0.061 and 0.056; median absolute deviation: 0.045 and 0.042; for stunting and overweight, respectively). These statistical methods can provide useful and robust information on child malnutrition trends over time, even when data are sparse.


Differences in Prevalence of Muscle Weakness (Sarcopenia) in Haemodialysis Patients Determined by Hand Grip Strength Due to Variation in Guideline Definitions of Sarcopenia.
Muscle weakness is associated with increased mortality, and hemodialysis (HD) patients are at an increased risk for muscle loss. There is no agreed definition for muscle weakness, so we determined whether using different cut-off criteria recommended by guideline groups altered the prevalence in HD patients. We measured hand grip strength (HGS) in HD outpatients, comparing HGS with clinical guideline cut-offs (European Working Group on Sarcopenia in Older People [EWGSOP] and North American Foundation for the National Institutes of Health Sarcopenia Project [FNIH]) used to define muscle wasting (sarcopenia) with age-matched and gender-matched normative data. We studied 459 patients, 61.4% male, 47.3% diabetic. The prevalence of muscle weakness was significantly different when measuring HGS; 84.5% using the EWGSOP cut-off and 73.2% with FNIH criteria, and 75.2% using North American normative data and 56.6% U.K. normative data (P < .01). On logistic regression, muscle weakness was associated with age (odds ratio [OR] 1.05, P < .001), weight (OR 0.96, P < .001), serum albumin (OR 0.89, P = .007), and being nondiabetic (OR 0.31, P = .001). Of patients with no comorbidity, 66.7% were weak when compared with 93.8% with the highest comorbidity scores (P < .001). There is currently no agreed universal definition for sarcopenia, but the EWGSOP and FNIH advocate HGS cut-offs as part of their definition. The prevalence of muscle weakness varies according to cut-off and whether age-matched and gender-matched normative data are used. In addition, patient characteristics in terms of age and comorbidity determine the prevalence of muscle weakness.


Microbotox of the Lower Face and Neck: Evolution of a Personal Technique and Its Clinical Effects.
Microbotox is the injection of multiple microdroplets of diluted onabotulinumtoxinA into the dermis or the interface between the dermis and the superficial layer of facial muscles. The intention is to decrease sweat and sebaceous gland activity to improve skin texture and sheen and to target the superficial layer of muscles that find attachment to the undersurface of the dermis causing visible rhytides. For treatment of the lower face and neck, hundreds of microdroplets of diluted Botox are injected into the dermis or immediate subdermal plane to improve skin texture, smoothen horizontal creases, and decrease vertical banding of the neck, as well as to achieve better apposition of the platysma to the jawline and neck, improving contouring of the cervicomental angle. The Microbotox solution is mixed in the syringe by adding a small volume of lidocaine to the calculated dose of onabotulinumtoxinA drawn from a standard bottle of Botox prepared with 2.5 mL saline. Each 1 mL syringe of Microbotox solution contains 20-28 units of onabotulinumtoxinA per mL of solution and is used to deliver 100-120 injections. The lower face and neck will usually require 1 mL per side. The injections are delivered intradermally using a 30- or 32-G needle raising a tiny blanched weal at each point. The author has over 1867 documented cases of Microbotox in various parts of the face (forehead, glabellar, crow's-feet, infraorbital, and cheeks) and neck, the majority of these patients being treated in forehead or the lower face and neck as described in this article.


Zebrafish as a New Model to Study the Crosstalk between Tumor and Host Metabolism.
The mechanism of metabolic crosstalk between different tissues in the host remains poorly understood but is likely to play important roles in tumor growth and cachexia. A recent study from Naser, Jackstadt, et al. utilizes isotope tracing in a zebrafish melanoma model and finds that tumors secrete alanine into circulation, which is taken up by the liver and used for gluconeogenesis.


Foraging behavior and locomotion of the invasive Argentine ant from winter aggregations.
The collective behavior of ant colonies, and locomotion of individuals within a colony, both respond to changing conditions. The invasive Argentine ant (Linepithema humile) thrives in Mediterranean climates with hot, dry summers and colder, wet winters. However, its foraging behavior and locomotion has rarely been studied in the winter. We examined how the foraging behavior of three distinct L. humile colonies was related to environmental conditions and the locomotion of workers during winter in northern California. We found that colonies foraged most between 10 and 15°C, regardless of the maximum daily temperature. Worker walking speed was positively associated with temperature (range 6-24°C) and negatively associated with humidity (range 25-93%RH). All colonies foraged during all day and night hours in a predictable daily cycle, with a correlation between the rate of incoming and outgoing foragers. Foraging activity was unrelated to the activity of a competing native ant species, Prenolepis imparis, which was present in low abundance, and ceased only during heavy rain when ants left foraging trails and aggregated in small sheltered areas on trees.


Tetraploid somatic hybrids of potato (Solanum tuberosum L.) obtained from diploid breeding lines.
Intraspecific somatic hybrids between 16 different diploid breeding lines of Solanum tuberosum L. were produced by PEG-induced fusion. Manually selected heterokaryons were cultured in a Millicells-CM using a post-fusion protoplast mixture. Plants were regenerated from calli derived from heterokaryons obtained from 10 out of 38 combinations of diploid lines. Of the tested putative somatic hybrids, 14.2% were diploid, 72.8% were tetraploid and 13% pentaploid. The DNA amplification pattern obtained with RAPD or semi-random primers confirmed that 6 fusion combinations were hybrids. In most cases, the morphological traits were intermediate to those of the diploid fusion partners. About 23.0% of the tested somatic hybrids showed variation in their morphology. Of the tested somatic hybrids, 78.0% flowered and 86.0% tuberized. The cytoplasm of 9 diploid lines and 6 somatic hybrid combinations was analysed. Two of the diploid lines had W/S chloroplasts and alpha or epsilon mitochondria; the remainder contained T chloroplasts and beta mitochondria. All the analysed somatic hybrids carried T chloroplasts and beta mitochondria.


A randomised controlled trial exploring the effects of different beverages consumed alongside a nitrate-rich meal on systemic blood pressure.
Ingestion of nitrate (NO3-)-containing vegetables, alcohol and polyphenols, separately, can reduce blood pressure (BP). However, the pharmacokinetic response to the combined ingestion of NO3- and polyphenol-rich or low polyphenol alcoholic beverages is unknown. The aim of this study was to investigate how the consumption of low and high polyphenolic alcoholic beverages combined with a NO3--rich meal can influence NO3- metabolism and systemic BP. In a randomised, crossover trial, 12 normotensive males (age 25 ± 5 years) ingested an acute dose of NO3- (∼6.05 mmol) in the form of a green leafy salad, in combination with either a polyphenol-rich red wine (NIT-RW), a low polyphenol alcoholic beverage (vodka; NIT-A) or water (NIT-CON). Participants also consumed a low NO3- salad and water as a control (CON; ∼0.69 mmol NO3-). BP and plasma, salivary and urinary [NO3-] and nitrite ([NO2-]) were determined before and up to 5 h post ingestion. Each NO3--rich condition elevated nitric oxide (NO) biomarkers when compared with CON ( P < 0.05). The peak rise in plasma [NO2-] occurred 1 h after NIT-RW (292 ± 210 nM) and 2 h after NIT-A (318 ± 186 nM) and NIT-CON (367 ± 179 nM). Systolic BP was reduced 2 h post consumption of NIT-RW (-4 mmHg), NIT-A (-3 mmHg) and NIT-CON (-2 mmHg) compared with CON ( P < 0.05). Diastolic BP and mean arterial pressure were also lower in NIT-RW and NIT-A compared with NIT-CON ( P < 0.05). A NO3--rich meal, consumed with or without an alcoholic beverage, increases plasma [NO2-] and lowers systemic BP for 2-3 h post ingestion.


β-Amyloid Peptide 1-42-Conjugated Magnetic Nanoparticles for the Isolation and Purification of Glycoproteins in Egg White.
Aβ1-42-conjugated magnetic nanoparticles, Aβ1-42@MNP, were prepared by covalently coupling Aβ1-42 to hyperbranched polyethyleneimine (PEI)-modified magnetic nanoparticles via N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC). Aβ1-42's high binding capacity to glycosyl groups facilitates Aβ1-42@MNP composite to be a promising selective adsorbent for glycoproteins in egg whites. In our study, under conditions of pH 4.0, the adsorption efficiency of Aβ1-42@MNP composite for ovalbumin (100 μg mL-1) was 98.4% and its maximum adsorption capacity was 344.8 mg g -1; under the condition of pH 4.0 and 200 mmol L-1 NaCl, its adsorption efficiencies for ovalbumin and ovotransferrin were 96.9% and 60.0%, respectively. According to these primary data, in practice, ovalbumin was removed from egg white by Aβ1-42@MNP composite at pH 4.0 (step I), and then after adding NaCl until the final salt concentration reached 200 mmol L-1 (pretreated egg white), we utilized the same adsorbent to further isolate/purify glycoproteins (step II). SDS-PAGE results showed that Aβ1-42@MNP composite could largely remove ovalbumin in step I and could isolate/purify the remaining ovalbumin and ovotransferrin in step II. LC-MS/MS analysis results showed that the removal of ovalbumin reduced its percentage in egg white samples from 32.93% to 11.05% in step I and the remaining ovalbumin and ovotransferrin were enriched in step II, where the final percentage reached 11.6% and 12.6%, respectively. In summary, 81 protein species were identified after two-step extraction with Aβ1-42@MNP on egg white, while only 46 protein species were identified directly from raw egg white without any pretreatment. This work well illustrates the excellent adsorption performance of Aβ1-42@MNP composite to glycoproteins and its potential in the application of proteomic studies on low-abundance proteins in egg white.


Treatment of esophageal cancer with multiple liver metastases: a case experience of sustained complete response.
Esophageal squamous cell cancer with distant metastases has a poor prognosis. The metastatic sites usually involve the liver, bones, and lungs. Treatment of metastatic disease is essentially palliative and based on chemoradiotherapy. A 57-year-old man with a solitary metastatic mass of 82 × 58 mm in the left liver was treated on 19 October 2012. Irinotecan and cisplatin combination chemotherapy and nimotuzumab targeted therapy were administered. The liver metastatic mass was treated by stereotactic Gamma Knife radiosurgery. Complete remission of the primary disease and hepatic lesion was achieved, and no local or distant recurrence was found during the 7-year follow-up. Because extrahepatic lesions were ruled out and the local disease was completely locoregionally controlled, the use of stereotactic Gamma Knife radiosurgery to remove the hepatic lesion was justified and produced a reasonable outcome.


Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome.
Despite the fundamental roles of sialyl- and fucosyltransferases in mammalian physiology, there are few pharmacological tools to manipulate their function in a cellular setting. Although fluorinated analogs of the donor substrates are well-established transition state inhibitors of these enzymes, they are not membrane permeable. By exploiting promiscuous monosaccharide salvage pathways, we show that fluorinated analogs of sialic acid and fucose can be taken up and metabolized to the desired donor substrate-based inhibitors inside the cell. Because of the existence of metabolic feedback loops, they also act to prevent the de novo synthesis of the natural substrates, resulting in a global, family-wide shutdown of sialyl- and/or fucosyltransferases and remodeling of cell-surface glycans. As an example of the functional consequences, the inhibitors substantially reduce expression of the sialylated and fucosylated ligand sialyl Lewis X on myeloid cells, resulting in loss of selectin binding and impaired leukocyte rolling.


Ejaculatory frequency and the risk of aggressive prostate cancer: Findings from a case-control study.
Recent literature reports inverse associations with ejaculator frequency and prostate cancer (PC). We sought to explore the relationship between ejaculatory frequency from ages 20 to 50 and subsequent development of aggressive PC. We conducted a case-control study sampling 2,141 men from private urology practices in Victoria, Australia. Cases were defined as men with high grade or high stage PC and controls being biopsy negative men. Ejaculation frequency recalled at age decades 20, 30, and 40 second was assessed by questionnaire. Unconditional multivariable logistic regression models were used to generate odds ratios (ORs). An inverse association with ejaculatory frequency at age 30 to 39 was observed (OR per 5-unit increase per week = 0.83, 95% CI: 0.72-0.96) but not at ages 20 to 29 (OR = 1.01, 95% CI: 0.89-1.14) or ages 40 to 49 (OR = 0.95, 95% CI: 0.81-1.12). This result differed between men with new sexual partners after age 30 (OR = 0.77, P = 0.009) and those with no new partners (OR = 0.97, P = 0.8) though the test for a difference between these estimates was not significant (P = 0.11). We found only weak evidence of an inverse association between ejaculatory frequency in the fourth decade of life and advanced PC, which was not significantly modified by number of new sexual partners. No relationship was found for ejaculatory frequency in the third and fifth decades of life.


Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters.
Iminoglycinuria (IG) is an autosomal recessive abnormality of renal transport of glycine and the imino acids proline and hydroxyproline, but the specific genetic defect(s) have not been determined. Similarly, although the related disorder hyperglycinuria (HG) without iminoaciduria has been attributed to heterozygosity of a putative defective glycine, proline, and hydroxyproline transporter, confirming the underlying genetic defect(s) has been difficult. Here we applied a candidate gene sequencing approach in 7 families first identified through newborn IG screening programs. Both inheritance and functional studies identified the gene encoding the proton amino acid transporter SLC36A2 (PAT2) as the major gene responsible for IG in these families, and its inheritance was consistent with a classical semidominant pattern in which 2 inherited nonfunctional alleles conferred the IG phenotype, while 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype when combined with mutations in the gene encoding the imino acid transporter SLC6A20 (IMINO). Additional mutations were identified in the genes encoding the putative glycine transporter SLC6A18 (XT2) and the neutral amino acid transporter SLC6A19 (B0AT1) in families with either IG or HG, suggesting that mutations in the genes encoding these transporters may also contribute to these phenotypes. In summary, although recognized as apparently simple Mendelian disorders, IG and HG exhibit complex molecular explanations depending on a major gene and accompanying modifier genes.


Interventions for drug-using offenders with co-occurring mental illness.
This is an updated version of an original Cochrane review published in Issue 3 2006 (Perry 2006). The review represents one from a family of four reviews focusing on interventions for drug-using offenders. This specific review considers interventions aimed at reducing drug use or criminal activity, or both for drug-using offenders with co-occurring mental illness. To assess the effectiveness of interventions for drug-using offenders with co-occurring mental illness in reducing criminal activity or drug use, or both. We searched 14 electronic bibliographic databases (searched between 2004 and 21 March 2013) and five internet resources (searched between 2004 and 11 November 2009). We contacted experts in the field for further information. We included randomised controlled trials designed to reduce, eliminate or prevent relapse in drug-using offenders with co-occurring mental illness. We also reported data on the cost and cost effectiveness of interventions. We used standard methodological procedures expected by The Cochrane Collaboration. We identified 76 trials across the four reviews. Following a process of pre-screening, we judged eight trials to meet the inclusion criteria for this specific review (three of the five trials are awaiting classification). The five included 1502 participants. The interventions reported on case management via a mental health drugs court, a therapeutic community, and an evaluation of a motivational interviewing technique and cognitive skills in comparison to relaxation training. The methodological quality of the trials was generally difficult to rate due to a lack of clear reporting. On most risk of bias items, we rated the majority of studies as unclear. Overall, the combined interventions did not show a statistically significant reduction in self reported drug use (2 studies, 715 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.44 to 1.55). A statistically significantly reduction was shown for re-incarceration (4 studies, 627 participants; RR 0.40, 95% CI 0.24 to 0.67 and mean difference (MD) 28.72, 95% CI 5.89 to 51.54) but not re-arrest (2 studies, 518 participants; RR 1.00, 95% CI 0.90 to 1.12). A specific subgroup analysis combining studies using therapeutic community interventions showed a statistically significant reduction in re-incarceration (2 studies, 266 participants; RR 0.29, 95% CI 0.16 to 0.54) but not re-arrest (1 study, 428 participants; RR 0.90, 95% CI 0.61 to 1.33). Case management via a mental health court and motivational interviewing with cognitive skills did not show a statistically significant reduction in criminal activity (1 study, 235 participants; RR 1.05, 95% CI 0.90 to 1.22) or self reported drug misuse (1 study, 162 participants; MD -7.42, 95% CI -20.12 to 5.28). Due to the small number of studies, we were unable to analyse the impact of setting on outcome. Some cost information was provided in the trials but not sufficient to be able to evaluate the cost effectiveness of the interventions. This review highlights the paucity of evidence for drug misusing offenders with co-occurring mental health problems. Two of the five trials showed some promising results for the use of therapeutic communities and aftercare, but only in relation to reducing subsequent re-incarceration. The studies overall, showed a high degree of statistical variation demonstrating a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. More evaluations are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems.


The in vitro genotoxicity potency of mixtures of pyrrolizidine alkaloids can be explained by dose addition of the individual mixture components.
Plant-based 1,2-unsaturated Pyrrolizidine Alkaloids (PAs) are responsible for liver genotoxicity/carcinogenicity following metabolic activation, making them a relevant concern for safety assessment. Due to 21st century toxicology approaches, risk of PAs can be better discerned though an understanding of differing toxic potencies, but it is often mixtures of PAs that are found as contaminants in foods, for example, herbal teas and honey, food supplements and herbal medicines. Our study investigated whether genotoxicity potency of PAs dosed individually or in mixtures differed when measured using micronuclei formation in vitro in HepaRG human liver cells, which we and others have shown to be suitable for observing genotoxic potency differences across different PA structural classes. When equipotent concentrations of up to six different PAs representing a wide range of potencies in vitro were tested as mixtures, the observed genotoxic potency aligned favorably with results for single PAs. Similarly, when the BMD confidence intervals of these equipotent mixtures were compared with the confidence intervals of the individual PAs, only minimal variation was observed. These data support a conclusion that for this class of plant impurities, all acting via the same DNA-reactive mode of action, genotoxic potency can be regarded as additive when assessing the risk of mixtures of PAs.


A Systematic Review of the Implementation and Effectiveness of 'The Daily Mile' on Markers of Children's Health.
Currently, a high percentage of children globally fail to meet the World Health Organisation's (WHO) recommended daily physical activity (PA) guidelines. The Daily Mile (TDM) is a school-based PA initiative, designed to improve primary school children's PA behaviour. The purpose of this review was to evaluate the extant TDM implementation process and identify its impact on health-related metrics. Three databases were used to search for articles from the time TDM originated in 2012 until February 2022. The identification and screening process of articles for their ability to meet this review's eligibility criteria were facilitated by use of PRISMA and Rayyan. Sixteen articles from the initial search (n = 202) were deemed eligible for inclusion. An analysis of these articles identified five common outcome categories that permeated throughout the research articles: (1) cardiorespiratory fitness (CRF); (2) anthropometry and body composition; (3) PA; (4) cognition; and (5) process evaluation. Results presented from the included articles suggests TDM positively impacts markers of a variety of health-related metrics, namely CRF and PA. However, implementation barriers including TDM's repetitive nature, time constraints associated with competing curriculum demands and inadequate facilities regularly necessitate the adaptation and development of the original TDM format by schools and teachers.


Distal radius fractures: surgical treatment with internal fixation.
To evaluate the efficacy of plates and screws with angular stability in osteosynthesis of fractures of the distal radius. We analyzed 52 patients undergone surgery for fracture of the distal radius at the Clinica Ortopedica dell'Università di Trieste; in half of the patients osteosynthesis was provided using Synthes' LCP plates, in the other half we utilized a multidirectional and angular stable plate ("Aptus Radius" by Medartis). Mean follow-up was 28 ± 10 months, patients were evaluated with DASH score (disability of arm shoulder and hand) and the modified Gartland Werley score. There were no significant differences between the two groups in terms of joint function, motility, volar and radial mean inclination. Based on clinical and radiological results using angular stability plates must be considered as the method of election in the treatment of fractures of the distal epiphysis of the radius; in particular, thanks to the broader technical capabilities that they allow, are particularly indicated in unstable fractures.


Application of the Composite Fibers Based on Chitosan and Chitin Nanofibrils in Cosmetology.
Chitosan and composite fibers containing chitin nanofibrils have been developed for use in cosmetology. The tensile strength of the chitosan multifilaments is 160.6 ± 19.0 MPa, and of the composite multifilaments containing chitin, nanofibrils are 198.0 ± 18.4 MPa. Chitin nanofibrils introduced into the chitosan solution contribute to the creation of a new spatial arrangement of chitosan chains and their denser packing. The studies carried out by optical, scanning electron, and atomic force microscopy has shown that the serum, consisting of a mixture of lactic acid and sodium lactate, contains extended oriented structures-"liquid filaments". It has been also shown that a mixture of serum and composite fibers based on chitosan and chitin nanofibrils has mucoadhesive, film-forming properties. The introduction of composite fibers containing chitin nanofibrils into the serum promotes the reinforcing effect of liquid filaments, the lifting effect of the film. The obtained composition can be used in cosmetology as a skin care product.


Self-motion and the origin of differential spatial scaling along the septo-temporal axis of the hippocampus.
Spatial scaling of place specific activity in the hippocampus varies systematically from the septal pole (high resolution) to the temporal pole (low resolution). Place fields get progressively larger, and the probability of observing a field in a given environment gets progressively smaller. It was previously found that decoupling movement in space from ambulation, by having the animal actively ride on a mobile platform, results in marked enlargement of the spatial scale factor in the dorsal hippocampus and a reduction in the increase in theta rhythm power with running speed, suggesting that a self-motion signal determines the spatial scale at which the hippocampal population vector updates. These results led to the hypothesis that the gain of the self-motion signal may vary systematically along the septo-temporal axis of the hippocampus. To test this hypothesis, EEG theta rhythm and ensembles of CA1 pyramidal cells and interneurons were recorded from the extreme dorsal and middle portions of the hippocampus. Pyramidal cell population vectors representing successive locations became decorrelated over substantially shorter distances in the dorsal than in the middle hippocampus. Dorsal pyramidal cells had smaller place fields, higher mean and peak firing rates, and higher intrinsic oscillation frequencies during track running than that of middle pyramidal cells. Both dorsal pyramidal cells and interneurons had more elevated mean rates during running, compared with rest, than that of the corresponding cell classes in the middle hippocampus, and both cell classes increased their rates more as a function of speed in the dorsal hippocampus.The amplitude, but not the frequency of fissure recorded theta rhythm, increased more as a function of running speed in the dorsal than in the middle hippocampus. We conclude that variation in the neuronal response to movement speed is the likely basis for the systematic variation in spatial scaling along the septo-temporal axis of the hippocampus.


Dry Swab-Based Nucleic Acid Extraction vs. Spin Column-Based Nucleic Acid Extraction for COVID-19 RT-PCR Testing: A Comparative Study.
Conventional nucleic acid extraction involves usage of spin columns to isolate the RNA, but this is labor intensive. This study compares the spin column method with a dry swab-based method of extraction using a proteinase K buffer and subsequent heat inactivation. A total of 56 subjects were tested for COVID-19 by RT-PCR with probes targeting the E and RdRp genes by collecting two nasopharyngeal and two oropharyngeal swabs and subjecting one set to nucleic acid extraction by spin column and the other set to dry swab-based methods. Out of the 56 samples tested, 27 were positive for VTM-based extraction and 29 were negative. Dry swab-based extraction produced 22 positive results (sensitivity = 81.48%) and 34 negative results. The E gene was detectable in 25 samples by the dry swab method out of 27 samples that tested positive by the VTM-based method (sensitivity = 92.5%). The RdRp gene was detectable in 22 samples by the dry swab method out of 27 samples that tested positive by the VTM-based method (sensitivity = 81.48%). Concordance was 91% with discordance at 9% and a Kappa value of 0.82, indicating almost perfect agreement between the two methods. Our findings indicate that the dry swab method of nucleic acid extraction is a useful alternative to conventional spin column-based extraction with comparable sensitivity and specificity. The trial was registered with the Clinical Trials Registry of India (CTRI) with a CTRI registration number of CTRI/2021/12/038792.


[The history of Lipiodol (1901-1994) or How a medication may evolve with the times].
The history of Lipiodol, an iodized oil perfected in 1901 by Marcel Guerbet and Laurent Lafay, offers the example of a product with multiple indications which, initially destined for therapeutic usage, was later successfully turned to radiologic applications; then, sixty years later, returned to its initial purposes. This shows that (1) very often new products find usages which their developers never suspected; (2) research can extend beyond the original synthesis and commercialization of the product; (3) at some point research on a medication becomes multidisciplinary.


Comprehensive Characterization for Ginsenosides Biosynthesis in Ginseng Root by Integration Analysis of Chemical and Transcriptome.
Herbgenomics provides a global platform to explore the genetics and biology of herbs on the genome level. Panax ginseng C.A. Meyer is an important medicinal plant with numerous pharmaceutical effects. Previous reports mainly discussed the transcriptome of ginseng at the organ level. However, based on mass spectrometry imaging analyses, the ginsenosides varied among different tissues. In this work, ginseng root was separated into three tissues-periderm, cortex and stele-each for five duplicates. The chemical analysis and transcriptome analysis were conducted simultaneously. Gene-encoding enzymes involved in ginsenosides biosynthesis and modification were studied based on gene and molecule data. Eight widely-used ginsenosides were distributed unevenly in ginseng roots. A total of 182,881 unigenes were assembled with an N50 contig size of 1374 bp. About 21,000 of these unigenes were positively correlated with the content of ginsenosides. Additionally, we identified 192 transcripts encoding enzymes involved in two triterpenoid biosynthesis pathways and 290 transcripts encoding UDP-glycosyltransferases (UGTs). Of these UGTs, 195 UGTs (67.2%) were more highly expressed in the periderm, and that seven UGTs and one UGT were specifically expressed in the periderm and stele, respectively. This genetic resource will help to improve the interpretation on complex mechanisms of ginsenosides biosynthesis, accumulation, and transportation.


Effects of early exercise on cardiac function and lipid metabolism pathway in heart failure.
We employed an early training exercise program, immediately after recovery from surgery, and before severe cardiac hypertrophy, to study the underlying mechanism involved with the amelioration of cardiac dysfunction in aortic stenosis (AS) rats. As ET induces angiogenesis and oxygen support, we aimed to verify the effect of exercise on myocardial lipid metabolism disturbance. Wistar rats were divided into Sham, trained Sham (ShamT), AS and trained AS (AST). The exercise consisted of 5-week sessions of treadmill running for 16 weeks. Statistical analysis was conducted by anova or Kruskal-Wallis test and Goodman test. A global correlation between variables was also performed using a two-tailed Pearson's correlation test. AST rats displayed a higher functional capacity and a lower cardiac remodelling and dysfunction when compared to AS, as well as the myocardial capillary rarefaction was prevented. Regarding metabolic properties, immunoblotting and enzymatic assay raised beneficial effects of exercise on fatty acid transport and oxidation pathways. The correlation assessment indicated a positive correlation between variables of angiogenesis and FA utilisation, as well as between metabolism and echocardiographic parameters. In conclusion, early exercise improves exercise tolerance and attenuates cardiac structural and functional remodelling. In parallel, exercise attenuated myocardial capillary and lipid metabolism derangement in rats with aortic stenosis-induced heart failure.


Cloning and sequence of several alpha 2u-globulin cDNAs.
We describe a simple cloning procedure for alpha 2u-globulin that requires neither enrichment of mRNA for cloning nor purification of a specific probe for screening recombinant colonies. Total adult male liver poly(A)+RNA was used as template for cloning, and the subsequent recombinant colonies were screened by comparing hybridization to radioactive cDNA probes prepared from hepatic male and female mRNA, respectively. Almost all of the selected "male-specific" clones were later shown to contain alpha 2u-globulin sequences. This cloned alpha 2u-globulin cDNA has been shown to specifically hybridize to male rat liver RNA, which, when isolated and translated in vitro, codes for a 21,000-dalton protein (pro-alpha 2u-globulin) immunologically identical to alpha 2u-globulin. When translation occurs in the presence of pancreatic microsomes this in vitro synthesized pro-alpha 2u-globulin is processed to the 19,000-dalton mature form of alpha 2u-globulin. The nucleotide sequence of the alpha 2u-globulin cDNA has been determined, thus elucidating the complete amino acid sequence of alpha 2u-globulin and most of the hydrophobic "leader" sequence of pro-alpha 2u-globulin. The amino acid sequence deduced from the cDNA is in agreement with the partial sequence that we previously determined by sequential Edman degradation of the purified protein. alpha 2u-Globulin cDNA clones contain within the 3'-untranslated region one or both of the two putative polyadenylylation/transcription termination sites (A-A-T-A-A-A and A-A-T-T-A-A-A). Either of these can be used, generating alpha 2u-globulin mRNA species of two lengths. A codon usage analysis of the cDNA showed that, although all six leucine codons are used for the 14 leucine residues in mature alpha 2u-globulin, the seven leucines in the partial leader sequence reported are all encoded by the same codon, CTG. The primary amino acid sequence contains a unique Asn-Gly-Ser sequence, likely to be in beta-turn conformation, as the probable site of glycosylation for this glycoprotein.


Spontaneous cell-mediated cytotoxicity (SCMC) in patients with alopecia universalis.
The spontaneous cell-mediated cytotoxicity (SCMC) of unfractionated lymphocytes was determined in 5 patients with alopecia universalis (AU). The target cells used were K562 and Chang cell lines. All patients had an increased SCMC as compared with age- and sex-matched donors. The results indicate that SCMC against K562 cells is more pronounced than that against Chang cells.


Diagnosis of bronchobiliary fistula by bilirubin crystallization in the alveolar lavage fluid: case reports and literature review.
Bronchobiliary fistula (BBF) refers to the abnormal traffic between the biliary tract and the bronchus. The condition is very rare and usually develops secondary to liver echinococcosis or amebiasis, liver abscess, trauma, biliary obstruction, or tumors. BBF has a high mortality rate and currently, there are no accurate and effective diagnostic methods. This study reports the diagnosis and treatment of two patients with BBF which were confirmed by detecting bilirubin crystallization in the sputum. The first patient was a 45-year-old woman admitted to the hospital with "recurrent cough and lung infection". She had a history of multiple biliary tract surgeries and bilirubin crystallization was detected in bronchoalveolar lavage fluid (BALF) upon examination. Computed tomography (CT) imaging and magnetic resonance cholangiopancreatography (MRCP), together with clinical features, confirmed a diagnosis of BBF. The second patient was a 53-year-old woman admitted to the hospital with coughing and bile-like sputum. She had a history of cholangiocarcinoma surgery and bilirubin crystallization was detected in the cytomorphological BALF examination. Endoscopic retrograde cholangiopancreatography (ERCP) combined with clinical features confirmed a diagnosis of BBF. Both patients recovered after treatment and were discharged from the hospital. The clinical diagnosis of BBF largely relies upon imaging combined with clinical standards, and BALF examinations are rarely performed. This current investigation retrospectively analyzed the diagnosis and treatment of two cases of BBF, and demonstrated that bilirubin crystallization in the BALF may be an important diagnostic indicator for BBF.


Current status and restoration options for floodplains along the Danube River.
Floodplains are key ecosystems of riverine landscapes and provide a multitude of ecosystem services. In most of the large river systems worldwide, a tremendous reduction of floodplain area has occurred in the last 100 years and this loss continues due to pressures such as land use change, river regulation, and dam construction. In the Danube River Basin, the extent of floodplains has been reduced by 68% compared to their pre-regulation area, with the highest losses occurring in the Upper Danube and the lowest in the Danube Delta. In this paper, we illustrate the restoration potential of floodplains along the Danube and its major tributaries. Via two case studies in the Upper and Lower Danube, we demonstrate the effects of restoration measures on the river ecosystem, addressing different drivers, pressures, and opportunities in these regions. The potential area for floodplain restoration based on land use and hydromorphological characteristics amounts to 8102 km(2) for the whole Danube River, of which estimated 75% have a high restoration potential. A comparison of floodplain status and options for restoration in the Upper and Lower Danube shows clear differences in drivers and pressures, but certain common options apply in both sections if the local context of stakeholders and societal needs are considered. New approaches to flood protection using natural water retention measures offer increased opportunities for floodplain restoration, but conflicting societal needs and legal frameworks may restrict implementation. Emerging issues such as climate change and invasive non-native species will need careful consideration in future restoration planning to minimize unintended effects and to increase the resilience of floodplains to these and other pressures.


Effect of loop length variation on quadruplex-Watson Crick duplex competition.
The effect of loop length on quadruplex stability has been studied when the G-rich strand is present along with its complementary C-rich strand, thereby resulting in competition between quadruplex and duplex structures. Using model sequences with loop lengths varying from T to T5, we carried out extensive FRET to discover the influence of loop length on the quadruplex-Watson Crick duplex competition. The binding data show an increase in the binding affinity of quadruplexes towards their complementary strands upon increasing the loop length. Our kinetic data reveal that unfolding of the quadruplex in presence of a complementary strand involves a contribution from a predominant slow and a small population of fast opening conformer. The contribution from the fast opening conformer increases upon increasing the loop length leading to faster duplex formation. FCS data show an increase in the interconversion between the quadruplex conformers in presence of the complementary strand, which shifts the equilibrium towards the fast opening conformer with an increase in loop length. The relative free-energy difference (Delta DeltaG(o)) between the duplex and quadruplex indicates that an increase in loop length favors duplex formation and out competes the quadruplex.


Outcome of patients with severe brain trauma who were treated either by neurosurgeons or by trauma surgeons.
In Central Europe, patients with severe traumatic brain injury (TBI) are frequently treated by trauma surgeons rather than neurosurgeons. The objective of this study was to compare outcomes of patients with TBI by trauma surgeons or neurosurgeons. This study is a retrospective analysis of prospectively collected data. Between January 2001 and December 2005, 10 centers enrolled 311 operatively treated patients with severe TBI and no significant other injuries into observational studies. Data on accident, treatment, and outcomes were collected. Using the Glasgow Outcome Scale, 1-year outcomes were classified as "favorable" (scores 5 and 4) or "unfavorable" (scores <4). Data from patients operated by trauma surgeons ("group T") were compared with those from patients operated by neurosurgeons ("group N") using univariate and multivariate statistics. The scores published by Hukkelhoven et al. were used to estimate expected rates of death and unfavorable outcomes. There were 191 patients in group N and 120 in group T. There were no significant differences regarding age, sex, and trauma mechanisms between the two groups. Patients from group N had significantly higher trauma severity. The observed versus expected hospital mortality ratio was 0.84 for group N and 0.97 for group T (p = 0.051). One-year outcome was better in group T (28% vs. 19% good recovery, 1.7% vs. 9.4% vegetative status; p = 0.017), whereas mortality was not different (43% in both groups). Multivariate analysis revealed that outcomes were influenced by age and severity of TBI, whereas surgical specialty and treatment factors had no effects. With respect to operatively treated patients with TBI, trauma surgeons and neurosurgeons achieve comparable results. II.


Effects of exercise training on autonomic modulation and mood symptoms in patients with obstructive sleep apnea.
We evaluated the effects of exercise training (ET) on the profile of mood states (POMS), heart rate variability, spontaneous baroreflex sensitivity (BRS), and sleep disturbance severity in patients with obstructive sleep apnea (OSA). Forty-four patients were randomized into 2 groups, 18 patients completed the untrained period and 16 patients completed the exercise training (ET). Beat-to-beat heart rate and blood pressure were simultaneously collected for 5 min at rest. Heart rate variability (RR interval) was assessed in time domain and frequency domain (FFT spectral analysis). BRS was analyzed with the sequence method, and POMS was analyzed across the 6 categories (tension, depression, hostility, vigor, fatigue, and confusion). ET consisted of 3 weekly sessions of aerobic exercise, local strengthening, and stretching exercises (72 sessions, achieved in 40±3.9 weeks). Baseline parameters were similar between groups. The comparisons between groups showed that the changes in apnea-hypopnea index, arousal index, and O2 desaturation in the exercise group were significantly greater than in the untrained group (P<0.05). The heart rate variability and BRS were significantly higher in the exercise group compared with the untrained group (P<0.05). ET increased peak oxygen uptake (P<0.05) and reduced POMS fatigue (P<0.05). A positive correlation (r=0.60, P<0.02) occurred between changes in the fatigue item and OSA severity. ET improved heart rate variability, BRS, fatigue, and sleep parameters in patients with OSA. These effects were associated with improved sleep parameters, fatigue, and cardiac autonomic modulation, with ET being a possible protective factor against the deleterious effects of hypoxia on these components in patients with OSA.


Variants of SERPINA1 and the increasing complexity of testing for alpha-1 antitrypsin deficiency.
Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, which encodes the alpha-1 antitrypsin (AAT) protein. Currently, over 200 SERPINA1 variants have been identified, many of which cause the quantitative and/or qualitative changes in AAT responsible for AATD-associated lung and liver disease. The types of these pathogenic mutations are varied, often resulting in misfolding, or truncating of the AAT amino acid sequence, and improvements in sequencing technology are helping to identify known and novel genetic variants. However, due to the diversity and novelty of rare variants, the clinical significance of many is largely unknown. There is, therefore, a lack of guidance on how patients should be monitored and treated when the clinical significance of their variant combination is unclear or variable. Nevertheless, it is important that physicians understand the advantages and disadvantages of the different testing methodologies available to diagnose AATD. Owing to the autosomal inheritance of the genetic mutations responsible for AATD, genetic testing should be offered not only to patients at increased AATD risk (e.g. patients with chronic obstructive pulmonary disease), but also to relatives of those with an abnormal result. Genetic counseling may help patients and family members understand the possible outcomes of testing and the implications for the family. While stress/anxiety can arise from genetic diagnosis or confirmation of carrier status, there can be positive consequences to genetic testing, including improved lifestyle choices, directed medical care, and empowered family planning. As genetic testing technology grows and becomes more popular, testing without physician referral is becoming more prevalent, irrespective of the availability of genetic counseling. Therefore, the Alpha-1 Foundation offers genetic counseling, as well as other support and educational material, for patients with AATD, as well as their families and physicians, to help improve the understanding of potential benefits and consequences of genetic testing.


Cryptic Methane-Cycling by Methanogens During Multi-Year Incubation of Estuarine Sediment.
As marine sediments are buried, microbial communities transition from sulfate-reduction to methane-production after sulfate is depleted. When this biogenic methane diffuses into the overlying sulfate-rich sediments, it forms a sulfate-methane transition zone (SMTZ) because sulfate reducers deplete hydrogen concentrations and make hydrogenotrophic methanogenesis exergonic in the reverse direction, a process called the anaerobic oxidation of methane (AOM). Microbial participation in these processes is often inferred from geochemistry, genes, and gene expression changes with sediment depth, using sedimentation rates to convert depth to time. Less is known about how natural sediments transition through these geochemical states transition in real-time. We examined 16S rRNA gene amplicon libraries and metatranscriptomes in microcosms of anoxic sediment from the White Oak River estuary, NC, with three destructively sampled replicates with methane added (586-day incubations) and three re-sampled un-amended replicates (895-day incubations). Sulfate dropped to a low value (∼0.3 mM) on similar days for both experiments (312 and 320 days, respectively), followed by a peak in hydrogen, intermittent increases in methane-cycling archaea starting on days 375 and 362 (mostly Methanolinea spp. and Methanosaeta spp., and Methanococcoides sp. ANME-3), and a methane peak 1 month later. However, methane δ13C values only show net methanogenesis 6 months after methane-cycling archaea increase and 4 months after the methane peak, when sulfate is consistently below 0.1 mM and hydrogen increases to a stable 0.61 ± 0.13 nM (days 553-586, n = 9). Sulfate-reducing bacteria (mostly Desulfatiglans spp. and Desulfosarcina sp. SEEP-SRB1) increase in relative abundance only during this period of net methane production, suggesting syntrophy with methanogens in the absence of sulfate. The transition from sulfate reduction to methane production in marine sediments occurs through a prolonged period of methane-cycling by methanogens at low sulfate concentrations, and steady growth of sulfate reducers along with methanogens after sulfate is depleted.


Pirfenidone for the treatment of idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a diffuse parenchymal lung disease with no cure. Up until recently, no treatment had been proven to alter its natural history as judged by rate of lung function decline. In 2014 however, the emergence of two novel anti-fibrotic agents, Pirfenidone and Nintedanib revolutionized the management of this condition. Both have demonstrated the ability to deliver a major reduction in the rate of chronic IPF progression. Areas Covered: This review article focuses on Pirfenidone - a pyridone derivative initially designed as an analgesic and anti-pyretic agent. Here we describe the history of the drug from its inception through to exploratory pre-clinical in-vitro and in-vivo studies where its anti-fibrotic potential was identified, and eventually to large multicenter randomized controlled trials. Expert Commentary: This article also summarizes some of the difficulties surrounding clinical end-point selection in IPF trials and addresses some of the challenges facing the IPF community over the coming years.


Prediction of mortality with unmeasured anions in critically ill patients on mechanical ventilation.
Acid-base disorders are common within critically ill patients. Physicochemical approach described by Stewart and modified by Figge gives precise quantification method of metabolic acidosis and insight into its main mechanisms, as well as influence of unmeasured anion on metabolic acidosis. The aims of this study were to determine whether the conventional acid-base variables are connected with survival rate of critically ill patients at Intensive care unit; whether strong ion difference/strong ion gap (SID/SIG) is a better predictor of mortality rate comparing to conventional acid-base variables; to determine all significant predictable parameters for the 28-day mortality rate at intensive care units. This retrospective observational analytic study included 142 adult patients requiring mechanical ventilation, survivors (n = 68) and nonsurvivors (n = 74). Apparent strong ion difference (SIDapp), effective strong ion difference (SIDeff) and SIG values were calculated with the Stewart-Figge's quantitative biophysical method. Descriptive and analytical statistical methods were used in the study [t-test, Mann-Whitney U test, χ2-test, binary logistic regression, Reciever operating characteristic (ROC) curves, calibration]. Age, Na+, acute physiology and chronic health evaluation (APACHE II), Cl-, albumin, SIG, SID app, SIDeff, and aninon gap (AG) were statistically significant predictors. AG represented a model with imprecise calibration, i.e. a model with little predictive power. APACHE II had p-value more than 0.05 if it was near it, and therefore it could be considered potentially unreliable for outcome prediction. SIDeff and SIG represented models with well-defined calibration. ROC analysis results showed that APACHE II, Cll-, albumin, SIDeff, SIG i AG had the largest area bellow the curve. By creation of logistic models with calibration methods, we found that outcome depends on SIG and APACHE II score. Based on our data, unmeasured anions provide prediction of mortality of critically ill patients on mechanical ventilation, unlike the traditional acid-base variables which are not accurate predictors of the 28-day mortality rate.


GM-DockZn: a geometry matching-based docking algorithm for zinc proteins.
Molecular docking is a widely used technique for large-scale virtual screening of the interactions between small-molecule ligands and their target proteins. However, docking methods often perform poorly for metalloproteins due to additional complexity from the three-way interactions among amino-acid residues, metal ions and ligands. This is a significant problem because zinc proteins alone comprise about 10% of all available protein structures in the protein databank. Here, we developed GM-DockZn that is dedicated for ligand docking to zinc proteins. Unlike the existing docking methods developed specifically for zinc proteins, GM-DockZn samples ligand conformations directly using a geometric grid around the ideal zinc-coordination positions of seven discovered coordination motifs, which were found from the survey of known zinc proteins complexed with a single ligand. GM-DockZn has the best performance in sampling near-native poses with correct coordination atoms and numbers within the top 50 and top 10 predictions when compared to several state-of-the-art techniques. This is true not only for a non-redundant dataset of zinc proteins but also for a homolog set of different ligand and zinc-coordination systems for the same zinc proteins. Similar superior performance of GM-DockZn for near-native-pose sampling was also observed for docking to apo-structures and cross-docking between different ligand complex structures of the same protein. The highest success rate for sampling nearest near-native poses within top 5 and top 1 was achieved by combining GM-DockZn for conformational sampling with GOLD for ranking. The proposed geometry-based sampling technique will be useful for ligand docking to other metalloproteins. GM-DockZn is freely available at www.qmclab.com/ for academic users. Supplementary data are available at Bioinformatics online.


Meeting report--9th IRIC International Symposium on Molecular Targets in Cancer Genomics.
Graduate students and postdoctoral fellows at the Institute for Research in Immunology and Cancer (IRIC) organized the 9th IRIC International Symposium on 14-15 May, 2015. The symposium was held at the IRIC, an ultra-modern research hub and training center located on the hilltop of the Université de Montréal campus in Montreal, Canada. This year's title was 'Molecular Targets in Cancer Genomics', reflecting the common interest of the IRIC student community. Through four broadly themed sessions, organizers sought to highlight the new generation of anti-cancer strategies including targeted therapies directed against actionable cancer-specific mutations, and immunotherapies, which enhance immune responses against cancer. Both targeted and immunotherapies are tailored to cancer-specific features, and require precise knowledge of cancer cells, from their genome to their proteome. The focus of this symposium was on translating the molecular basis of cancer into a functional understanding of aberrant pathways, and to uncover novel targets to be exploited for cancer therapeutic strategies.


Multidetector computed tomography imaging of the spine.
This article discusses applications of multidetector computed tomography imaging of the spine as they were presented at the "Advances in Multidetector CT" meeting held in Washington, DC, September 13-14, 2003. These include imaging the spine in the setting of trauma, postoperative fusion, chronic pain, radiculopathy, or bony lesions and performing image-guided biopsies.


Winning isn't everything: mood and testosterone regulate the cortisol response in competition.
Dominance contests are recurrent and widespread causes of stress among mammals. Studies of activation of the stress axis in social defeat - as reflected in levels of adrenal glucocorticoid, cortisol - have generated scattered and sometimes contradictory results, suggesting that biopsychological individual differences might play an important mediating role, at least in humans. In the context of a larger study of the regulation of endocrine responses to competition, we evaluated the notion that mood states, such as self-assurance and hostility, may influence cortisol reactivity to dominance cues via an interplay with baseline testosterone, considered as a potential marker of individual differences in dominance. Seventy healthy male university students (mean age 20.02, range 18-26) provided saliva samples before and after competing for fifteen minutes on a rigged computer task. After a winner was determined, all participants were assessed on their mood states through a standardized psychometric instrument (PANAS-X). Among winners of a rigged videogame competition, we found a significant interaction between testosterone and self-assurance in relation to post-competition cortisol. Specifically, self-assurance was associated with lower post-competition cortisol in subjects with high baseline testosterone levels, but no such relationship was observed in subjects with lower baseline testosterone levels. In losers of the competition no interaction effect between basal testosterone and hostility was observed. However, in this subgroup a significant negative relationship between basal testosterone and post-competition cortisol was evident. Overall, these findings provide initial support for the novel hypothesis that biological motivational predispositions (i.e. basal testosterone) and state (i.e. mood changes) may interact in regulating the hypothalamic-pituitary-adrenal axis activation after a social contest.


Demonstration of a primary antidiuretic action of angiotensin II: effects of intrarenal converting enzyme inhibition in the conscious dog.
This study was designed to determine whether angiotensin II of renal origin physiologically mediates free water production by the kidney. The effect of renal arterial infusion of the angiotensin-converting enzyme inhibitor, teprotide, on renal function was studied under conditions of hydropenia and hydration in uninephrectomized conscious dogs after 5 days of equilibration on a normal or low sodium diet. In low sodium animals, intrarenal infusion of teprotide (0.25 microgram/kg.min) after 12 h of water restriction elicited marked increases in the glomerular filtration rate (GFR) and free water formation. After 24 h of water restriction, vasopressin (10 microU/min) was infused iv to achieve an effective maximal urine concentration. Under these conditions, the inhibitor again increased the GFR and free water formation. After the production of a state of stable hydration, intrarenal infusion of teprotide also increased the GFR and free water formation. In the normal sodium animals, intrarenal infusion of the converting enzyme inhibitor (2.5 microgram/kg.min) in 12-h hydropenic dogs failed to change the GFR but increased free water formation, while the inhibitor decreased effective renal plasma flow and free water formation in normal sodium, hydrated animals. These data suggest that angiotensin II of renal origin plays an important role in the control of free water production by the kidney.


Quantitative determination of higher harmonic content in the soft x-ray spectra of toroidal grating monochromator using a reflection multilayer.
Use of a grating monochromator causes a problem of higher harmonic contaminations in a synchrotron beamline operating in the soft x ray/vacuum ultraviolet region. Generally gratings are used to experimentally determine the higher harmonic contaminations. In this method, the relative contribution of contaminant wavelengths is measured with respect to the first harmonic wavelength (desired wavelength). The quantitative fit of grating spectra is rather complex, and therefore qualitative analysis is carried out. Analysis of multilayer reflectivity data has become rather simple with recent advances in the theoretical modeling. Therefore we propose to use a multilayer mirror and analyze its reflectivity data for quantitative determination of harmonic contamination in a soft x ray beamline. In the present study we used a Mo/Si multilayer of d=97 Å to quantify the spectral purity of 600 lines/mm toroidal grating at the reflectivity beamline of Indus-1 450 MeV synchrotron source. The measured reflectivity spectra at each wavelength is analyzed and the actual contribution of higher harmonics in the incident beam is obtained. Details of methodology and results are discussed.