Mechanism and Reaction Pathways for Microcystin-LR Degradation through UV/H2O2 Treatment.
Microcystin-LR (MCLR) is the most common cyanotoxin in contaminated aquatic systems. MCLR inhibits protein phosphatases 1 and 2A, leading to liver damage and tumor formation. MCLR is relatively stable owing to its cyclic structures. The combined UV/H2O2 technology can degrade MCLR efficiently. The second-order rate constant of the reaction between MCLR and hydroxyl radical (·OH) is 2.79(±0.23)×1010 M-1 s-1 based on the competition kinetics model using nitrobenzene as reference compound. The probable degradation pathway was analyzed through liquid chromatography mass spectrometry. Results suggested that the major destruction pathways of MCLR were initiated by ·OH attack on the benzene ring and diene of the Adda side chain. The corresponding aldehyde or ketone peptide residues were formed through further oxidation. Another minor destruction pathway involved ·OH attack on the methoxy group of the Adda side chain, followed by complete removal of the methoxy group. The combined UV/H2O2 system is a promising technology for MCLR removal in contaminated aquatic systems.


Dynamics of cancerous tissue correlates with invasiveness.
Two of the classical hallmarks of cancer are uncontrolled cell division and tissue invasion, which turn the disease into a systemic, life-threatening condition. Although both processes are studied, a clear correlation between cell division and motility of cancer cells has not been described previously. Here, we experimentally characterize the dynamics of invasive and non-invasive breast cancer tissues using human and murine model systems. The intrinsic tissue velocities, as well as the divergence and vorticity around a dividing cell correlate strongly with the invasive potential of the tissue, thus showing a distinct correlation between tissue dynamics and aggressiveness. We formulate a model which treats the tissue as a visco-elastic continuum. This model provides a valid reproduction of the cancerous tissue dynamics, thus, biological signaling is not needed to explain the observed tissue dynamics. The model returns the characteristic force exerted by an invading cell and reveals a strong correlation between force and invasiveness of breast cancer cells, thus pinpointing the importance of mechanics for cancer invasion.


E3 ligase Fbw7 participates in oxidative stress‑induced myocardial cell injury via interacting with Mcl‑1.
Oxidative stress participates in several heart diseases and is an important mechanism contributing to the pathological alterations of myocardial cell injury. In recent years, ubiquitylation has been demonstrated to be an important biochemical reaction associated with apoptosis. To investigate the effects and interactions of the E3 ligase F‑box and WD repeat domain containing 7 (Fbw7) and MCL1 apoptosis regulator, BCL2 family member (Mcl‑1) in myocardial cells during oxidative stress, Cell Counting Kit‑8, flow cytometry, western blot, reactive oxygen species and co‑immunoprecipitation assays were conducted. The current study revealed that Fbw7 may facilitate apoptosis via the Mcl‑1‑Bax pathway in oxidative stress‑induced myocardial H9c2 cell injury. Mcl‑1 inhibits the functions of Bcl‑2 family members, including the mitochondrial apoptosis factor Bax, to maintain cell viability; however, the present study suggested that Fbw7 may degrade Mcl‑1 and impaired this process. Therefore, it may be hypothesized that Fbw‑7 promotes myocardial cell injury via interacting with Mcl‑1.


A meta-analysis to determine the efficacy and tolerability of anti-B-cell monoclonal antibodies in multiple sclerosis.
The present study performed a meta-analysis of randomized controlled trials in multiple sclerosis (MS) patients to evaluate the efficacy and safety of anti-B-cell monoclonal antibodies (mAbs). To the best of our knowledge, no previous meta-analysis has evaluated this. Relevant studies published until March 2015 were retrieved from the PubMed, EMBASE and Cochrane Library using the following keywords: 'Clinical trial', 'randomized', 'multiple sclerosis' or 'MS' and 'monoclonal antibodies' or 'mAbs'. Two authors independently selected the articles and extracted the data. The meta-analysis was performed using Review Manager version 5.3 software. Four randomized clinical trials comprising a total of 745 patients were selected. Anti-B-cell mAb treatment reduced the formation of gadolinium-enhancing lesions [mean difference (MD)=-5.62; 95% confidence interval (CI)=-8.00 to -3.24; P<0.001) and was associated with smaller volume changes of lesions on T2-weighted magnetic resonance imaging (MD=-604.40; 95% CI=-941.23 to -267.57; P<0.001). It also significantly reduced the proportion of MS patients having at least one relapse [odds ratio (OR)=0.25; 95% CI=0.14-0.44; P<0.001). Compared to placebo, anti-B-cell mAb treatment did not increase the frequency of adverse events (OR=0.90; 95% CI=0.54-1.49; P=0.68) and serious adverse events (OR=1.13; 95% CI=0.70-1.80; P=0.62). In conclusion, the present meta-analysis suggested that anti-B-cell mAbs are a relatively effective and safe treatment for MS.


Emergence of coherent transport in UBe13: an optical investigation in both the normal and superconducting states.
The far-infrared reflectance of heavy-fermion superconductor UBe13 has been measured from 0.5 K in the superconducting state, to 300 K. Coherent transport, characterized by an optical conductivity that exhibits a renormalized Drude peak at low frequencies, emerges between 45 and 85 K although the dc resistivity of UBe13 continues to increase with decreasing temperature down to approximately 2.5 K. In the superconducting state, the low frequency scattering rate falls abruptly, implying that the formation of the condensate alters dramatically the interaction between the heavy electrons.


[Doctor Francisco Pérez Cascales. Biography and odontologycal chapter of his work].
Given the absence of odontological texts and against the background of the very poor development of this branch of surgery during the XVII century, we have thoroughly investigated the medical, surgical and paediatric texts of the century, all scattered around and of different length, and have bumped against the text of the noteworthy "paediatrician" of the Rénaissance, Francisco Pérez Cascales who, in his "Liber de affectionibus puerorum", tackles, in hand with the Greek and Roman classical authors, only one oral and dental problem: mouth ulcers, and lingers on their aethiology, diagnosis and clinical treatment. We are also remaking the biography of the author, trying to fill in the many blanks found in it and correct the multiple errors through the incorporation of appropriate documents and references.


[Aminoglycoside antibiotics and post-antibiotic effects].
Man has been fighting diseases for centuries. One of the major battles is against microorganisms and diseases they cause. A health education course was organized on prescribing aminoglycoside antibiotics and postantibiotic effect. The aim of the course was to change the prescription habits in our colleagues. The postantibiotic effect of aminoglycoside antibiotics as well as impact of subinhibiting doses on duration of postantibiotic effect requires modification of previous therapeutic protocols. Single daily dose has the same or even greater effect than multiple daily doses. The toxicity of aminoglycosides is not increased and remains the same or smaller in single daily regimens. The single daily dose regimen of aminoglycosides has been used in 63.6% of cases in Clinic for Infectious Diseases of the Clinical Center of Novi Sad, 41.2% in Outpatient Health Care Center of Novi Sad "Liman" and this regimen has not been used in General Practice Department, Children's Health Care Department and Ear, Nose and Throat Clinic at all. The twice daily regimen has been used instead. Doctors are aware of the postantibiotic effect, but vast majority are still bound to their old habits in regard to prescribing antibiotics. Our educational course failed to achieve its goal.


Double Bond Position Plays an Important Role in Delta-9 Desaturation and Lipogenic Properties of Trans 18:1 Isomers in Mouse Adipocytes.
The objective of this research was to study the delta-9 desaturation of individual trans (t) fatty acids that can be found in ruminant fat or partially hydrogenated vegetable oils (PHVO) and determine their effects on lipogenic gene expression in adipocytes. It was hypothesized that delta-9 desaturation and lipogenic properties of t-18:1 isomers depend on the position of double bond. Differentiated 3T3-L1 adipocytes were treated with 200 µM of t6-18:1, t9-18:1, t11-18:1, t13-18:1 or t16-18:1, cis (c)-9 18:1 or bovine serum albumin (BSA) vehicle control for 48 h. Cells were then harvested for fatty acid and gene expression analyses using gas chromatography and quantitative PCR respectively. Among t-18:1 isomers, t13-18:1 and t11-8:1 had the greatest percent delta-9 desaturation (44 and 41 % respectively) followed by t16-18:1 and t6-18:1 (32 and 17 % respectively), while c9-18:1 and t9-18:1 did not undergo delta-9 desaturation. Trans9-18:1 up-regulated (P < 0.05) the expression of lipogenic genes including fatty acid synthase and stearoyl-CoA desaturase-1 (P < 0.05), whereas the expression of these genes were not affected with other t-18:1 isomers (P > 0.05). Consistent with gene expression results, t9-18:1 increased the de novo lipogenic index (16:0/18:2n-6) compared with control cells and increased delta-9 desaturation index (c9-16:1/18:0) compared to other t-18:1 isomers (P < 0.05). The current study provides further evidence that the predominant trans fatty acid in PHVO (t9-18:1) has isomer specific lipogenic properties.


High HDAC5 expression correlates with a poor prognosis and the tumor immune microenvironment in gastric cancer.
Gastric cancer (GC) is one of the most common malignant tumors worldwide and has a poor prognosis. Previous studies have confirmed differential histone deacetylase 5 (HDAC5) expression in various common tumors. HDAC5 is also associated with prognosis and plays a role in cancer cell proliferation, invasion, and metastasis, as well as the tumor immune microenvironment (TIME). However, HDAC5 in GC is not well understood. The aims of study were to investigate the HDAC5 expression correlates with prognosis and the TIME in GC. A total of 355 tumor tissues and 300 matched paracancerous tissues were collected from GC patients who underwent radical surgery. The correlation between clinicopathological characteristics, immune-related factors and HDAC5 expression were analyzed. Univariate and multivariate Cox regression analyses were used to confirm the independent factors affecting the prognosis of GC. Survival curves were plotted using the Kaplan-Meier method. Furthermore, the stomach adenocarcinoma (STAD) dataset was downloaded from The Cancer Genome Atlas (TCGA). The expression levels of HDAC5 were defined as high or low using the gene set variance analysis (GSVA) package. Identification of differential immune infiltrating cells was performed by single sample gene set enrichment analysis (ssGSEA). The positive expression rate of HDAC5 was higher in tumor tissues than in paracancerous tissues (38.87% vs. 14.67%, P<0.001). Univariate and multivariate Cox analyses showed that HDAC5 was an independent factor affecting the prognosis of GC. The HDAC5 expression levels were correlated with age (P=0.046), smoking history (P=0.001), Lauren type (P=0.042), and pM stage (P=0.012). Furthermore, these levels were correlated with CD3+ T cells (P<0.001), CD4+ T cells (P<0.001), CD8+ T cells (P<0.001) and PD-L1 (P=0.001). Further analysis of patients in TCGA cohort confirmed the association between HDAC5 and activated CD4 T cells, activated CD8 T cells, and other immune infiltrating cells. HDAC5 is highly expressed in tumor tissues and is an independent factor affecting the prognosis of GC. Additionally, HDAC5 can regulate the TIME of GC and is a potential target for immunotherapy.


New Insights in (Poly)phenolic Compounds: From Dietary Sources to Health Evidence.
Nowadays, there is a gap between the theoretical bioactivity of (poly)phenols and their real influence in health, once ingested. Due to this, new studies, including in vitro and in vivo models that allow for exploring bioaccessibility, bioavailability, and bioactivity, need to be developed to understand the actual importance of consuming functional foods, rich in these plant secondary metabolites. Moreover, current new strategies need to be developed to enhance the content of these foods, as well as setting up new formulations rich in bioaccessible and bioavailable compounds. Altogether, it could give a new horizon in therapy, expanding the use of these natural functional compounds, ingredients, and foods in the clinical frame, reducing the use of synthetic drugs. As a result, the joint contribution of multidisciplinary experts from the food science, health, and nutrition areas, together with the industrial sector, would help to reach these objectives. Taking this into account, diverse studies have been included in this study, which comprises different strategies to approach these objectives from different, complementary, points of view, ranging from the enrichment of by-products in bioactive compounds, through different agricultural techniques, to the assimilation of these compounds by the human body, both in vitro and in vivo, as well as by clinical studies.


[Predictive factors for determination of menopausal age].
In western Europe the average age at menopause is 52 years. This means that a woman spends approximately 30 years of her life in the postmenopausal status. The possibility to predict the actual age AT menopause would have major implications for family planning, sterility treatment and for the decision to apply HRT. There are numerous associations between socio-economic factors and the age at menopause. A positive correlation has been shown between cigarette smoking and menopausal age. Furthermore several lifestyle factors have an influence on the onset of menopause. However it is not clear in how far generative and socio-economic factors such as marital status interfere with ovarian function.


"Location is surprisingly a lot more important than you think": a critical thematic analysis of push and pull factor messaging used on Caribbean offshore medical school websites.
Offshore medical schools are for-profit, private enterprises located in the Caribbean that provide undergraduate medical education to students who must leave the region for postgraduate training and also typically to practice. This growing industry attracts many medical students from the US and Canada who wish to return home to practice medicine. After graduation, international medical graduates can encounter challenges obtaining residency placements and can face other barriers related to practice. We conducted a qualitative thematic analysis to discern the dominant messages found on offshore medical school websites. Dominant messages included frequent references to push and pull factors intended to encourage potential applicants to consider attending an offshore medical school. We reviewed 38 English-language Caribbean offshore medical school websites in order to extract and record content pertaining to push and pull factors. We found two push and four pull factors present across most offshore medical school websites. Push factors include the: shortages of physicians in the US and Canada that require new medical trainees; and low acceptance rates at medical schools in intended students' home countries. Pull factors include the: financial benefits of attending an offshore medical school; geographic location and environment of training in the Caribbean; training quality and effectiveness; and the potential to practice medicine in one's home country. This analysis contributes to our understanding of some of the factors behind students' decisions to attend an offshore medical school. Importantly, push and pull factors do not address the barriers faced by offshore medical school graduates in finding postgraduate residency placements and ultimately practicing elsewhere. It is clear from push and pull factors that these medical schools heavily focus messaging and marketing towards students from the US and Canada, which raises questions about who benefits from this offshoring practice.


A modern approach for controlled transdermal delivery of diflunisal: optimization and in vivo evaluation.
The purpose of the present work was to elaborate an optimized transdermal therapeutic system for diflunisal. Selection of suitable ingredients was done via solubility and phase behavior studies. Composition of microemulsion (ME) systems consisting of butyl lactate, Brij(®) 97, Transcutol(®) and water was optimized using augmented simplex lattice mixture design. The independent variables selected were the percentages of butyl lactate, surfactant mixture and water. The dependent variables were refractive index, pH, conductivity, viscosity, drug solubility in the ME formulation and the ex vivo skin permeation flux. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The statistical validity of the polynomials was established. Optimized formulation factors were selected by desirability approach. The optimized ME formulation was converted into gel using Carbomer(®) 934. The microemulsion based gel (MBG) showed better spreadability and 5.07-fold increase in the transdermal flux than Carbomer(®) 934 gel. The in vivo antihyperalgesia assay performed on mice showed significant reduction of the licking time in the treated group compared to the control group. This demonstrated the reliability of the simplex lattice statistical design for predicting optimum ME formulation. The developed MBG proved its in vivo efficiency for transdermal delivery of diflunisal.


Modification in nucleocytoplasmic transport of RNA in vitro after whole-body X-irradiation.
Rats were sacrificed at different times after injection of 14C-orotate and liver nuclei were isolated and incubated in a cell-free system made of soluble cytoplasmic fraction from non-irradiated rat livers. The release of ribonucleoproteins from labelled nuclei to the incubation medium was measured on nuclei from normal and total-body irradiated rats (500 to 2000 R). When using short labelling times in vivo (30 min), which would label predominantly messenger-type RNP, the nuclear transport activity was depressed at early times (3 h) after whole-body irradiation, but increased at later times (24 h). When the labelling time in vivo is increased to 2 h, no significant difference was observed between control and irradiated groups. Transport of the stable ribosomal-type RNP, observed 24 h after both labelling and irradiation, was depressed. These results are discussed in view of previous personal studies on radiation effect on liver RNA synthesis and polyribosomes formation in vivo.


[Pharmacological action of eptazocine (l-1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-banzazonine). (II) Relationship between the analgesic action of eptazocine and brain 5-hydroxytryptamine (5-HT) (author's transl)].
The relationship between the analgesic action of eptazocine and brain 5-HT was investigated by pharmacological and neurochemical methods in comparison with pentazocine (PZC) and morphine (MOR). The analgesic effects of eptazocine, PZC, and MOR as determined by the pressure method were decreased by pretreatment with rho-chlorophenylalanine or 5,6-dihydroxytryptamine. The analgesic effects of all three drugs were also diminished by a lesion in the dorsal half of the spinal cord (C5-6) or the raphe magnus. A lesion in the central gray produced a decrease in the analgesic effects of MOR or PZC, but had a weak effect on that of eptazocine. All three drugs increased 5-hydroxyindole acetic acid (5-HIAA) levels in the brain stem, the striatum, and the spinal cord. In addition, eptazocine decreased the 5-HIAA level in the cortex and the 5-HT level in the hippocampus, but increased the 5-HT level in the spinal cord. An increase of 5-HIAA in the cortex and a decrease of 5-HT in the brain stem were observed after PZC-administration. On the other hand, MOR decreased the 5-HT level in the brain stem and striatum. These results suggest that the effects of eptazocine on 5-HT neurons are similar to those of PZC and MOR, but part of the action mechanism of eptazocine is different from those of PZC and MOR.


Modafinil in schizophrenia: is the risk worth taking?
Schizophrenia is a severe mental disorder characterised by positive and negative symptoms. Negative symptoms are difficult to treat and there is no specific treatment. In small trials, modafinil has been studied in association with antipsychotic treatment. We present three cases of its use; two have developed positive symptoms and one developed renal impairment. Further studies are needed to assess its usefulness in schizophrenia and safety in this group of patients.


[Effects of simulated weightlessness on ALP, ACP, collagen I, and biomechanics of hind-limb bones in rats].
To investigate effects of 3 weeks simulated weightlessness on biomechanical parameters, alkaline phosphatase (ALP), acid phosphatase (ACP) and collagen I of hind-limb bones in tail-suspended rats. Fourteen male SD rats were divided equally into control group (CON) and experimental group; tail-suspended (TS) was used to simulate weightlessness. After 3 weeks tail-suspension, biomechanical parameters of femur were measured; ALP, ACP and collagen I of tibia were observed. Elastic load, maximum load, and bending rigidity coefficient decreased significantly (P<0.01), while the maximum deformation and bending toughness coefficient increased markedly (P<0.01 or P<0.05). Morphological results showed that ALP declines significantly in TS group, ACP and type I collagen increased significantly in TS group. After tail-suspension for 3 weeks, growth of rat's weight bearing bones are suppressed, biomechanical capability declines, and collagen I metabolism becomes disordered.


Autocrine/paracrine action of vitamin D on FGF23 expression in cultured rat osteoblasts.
To explore the local mechanisms of fibroblast growth factor (FGF) 23 regulations, we examined the FGF23 expression patterns in an osteoblast culture model. The characteristics of cultured rat calvaria osteoblasts in half-confluence, confluence, osteoid deposition, and osteoid mineralization stages might reflect the proliferation, differentiation, maturation, and matrix mineralization stages, respectively. Compared with proliferating cells in half-confluence, FGF23 expression was upregulated by 7.5-fold at the mRNA level and 126% at the protein level in confluent differentiated cells as determined by real-time RT-PCR and Western blot analysis. Interestingly, mRNA levels of CYP27B1 (the gene coding for 1alpha-hydroxylase enzyme which catalyses the conversion of 1alpha,25-dihydroxyvitamin D, 1alpha,25[OH]2D, from its inactive form, 25-hydroxycholecalciferol, 25[OH]D) and CYP24A (the gene coding for 24-hydroxylase, a target gene of 1alpha,25[OH]2D) were significantly increased by twofold and 34-fold, respectively, in differentiated osteoblasts compared with proliferating cells. We next examined if the local production of 1alpha,25(OH)2D might contribute to the FGF23 upregulation. We cultured osteoblasts in serum-free medium with or without 25-(OH)D (the substrate of 1alpha-hydroxylase). FGF23 mRNA levels were increased in proliferating cells (16-fold) and in differentiated cells (28-fold) by the physiological dose of 25-(OH)D3 treatment. CYP27B1 was slightly but significantly upregulated and CYP24A was increased by 1,700-fold and 800-fold, respectively, in transcriptional levels. Because FGF23 was upregulated in confluent osteoblasts regardless of the presence or absence of 25-(OH)D in serum-free medium, we further examined the possible impact of cell communication on FGF23 expression. We treated osteoblasts with carbenoxolone, a gap junction Cx43 blocker in serum-free medium. The FGF23 mRNA level was reduced by 50% in confluent differentiated cells and slightly but not significantly reduced in half-confluent cells by carbenoxolone treatments. The results suggested that upregulation of FGF23 in differentiated osteoblast appeared to be due to increased autocrine/paracrine action of osteoblast-derived 1alpha,25(OH)2D and increased cell communication, which were identified in cultured rat calvaria osteoblasts. These results indicate that FGF23 expression was stimulated not only by circulating calcitriol but also by locally produced 1alpha,25(OH)2D. The local mechanisms of FGF23 expression remain to be characterized.


Structural infrasound from a barge collision with the Mississippi river bridge.
The Mississippi River Bridge in Vicksburg, Mississippi, is a seven-span cantilever bridge that is 1033 m long by 20.9 m wide and is part of the Interstate-20 corridor. On March 23, 2011, at approximately 14:30 CST, a barge moving downstream struck a pier of the bridge. An infrasound array located at the U.S. Army Engineer Research and Development Center (ERDC) detected the impact. Finite Element (FE) models were developed to investigate the structural behavior of the bridge due to the impact. The FE models identified events within the infrasound record that were possibly produced by the different modes of vibration of the bridge structure. The emerging technology of structural infrasound monitoring and the potential for using infrasound as a forensic tool is demonstrated with the results of the bridge-barge collision event and capability of deployment in the future.


Csk Regulates Blood Pressure by Controlling the Synthetic Pathways of Aldosterone.
Blood pressure is regulated by a network of diverse physiological pathways. The C-terminal Src kinase (CSK) locus (15q24) is associated with blood pressure in various ethnic groups. It was recently reported thatCskinsufficiency increases blood pressure through Src. The mechanisms of hypertension inCsk+/-mice are examined further in this study.Methods and Results:To identify a causal component responsible for hypertension inCsk+/-, the heart rate was measured by electrocardiogram and plasma volume by Evans blue dilution. Plasma volume increased inCsk+/-compared with wild-types, while the heart rate did not change. Plasma sodium and aldosterone levels rose consistently inCsk+/-vs. wild-types, and spironolactone, a mineralocorticoid receptor antagonist, reduced blood pressure. The amounts of Sgk1 and Na+/K+-ATPase (NKA) increased in the kidney ofCsk+/-compared with wild-types. It was also found that Cyp11b2 (aldosterone synthase) was upregulated in the adrenal glands ofCsk+/-, and that Csk was enriched in the zona glomerulosa of adrenals, the major site of aldosterone production in the normal mouse. The results of the present study identify a physiological pathway by which blood pressure is regulated, in which the insufficiency ofCskinduces aldosterone production with zonal specificity in the adrenal glands, increasing sodium reabsorption and plasma volume and thus resulting in hypertension.


The effects of velvet antler polypeptides on the phenotype and related biological indicators of osteoarthritic rabbit chondrocytes.
To study the effects of velvet antler polypeptides (VAPs) on osteoarthritic chondrocytes (OCs) in rabbits. An osteoarthritic rabbit model was established according to Hulth's method. OCs were isolated and cultured for observation of the cell cycle. Cell proliferation was detected by MTT assay and the cell cycle was monitored by flow cytometry. The phenotype was determined by toluidine blue staining as well as immunohistochemical staining for collagen type II. The expression of MMP-1, MMP-3, MMP-13, TIMP-1, and collagen I and X mRNA by chondrocytes was assayed by RT-PCR. The VAPs had no obvious proliferative effect on OCs and did not affect the cell cycle. However, they significantly reduced the proportion of early apoptotic cells in a dose-dependent manner. Further, VAPs inhibited the expression of collagen I and X mRNA and induced abnormal expression of MMP-1 and MMP-13 mRNA. VAPs had no significant effect on MMP-3 and TIMP-1 mRNA levels. The toluidine blue and collagen type II immunohistochemical staining intensities of VAP-treated chondrocytes were positively correlated with the concentration of VAPs used. VAPs had no significant effect on OC proliferation and the cell cycle, but did increase the glycosaminoglycan (GAG) and collagen type II expression levels in the extracellular matrix, and down-regulated collagen I and X mRNA expression. Treatment of cartilage cells with VAPs maintained their normal phenotype, inhibited matrix metalloproteinases (MMPs) secretion, kept the balance of cartilage matrix metabolism, and sustained an external environment where the cartilage cells could survive. Moreover, VAPs reduced the proportion of early apoptotic cells, suggesting that they may block the apoptotic pathway in OCs.


Complications of intra-articular fractures of the calcaneus.
Most complications of calcaneal fractures are due to the combination of the dynamic nature and the mechanism of the injury itself. Complications are usually secondary to three integral parts of this complex fracture pattern: 1) fracture and depression of the subtalar joint, 2) loss of the height of the calcaneal body with varus rotation, and 3) expansion of the lateral wall of the calcaneus. Other complications occur with less frequency. This article describes the complications and sequelae of old, malunited intra-articular calcaneal fractures in relation to the nature and the components of these unique fractures.


Changing the culture of long-term care facilities: pharmacists needed.
A growing number of facilities are changing environments, practices, and philosophies to create a culture of patient-directed or patient-centered care. The ultimate goal of these "culture-change" efforts is to maximize patient choice and create a homelike setting that is appealing for residents and staff alike. As interdisciplinary team leaders, pharmacists not only need to understand culture change, but they also need to embrace it.


Comparing various off-the-shelf methods for bone tissue engineering in a large-animal ectopic implantation model: bone marrow, allogeneic bone marrow stromal cells, and platelet gel.
Construction of bone grafts for regenerative medicine would highly benefit from off-the-shelf components, such as allogeneic bone marrow stromal cells (BMSCs) and blood-derived growth factors from platelet concentrate. Although allogeneic BMSCs are considered immunosuppressive, their use in transplantation studies is still cautioned. In this study, we used off-the-shelf goat allogeneic BMSCs, per-operatively aspirated bone marrow (BM) and platelet gel (PLG). Ten goats received six different hybrid constructs consisting of biphasic calcium phosphate scaffolds seeded with PLG or plasma that were mixed with BM, allogeneic BMSCs or left without cells. All constructs were implanted in the paraspinal muscles for 9 weeks. Fluorochromes were administered at 2, 3, and 5 weeks to assess onset of bone formation. Analysis revealed that the scaffolds without cells yielded small amounts of bone. Allogeneic BMSCs had a positive effect on the amount and early onset of bone formation. Fresh BM did not enhance ectopic bone formation. The PLG, which contained higher levels of transforming growth factor beta than plasma, did not result in more bone either. Fluorochrome incorporation results indicate that the presence of seeded cells in the constructs accelerates bone formation. This study shows a potential role of allogeneic BMSCs in bone tissue-engineering research.


Tumor-cell-platelet aggregation does not correlate with metastatic potential of rat 13762NF mammary adenocarcinoma tumor cell clones.
The ability of tumor cells to induce platelet aggregation has been correlated with their capacities to colonize the lungs of experimental animals. We tested this hypothesis by studying the ability of cloned, low-passage metastatic tumor cell lines derived from rat 13762NF mammary adenocarcinoma to aggregate rat platelets in vitro and in vivo, and we then compared this activity to metastatic potential by determining the incidence of lung metastasis after subcutaneous or intravenous inoculation of the tumor cell clones into syngeneic rats. Our results failed to show a correlation between in vitro platelet-aggregating activity and metastatic potential. In this system we could not detect platelet-aggregation activity with the most metastatic tumor clone, while least metastatic clone clearly possessed high platelet-aggregating activity. In addition, by measuring changes in blood platelet and fibrinogen concentrations at various intervals following intravenous injection of tumor cell clones, we were able to confirm in vivo the observed in vitro differences in their platelet-aggregating activities. Thus, platelet aggregating activity is heterogeneously expressed among 13762NF cell clones and appears unrelated to spontaneous or experimental metastasis in this tumor system.


Course of psychomotor agitation during pharmacotherapy of depression: analysis from double-blind controlled trials with fluoxetine.
Psychomotor agitation, a common clinical feature of major depression, may first emerge or intensify during pharmacotherapy. Whether agitation is part of the underlying course of depression or iatrogenic complicates treatment planning. We analyzed data from blinded clinical trials involving 4,737 patients with major depression assigned to a selective serotonin reuptake inhibitor (fluoxetine), a comparator antidepressant (usually a tricyclic antidepressant [TCA]), or placebo. Item 9 of the Hamilton Depression Rating Scale was used to assess the degree of psychomotor agitation. The vast majority of depressed patients exhibited baseline psychomotor agitation. The rate of increased agitation from baseline during acute pharmacotherapy was comparable between fluoxetine and either placebo or TCAs. Substantial emergence of psychomotor agitation also occurred at a similar incidence across the three treatment groups and typically appeared within the first 3 wk. Improvement in agitation was significantly more prominent (P < 0.001) among fluoxetine-treated than among placebo-treated patients. Fluoxetine-treated patients demonstrated numerically superior improvement rates compared with TCA-treated patients; however, this difference was not significant. Data derived from this large series of clinical trials suggested no evidence that either fluoxetine or TCAs induced psychomotor agitation at rates exceeding the natural course of the disorder over time (placebo cohort). On the contrary, pharmacotherapy with either fluoxetine or TCAs was typically associated with diminished agitation, probably as part of the response pattern of depression.


Pulmonary Venous Obstruction in Cancer Patients.
Background. We study the clinical significance and management of pulmonary venous obstruction in cancer patients. Methods. We conducted a prospective cohort study to characterize the syndrome that we term "pulmonary vein obstruction syndrome" (PVOS) between January 2005 and March 2014. The criteria for inclusion were (1) episodes of shortness of breath; (2) chest X-ray showing abnormal pulmonary hilum shadow with or without presence of pulmonary edema and/or pleural effusion; (3) CT scan demonstrating pulmonary vein thrombosis/tumor with or without tumor around the vein. Results. Two hundred and twenty-two patients developed PVOS. Shortness of breath was the main symptom, which was aggravated by chemotherapy in 28 (13%), and medical/surgical procedures in 21 (9%) and showed diurnal change in intensity in 32 (14%). Chest X-rays all revealed abnormal pulmonary hilum shadows and presence of pulmonary edema in 194 (87%) and pleural effusion in 192 (86%). CT scans all showed pulmonary vein thrombosis/tumor (100%) and surrounding the pulmonary veins by tumor lesions in 140 patients (63%). PVOS was treated with low molecular weight heparin in combination with dexamethasone, and 66% of patients got clinical/image improvement. Conclusion. Physicians should be alert to PVOS when shortness of breath occurs and chest X-ray reveals abnormal pulmonary hilum shadows.


Working With Interpreters as a Team in Health Care (WITH Care) Curriculum Tool Kit for Oral Health Professions.
Limited English proficiency (LEP) patients face multiple care barriers and disproportionate risks for communication errors. Working with trained interpreters as a health care team can improve communication and drive high-quality care for LEP patients. Simulation and interprofessional education provide key strategies to address the critical training gap that exists at the intersection of patient safety, interprofessional practice, and cultural competence. Using action research principles across 16 months, we created a 3.5-hour simulation-based training for oral health and interpreting learners. The curriculum included profession-specific orientations with didactic and experiential content, three immersive simulations using start-stop-rewind methodology, virtual scenarios, and summary reflection discussions. A comprehensive tool kit facilitated curriculum implementation and standardization. Forty-nine students from dentistry (first- through third-year predoctoral), dental hygiene, and dental therapy participated in this elective training during the 2017-2018 academic year; as required training, 126 third-year dental students participated in fall 2018. Students' familiarity with provider and interpreter best practices, appreciation of challenges faced by LEP patients, and confidence in skills working with spoken language interpreters increased. For all evaluation parameters, pre- and postsurvey ratings were statistically significant (chi-square tests, p < .001). The curriculum efficiently and effectively develops oral health and interpreting learners' abilities to work as a team with LEP patients. Curriculum design and resources address key barriers to feasibility and sustainability. The curriculum informs communication across all patient populations, revealing that getting by with partial understanding can be insufficient for any patient and any health care team.


Identification and characterization of murine mitochondria-associated neutral sphingomyelinase (MA-nSMase), the mammalian sphingomyelin phosphodiesterase 5.
Sphingolipids play important roles in regulating cellular responses. Although mitochondria contain sphingolipids, direct regulation of their levels in mitochondria or mitochondria-associated membranes is mostly unclear. Neutral SMase (N-SMase) isoforms, which catalyze hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine, have been found in the mitochondria of yeast and zebrafish, yet their existence in mammalian mitochondria remains unknown. Here, we have identified and cloned a cDNA based on nSMase homologous sequences. This cDNA encodes a novel protein of 483 amino acids that displays significant homology to nSMase2 and possesses the same catalytic core residues as members of the extended N-SMase family. A transiently expressed V5-tagged protein co-localized with both mitochondria and endoplasmic reticulum markers in MCF-7 and HEK293 cells; accordingly, the enzyme is referred to as mitochondria-associated nSMase (MA-nSMase). MA-nSMase was highly expressed in testis, pancreas, epididymis, and brain. MA-nSMase had an absolute requirement for cations such as Mg(2+) and Mn(2+) and activation by the anionic phospholipids, especially phosphatidylserine and the mitochondrial cardiolipin. Importantly, overexpression of MA-nSMase in HEK293 cells significantly increased in vitro N-SMase activity and also modulated the levels of SM and ceramide, indicating that the identified cDNA encodes a functional SMase. Thus, these studies identify and characterize, for the first time, a mammalian MA-nSMase. The characterization of MA-nSMase described here will contribute to our understanding of pathways regulated by sphingolipid metabolites, particularly with reference to the mitochondria and associated organelles.


Tremor/ataxia syndrome and fragile X premutation: diagnostic caveats.
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly discovered late-onset neurodegenerative disorder caused by a premutation in the FMR1 X-linked gene. We present examples of a discrepancy between obvious brain changes observed on MRI, and minimal clinical neurological manifestations in three older carriers of this premutation. This discrepancy occurred in three of nine carriers ascertained in an unbiased manner. If the systematic follow-up studies of adult carriers confirm this trend, this will have an impact on early diagnosis of neurological involvement and possible prevention. If MRI changes precede clinical manifestation of FXTAS this may explain the low detection rate of fragile X carriers among patients with neurological syndromes associated with tremor/ataxia.


Extragalactic chemistry of molecular gas: lessons from the local universe.
Observational constraints provided by high resolution and high sensitivity observations of external galaxies made in the millimetre and sub-millimetre range have started to put on a firm footing the study of the extragalactic chemistry of molecular gas. In particular, the availability of multi-species and multi-line surveys of nearby galaxies is central to the interpretation of existent and forthcoming millimetre observations of the high redshift universe. Probing the physical and chemical status of molecular gas in starbursts and active galaxies (AGN) requires the use of specific tracers of the relevant energetic phenomena that are known to be at play in these galaxies: large-scale shocks, strong UV fields, cosmic rays and X-rays. We present below the first results of an ongoing survey, allying the IRAM 30 m telescope with the Plateau de Bure interferometer (PdBI), devoted to the study of the chemistry of molecular gas in a sample of starbursts and AGN of the local universe. These observations highlight the existence of a strong chemical differentiation in the molecular disks of starbursts and AGN.


5,7-Dihydroxytryptamine identifies living dopaminergic neurons in mesencephalic cultures.
The autofluorescent serotonin analogue 5,7-dihydroxytryptamine (5,7-DHT) was used to identify living catecholaminergic neurons in monolayer cultures derived from the embryonic rat mesencephalon. A high correlation between 5,7-DHT accumulation and aldehyde-induced catecholamine fluorescence as well as tyrosine hydroxylase but not dopamine-beta-hydroxylase or phenylethanolamine-N-methyltransferase immunoreactivity was found. This indicates that these cells were dopamine-containing neurons. Whole-cell patch recordings showed that all mesencephalic neurons had resting membrane potentials of -50 mV or greater and input resistances ranging between 200 and 700 M omega and exhibited spontaneous action potentials and postsynaptic potentials. The duration of the action potential of the dopamine-containing neurons was characteristically longer than that of the non-dopamine-containing mesencephalic cells. In some dopamine-containing neurons, repolarization of the action potential was clearly biphasic, and the slow phase of repolarization was reversibly blocked by local application of Cd2+ or Co2+. This "shoulder" in the action potential was never observed in non-dopamine-containing neurons, where Cd2+ or Co2+ application was always without effect. It is concluded that 5,7-DHT can be used to identify living dopamine-containing neurons in dissociated mesencephalic cultures and these neurons express distinct electrical properties.


Locking compression plate in the treatment of forearm fractures: a prospective study.
To evaluate the use of locking compression plates (LCPs) in diaphyseal forearm fractures. 9 women and 23 men (mean age, 35; range, 12-70 years) with 45 forearm fractures were treated by open reduction and internal fixation with 3.5-mm stainless steel LCPs. All patients were followed up monthly until union; the mean duration being 20 months. Radiographic assessment was performed at 3, 6, 12, and 18 months. Clinical assessments regarding pain and function were undertaken at the final follow-up. Two patients had delayed union but none had nonunion. There was no deep infection and only one superficial infection. Two refractures occurred after implant removal, both were of simple transverse type and at the sites of the original fractures. 33% of the fractures were reduced anatomically. 56% of the fractures healed with no or minimal callus formation and 44% with moderate callus formation. In total, 13% of the anatomically reduced fractures had moderate or abundant callus formation. 22 patients opted for removal of the implants (29 LCPs), after a mean of 16 (range, 9-21) months. The LCP is an effective bridging device used for treating comminuted fractures, but for treating simple fractures its superiority over conventional plating is yet to be proven.


Supplying emergency contraception to adolescents: the nurse's role.
This article explores issues surrounding the supply of emergency contraception to adolescents to reduce the risk of unintended pregnancy. It explains the female reproductive cycle, and describes the types of emergency contraception that may be supplied following unprotected sexual intercourse or contraception failure. The aftercare that should be offered to adolescents following the supply of emergency contraception is discussed, alongside issues surrounding the safeguarding of children and vulnerable adults.


IR spectra and IR spectral maps of individual normal and cancerous cells.
The IR microspectra for individual normal and cancerous cells are reported at a spatial resolution that permits a distinction between the nuclear and cytoplasmic regions. The observed spectra reveal large differences in the spectral contributions of RNA, DNA, and phospholipids: metabolically inactive cells show spectral patterns of proteins only, whereas actively dividing cells also show spectral signatures of nucleic acids and phospholipids. These spectral variations are independent of the state of health of a cell.


Cartilage-sparing Arthroscopic Technique for Curettage and Bone Grafting of Cystic Lesion of Talus -A Case Report.
True cysts in talar body are extremely rare lesions and their treatment options are yet undefined. The standard of care for a large symptomatic talar bone cyst comprises debridement and bone grafting, often requiring extensive soft tissue dissection, damaging talar cartilage, and sometimes, malleolar osteotomy. Alternatively, an arthroscopic debridement of the cyst cavity with bone grafting may be performed, sparing talar cartilage. Here, we describe such a case of a talar body cyst treated successfully by arthroscopic technique. A 12-year-old boy presented with unicameral bone cyst in the body of talus, with fracture of the subchondral bone. Radiological evaluation suggested a simple bone cyst (SBC). Thereafter, posterior ankle arthroscopy was performed and the cyst was approached through posteriortalar process. Debridement of the cystic lesion was done along with curettage, sparing a thin rim of surrounding subchondral bone. The articular cartilage was found intact on both superior and inferior aspects. Subsequently, the defect was filled arthroscopically with cancellous bone graft harvested from the ipsilateral calcaneum through osteochondral autograft transfer system. Outcome of the procedure was assessed clinically as well as radiologically. The histopathological report confirmed the lesion to be a SBC. The child was asymptomatic and resumed sports in school by 6 months. The cystic lesion of talus healed completely by 8 months. According to the modified Neer classification, the lesion had 'healed' radiologically.


An infant with biliary ascites.
Biliary ascites in children due to perforation of bile duct is a rare entity. The exact pathogenesis is not known but there are proposed mechanisms including congenital weakness of ductal wall, pancreaticobiliary malunion, tuberculosis, necrotizing enterocolitis and rupture of choledochal cyst. Presentation may be acute or sub-acute. Progressive insidious course is the common presentation in children with jaundice, clay colored stool, abdominal distension with slightly elevated liver enzymes but well documented cholestasis. Clinical suspicion with ultrasound, CT, MRCP and ascitic tap provides clue to the diagnosis. Both conservative and surgical interventions are in practice for managing these children. We report a 7 months old infant with biliary ascites due to perforation of bile duct.


Cortical Neurons Derived from Equine Induced Pluripotent Stem Cells Are Susceptible to Neurotropic Flavivirus Infection and Replication: An In Vitro Model for Equine Neuropathic Diseases.
Horses are susceptible to a number of neurotropic viruses, including West Nile virus (WNV), which is a pathogen of global significance in both horses and humans. However, there are no in vitro models with which to study infectious neuropathic diseases in the horse. In an effort to redress this, we have generated neurons from equine induced pluripotent stem cells (equiPSCs) that express a range of cortical neuron-specific markers, in addition to the membrane-bound ligand ephrin B3, which plays an important role in axon guidance as well as functioning as the receptor through which henipaviruses, such as Hendra virus, enter mammalian neurons. EquiPSC-derived neurons spontaneously depolarize with waves of depolarization conducted unidirectionally to adjacent neurons. We sought to confirm that equiPSC-derived neurons are a possible in vitro model for viral neuropathic diseases in the horse by examining their susceptibility to infection with flaviviruses that are known to be neurotropic in horses, including WNV and Murray Valley encephalitis virus (MVEV), and to compare these to nonpathogenic flaviviruses such as Fitzroy River virus (FRV) and Bamaga virus (BgV). All three strains of WNV tested in this study grew to high titres in the equiPSC-derived neurons, inducing a strong cytopathic effect (cpe), as did MVEV. In contrast, FRV showed restricted replication, and no cpe, which is consistent with the observation that FRV infects, but does not cause disease, in horses. BgV, which is thought to infect only marsupials, did not replicate in the equiPSC-derived neurons. Hence, our equiPSC-derived neurons display virus-specific differences in terms of viral titre and cpe that are similar to observations made in vivo, thus supporting their use as an in vitro model for neurotropic viral infection in horses.


Design and selection of soy breads used for evaluating isoflavone bioavailability in clinical trials.
To modulate isoflavone aglycone composition within a soy functional food, soy ingredients were processed and evaluated in a soy bread system intended for clinical trials. A soy flour/soy milk mixture (SM) was boiled, fermented, steamed, or roasted prior to dough preparation. The isoflavone compositions of five processed SM and their corresponding breads combined with and without β-glucosidase-rich almonds were examined using HPLC. Isoflavone malonyl-glucosides (>80%) were converted into acetyl and simple glucoside forms (substrates more favorable for β-glucosidase) in steamed and roasted SM. Their corresponding breads had isoflavones predominately as aglycones (∼75%) with soy-almond bread with steamed SM being more consumer acceptable than roasted. Isoflavone composition in soy bread was stable during frozen storage and toasting. A suitable glycoside-rich soy bread (31.6 ± 2.1 mg aglycone equiv/slice) using unprocessed SM and an aglycone-rich soy-almond bread (31.1 ± 1.9 mg aglycone equiv/slice) using steamed SM were developed to evaluate fundamental questions of isoflavone bioavailability in clinical trials.


Family planning considerations in people with multiple sclerosis.
Multiple sclerosis is often diagnosed in patients who are planning on having children. Although multiple sclerosis does not negatively influence most pregnancy outcomes, less is known regarding the effects of fetal exposure to novel disease-modifying therapies (DMTs). The withdrawal of some DMTs during pregnancy can modify the natural history of multiple sclerosis, resulting in a substantial risk of pregnancy-related relapse and disability. Drug labels are typically restrictive and favour fetal safety over maternal safety. Emerging data reporting outcomes in neonates exposed to DMTs in utero and through breastfeeding will allow for more careful and individualised treatment decisions. This emerging research is particularly important to guide decision making in women with high disease activity or who are treated with DMTs associated with risk of discontinuation rebound. As increasing data are generated in this field, periodic updates will be required to provide the most up to date guidance on how best to achieve multiple sclerosis stability during pregnancy and post partum, balanced with fetal and newborn safety.


Immunochemical identification of mouse hepatic protein adducts derived from the nonsteroidal anti-inflammatory drugs diclofenac, sulindac, and ibuprofen.
Reactive metabolite-modified hepatic protein adducts have been proposed to play important roles in the mechanism(s) of hepatotoxicity of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, immunochemical techniques have been used to compare the patterns of drug-protein adducts expressed in livers of mice given single doses of one or other of three different NSAIDs. These were diclofenac and sulindac, which are widely used but potentially hepatotoxic drugs, and ibuprofen, which is considered to be nonhepatotoxic. Specific polyclonal antisera were produced by immunization of rabbits with conjugates prepared by coupling each of the NSAIDs to the carrier protein keyhole limpet hemocyanin. Immunoblotting studies revealed dose-dependent formation of major 110 kDa polypeptide adducts in livers from mice sacrificed 6 h after administration of single doses of either diclofenac (0-300 mg/kg) or sulindac (0-100 mg/kg). Lower levels of several other adducts, of 140 and 200 kDa, were also expressed in livers from these animals. In contrast, livers from mice treated with ibuprofen (0-200 mg/kg) predominantly expressed a 60 kDa adduct and only relatively low levels of a 110 kDa adduct. The various adducts were shown by differential centrifugation to be concentrated in the nuclear fraction of liver homogenates. Those derived from diclofenac and sulindac were further localized, by Percoll density gradient centrifugation, to a subfraction which contained a high activity of the bile canalicular marker enzyme alkaline phosphatase. This suggests that they are concentrated in the bile canalicular domain of hepatocytes. The different patterns of adduct formation raise the possibility that formation of certain NSAID protein adducts, particularly 110 kDa adducts, has toxicological significance.


Dental management of pediatric HIV patients--state of Israel, Ministry of Health Project at Rambam Health Care Campus, 2006-2011.
Over two million children around the world are living with AIDS. Oral health and oral manifestations, such as dental caries and periodontitis, are important issues requiring focus when treating these children. Descriptive data of a project conducted at Rambam Hospital, financed by the Israeli Ministry of Health, are presented in order to investigate and characterize dental treatment for HIV infected children. Thirty-seven infected children, most originating from the Ethiopian community, participated in the project between 2006 and 2011. A total of 724 dental procedures during 185 dental appointments were performed successfully. These children should be provided proactive preventive dental care, while health service providers should undergo further training on prevention and early identification and management of orofacial manifestations. All dental and medical personnel should be made aware of this service in order to refer HIV infected children who can greatly benefit from this special program.


Acute toxicity profiling of the ethyl acetate fraction of Swietenia macrophylla seeds and in-vitro neuroprotection studies.
Swietenia macrophylla (SM) is a medicinally important plant found in tropical and subtropical regions of the world. The ethyl acetate fraction of the seeds of S. macrophylla (SMEAF) is reported to exhibit potent anticancer, antitumor, anti-inflammatory and antifeedant activities. Till date, there have been no studies reported on the acute oral toxicity profile of the ethyl acetate fraction of the seeds of SM. The objective of the present study was to determine the acute toxicity of SMEAF and evaluate the in-vitro neuroprotective activity of SMEAF using primary neuronal cell cultures. In acute oral toxicity study, the SMEAF did not produce any lethal signs of morbidity and mortality. Histo-pathological findings, support the safety of SMEAF, as there were no significant changes observed in any of the parameters studied. Based on the results obtained in MTT assay, we infer that SMEAF has a significant neuroprotective effect, as it increased the cell viability and exhibited protection to the neuronal cells against TBHP induced oxidative stress. Thus, SMEAF can be suggested for use in the development of herbal drug formulations with neuroprotective potential.


Vascular endothelial growth factor expression in airways of patients with lung cancer: a possible diagnostic tool of responsive angiogenic status on the host side.
We evaluated the expression of vascular endothelial growth factor (VEGF) in airways in patients with lung cancer. BAL fluid (BALF) and plasma samples were obtained from 41 patients with primary lung carcinomas and 7 patients with noncancerous diseases, and were analyzed for VEGF by an enzyme-linked immunosorbent assay. After standardization with the albumin protein levels, the relative intensity (VEGF index) was determined as the ratio of VEGF expression on the disease side to that on the healthy side. In all cases, VEGF concentrations in BALF were greater than those in plasma samples. On the healthy side, the mean value of VEGF in BALF was significantly greater in lung cancer patients than in patients with noncancerous diseases (p = 0.0470). While age, gender, location of cancer (right vs left), histology (adenocarcinoma vs squamous cell carcinoma), and T factor (T1/2 vs T3/4) did not affect the VEGF levels in BALF, the VEGF index was inversely associated with distant metastasis and nodal involvement. The VEGF index of patients in stage I was significantly greater than that of patients in stage IV (p = 0.0308). The VEGF expression in airways is likely to reflect the response to tumor angiogenesis on the host side. Of direct clinical relevance is that the assessment of VEGF concentrations in airways may provide information concerning the dependency of tumor angiogenesis on VEGF, which is variable according to tumor progression.


[Anti-signal recognition particle autoantibody positive myopathy].
Idiopathic inflammatory myopathies are systemic, autoimmune diseases characterized by proximal symmetrical muscle weakness. We review the myositis-associated and myositis-specific autoantibodies, among them the anti-SRP autoantibody. Among those autoimmune myopathy cases, that are associated with autoantibodies, we can detect anti-SRP autoantibody positive myositis cases. We describe the role of signal recognition particle, its structure and role in protein biosynthesis. We review how necrotizing autoimmune myopathy is identified, and the differences from classical polymyositis. The anti-SRP titer correlates with disease activity. We present some cases to show how the disease appears in childhood and also some rare cases from the literature. Finally we present a case to draw attention to the importance of this disease.


Quantitation of VEGFR2 (vascular endothelial growth factor receptor) inhibitors--review of assay methodologies and perspectives.
The introduction of small-molecule tyrosine kinase VEGFR2 (vascular endothelial growth factor receptor) inhibitors has added another dimension in the treatment of several oncology indications as they offer a unique mechanism. The VEGFR2 inhibitors have demonstrated superior benefits in treating certain types of cancer, such as renal cell carcinoma and hepatocellular carcinoma, as a monotherapy option. Many of the approved VEGFR2 inhibitors have also shown promise when used in combination with other anticancer agents. There are numerous bioanalytical methods published for the analysis of VEGFR2 inhibitors in preclinical and clinical samples. This review covers VEGFR2 inhibitors such as sunitinib, sorafenib, pazopanib and JI-101. In addition to providing a comprehensive review of the available methods for the above-mentioned VRGFR2 inhibitors, it also provides information on assays that can simultaneously measure multiple tyrosine kinase inhibitors, including VEGFR2 molecules. Based on the review, the published methodologies using LC/MS-MS or HPLC-UV are adequate for the quantification of the VEGFR2 inhibitors and can easily be established in a modern day bioanalytical laboratory. The availability of a plethora of assays for multiple tyrosine kinase inhibitors makes it easy to analyze a panel of compounds to support either therapeutic drug monitoring and/or clinical pharmacokinetics.


LOCAL CYTONUCLEAR EXTINCTION OF THE GOLDEN-WINGED WARBLER.
I compared the mtDNA compositions of two adjacent populations of Vermivora chrysoptera (golden-winged warbler) at different stages of transient hybridization with its sister species V. pinus (blue-winged warbler). Pinus mtDNA introgresses asymmetrically and perhaps rapidly into chrysoptera phenotypes without comparable reverse introgression of chrysoptera mtDNA into replacing pinus populations. Pinus mtDNA was virtually fixed (98%) in an actively hybridizing lowland population with varied phenotypes. Pinus mtDNA increased from 27% (n = 11) in 1988 to 70% (n = 10) in 1992 in successive samples of a highland population in the initial stages of hybridization. This population comprised mostly pure and slightly introgressed chrysoptera phenotypes. The rapid pace of asymmetrical introgression may be the result of initial invasion of chrysoptera populations by pioneering female pinus and/or an unknown competitive advantage of pinus females and their daughters over chrysoptera females.


Real-Time Sequencing of Mycobacterium tuberculosis: Are We There Yet?
Whole-genome sequencing has taken a leading role in epidemiologic studies of tuberculosis, but thus far, its real-time clinical utility has been low, in part because of the requirement for culture. In their report in this issue, Votintseva et al. (A. A. Votintseva, P. Bradley, L. Pankhurst, C. del Ojo Elias, M. Loose, K. Nilgiriwala, A. Chatterjee, E. G. Smith, N. Sanderson, T. M. Walker, M. R. Morgan, D. H. Wyllie, A. S. Walker, T. E. A. Peto, D. W. Crook, and Z. Iqbal, J Clin Microbiol 55:1285-1298, 2017, https://doi.org/10.1128/JCM.02483-16) present a new method for extracting Mycobacterium tuberculosis DNA directly from smear-positive respiratory samples, making it feasible to generate drug resistance predictions and phylogenetic trees in 44 h with the Illumina MiSeq. They also illustrate the potential for a <24-h turnaround time from DNA extraction to clinically relevant results with Illumina MiniSeq and Oxford Nanopore Technologies MinION. We comment on the promise and limitations of these approaches.


Investigating the effect of longitudinal micro-CT imaging on tumour growth in mice.
The aim of this study is to determine the impact of longitudinal micro-CT imaging on the growth of B16F1 tumours in C57BL/6 mice. Sixty mice received 2 × 10(5) B16F1 cells subcutaneously in the hind flank and were divided into control (no scan), 'low-dose' (80 kVp, 70 mA, 8 s, 0.07 Gy), 'medium-dose' (80 kVp, 50 mA, 30 s, 0.18 Gy) and 'high-dose' (80 kVp, 50 mA, 50 s, 0.30 Gy) groups. All imaging was performed on a fast volumetric micro-CT scanner (GE Locus Ultra, London, Canada). Each mouse was imaged on days 4, 8, 12 and 16. After the final imaging session, each tumour was excised, weighed on an electronic balance, imaged to obtain the final tumour volume and processed for histology. Final tumour volume was used to evaluate the impact of longitudinal micro-CT imaging on the tumour growth. An ANOVA indicated no statistically significant difference in tumour volume (p = 0.331, α = β = 0.1) when discriminating against a treatment-sized effect. Histological samples revealed no observable differences in apoptosis or cell proliferation. We conclude that four imaging sessions, using standard protocols, over the course of 16 days did not cause significant changes in final tumour volume for B16F1 tumours in female C57BL/6 mice (ANOVA, α = β = 0.1, p = 0.331).


The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma.
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.


Anthropometric and biomechanical characteristics of body segments in persons with spinal cord injury.
People with spinal cord injury (SCI) experience bone and muscle loss in their paralyzed limbs that is most rapid and severe in the first 3years after injury. Restoration of mechanical loading through therapeutic physical activity may potentially slow or reverse post-SCI bone loss, however, therapeutic targets cannot be developed without accurate biomechanical models. Obesity is prevalent among SCI population, and it alters body composition and further affects parameters of these models. Here, clinical whole body dual-energy X-ray absorptiometry data from people with acute (n=39) and chronic (n=61) SCI were analyzed to obtain anthropometric parameters including segment masses, center of mass location, and radius of gyration for both obese and non-obese individuals. Chronic SCI was associated with higher normalized trunk mass of 3.2%BW and smaller normalized leg mass of 1.8%BW in males, but no significant changes in segment centers of mass or radius of gyration. People with chronic SCI had 58.6% lean mass in the trunk, compared to 66.6% lean mass in those with acute SCI (p=0.01), with significant changes in all segments. Obesity was associated with an increase in trunk mass proportion of 3.1%BW, proximal shifts in thigh and upper arm center of mass, and changes to thigh and shank radius of gyration. The data presented here can be used to accurately represent the anthropometrics of SCI population in biomechanical studies, considering obesity and injury duration.


Adenocarcinoma of the kidney. III. Histogenesis of renal adenocarcinomas induced in rats by N-(4'-fluoro-4-biphenylyl)acetamide.
The histogenesis of renal adenocarcinoma induced in F344 rats by the carcinogen N-(4'-fluoro-4-biphenylyl)acetamide (FBPA) was described in order to clarify the site of origin of this neoplasm within the nephron. FBPA was added to the diet up to 48 weeks, and the animals were killed at intervals from 4 to 52 weeks after initiation of the carcinogenic diet. As seen by light microscopy, tumors appeared to arise from the pars recta of the proximal tubule in a series of stages progressing from focal hyperplasia with dysplasia to development of small, then large, neoplastic nodules composed of moderately basophilic, closely packed tumor cells arranged in individual aggregates or lobules surrounded by basement membrane-like material. Karyomegaly, cystic lesions, foam cell lesions, interstitial fibrosis, and casts also accompanied tumorigenesis in this animal model.


An Unusual Case of Severe Persistent Neonatal Thrombocytopenia in an Extremely Low Birth Weight, Extreme Preterm Neonate.
Neonatal thrombocytopenia is a common hematological problem but refractory thrombocytopenia is very rare in neonates. A systematic and diligent workup will result in arriving at the proper diagnosis and providing accurate management in rare causes of neonatal thrombocytopenia. We report a case of severe refractory thrombocytopenia in an extremely low birth weight (ELBW)/extreme preterm baby who presented with early onset severe thrombocytopenia associated with anemia and required multiple platelet transfusions. After ruling out COVID-19 infection, sepsis and neonatal alloimmune thrombocytopenia (NAIT), the cause for severe refractory thrombocytopenia was diagnosed as Type II congenital amegakaryocytic thrombocytopenia (CAMT) by bone marrow examination and MPL gene mutation studies.


Metabolism of acetonitrile and propionitrile by Nocardia rhodochrous LL100-21.
Six nitrile compounds and two amide derivatives were degraded by Nocardia rhodochrous LL100-21. Acetonitrile, hydroacrylonitrile, and propionitrile were the best sources of carbon and nitrogen for growth, whereas butenenitrile, succinonitrile, and acetamide supported less growth. Acrylonitrile and acrylamide supported growth but only as a source of nitrogen. Gas chromatography of the culture medium revealed a decrease in acetonitrile with the sequential formation of acetamide and acetic acid. Ammonia was also detected by colorimetric procedures. The enzyme system responsible for the hydrolysis of acetonitrile was shown to be intracellular and inducible. The breakdown of acetonitrile by a crude bacterial extract was a two-step enzymatic hydrolysis with acetamide as the intermediate product and acetic acid and ammonia as the final products. Product formation was stoichiometric with substrate disappearance. When propionitrile was the growth substrate, there was complete conversion of the nitrile to propionic acid and ammonia as the major products. The enzymatic breakdown of the propionitrile, although slower than acetonitrile, yielded the corresponding carboxylic acid and ammonia. Propionamide was produced in very small amounts as an intermediate product.


Muscle imbalance in the aetiology of scoliosis.
At the apex of an idiopathic scoliotic curve there is a greater proportion of "slow twitch" muscle fibres in multifidus on the convex as compared to the concave side. To determine whether this represents a primary muscular imbalance relevant to the aetiology of idiopathic scoliosis or merely a secondary change, the lengths of multifidus on opposite sides of the curve were measured. Multifidus is shorter on the convex side. This is consistent with the theory of primary muscular imbalance, in which the more tonically acting muscle with its higher proportion of "slow twitch" fibres contracts and shortens as the deformity is produced. The paradox of multifidus being shorter on the convex rather than on the concave side is explained by consideration of its action.


Regulation of iodothyronine deiodinase activity as studied in thyroidectomized rats infused with thyroxine or triiodothyronine.
To provide new insights into the in vivo regulation of iodothyronine deiodinases in the different tissues of the rat, we have evaluated the effects on these enzymatic activities of T4 or T3 infusions into thyroidectomized rats. Thyroidectomized rats were infused with placebo, T4, or T3. Placebo-infused intact rats served as euthyroid controls. Plasma and samples of cerebral cortex, brown adipose tissue, pituitary, liver, and lung were obtained after 12-13 days of infusion. Plasma TSH, plasma and tissue T4 and T3, and iodothyronine deiodinase activities were determined. Type II 5'-deiodinase (DII) was increased in cortex, brown adipose tissue, and pituitary from animals infused with placebo. DII activity returned to normal only with T4 infusion, remaining elevated in the animals infused with T3 alone despite normal tissue T3 concentrations. Cortex type III 5-deiodinase was only increased when hyperthyroidism was induced by infusion of T3. Liver type I 5'-deiodinase (DI) paralleled the changes in plasma and tissue T3 regardless of whether T4 or T3 was infused. On the contrary, the increase in lung DI, proportional to the increases in plasma and tissue T3, was higher when T4 was infused. As a rule, the tissues with DII presented a tighter homeostasis in their T3 concentrations than the tissues with DI. In conclusion, the regulation of iodothyronine deiodinases depends on the hormone infused into the thyroidectomized animals and on the tissue in which the deiodinase is studied, demonstrating the existence of tissue-specific regulation of its thyroid hormone concentrations.


Vocal cord paralysis: clinical and electrophysiologic features.
Vocal cord paralysis may occur in isolation or as part of a constellation of findings in neurological disease. We investigated the pathophysiology of these disorders with laryngeal electromyography (LEMG). We studied 44 patients with idiopathic vocal cord paralysis, confirmed by laryngoscopy. The major LEMG finding, present in 29 vocal cords, was evidence of active or chronic denervation in the thyroarytenoid (TA), indicating recurrent laryngeal neuropathy. Denervation of the cricothyroid (CT) in 5 patients indicated superior laryngeal neuropathy. TA and CT involvement in 1 patient indicated proximal laryngeal or vagus nerve damage. LEMG was performed in 48 patients with other laryngeal disorders. LEMG proved to be a safe and effective procedure in the diagnosis of laryngeal neuropathy as distinguished from supranuclear and mechanical disorders of the larynx.


Conjugated linoleic Acid supplementation during pregnancy and lactation reduces maternal high-fat-diet-induced programming of early-onset puberty and hyperlipidemia in female rat offspring.
A maternal high-fat (HF) diet during pregnancy and lactation can result in adverse metabolic and reproductive outcomes in female offspring independent of postnatal diet. Interventions during critical windows of developmental plasticity may prevent developmental programming in offspring. The effects of maternal supplementation with the anti-inflammatory lipid conjugated linoleic acid (CLA) on early-onset puberty, metabolic dysfunction, and estrous cycle dysfunction was assessed. Sprague-Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA). Diets were fed ad libitum for 10 days prior to time mating and throughout gestation and lactation. Offspring plasma/tissues were taken at Day 24 (prepubertal) or Day 150 (adult). Puberty was assessed from Day 26 and estrous cycle from Day 128. Female offspring from HF mothers had lower birth weights but by Postnatal Day 24 had exhibited catch-up growth concomitant with increased fat mass, hyperleptinemia, and dyslipidemia. Maternal CLA supplementation reversed these effects. Early-onset puberty was only observed in HF offspring; this was reversed in HFCLA offspring. In adulthood, despite no evidence of glucose intolerance or altered insulin sensitivity, HF offspring displayed increased fat mass, dyslipidemia, disrupted estrous cyclicity. and hyperleptinemia; this was reversed by maternal CLA supplementation. Data presented in this study demonstrate the importance of diet in women of reproductive age and during pregnancy on reproductive and metabolic parameters in their offspring and that supplementation with CLA during critical windows of development may represent a therapeutic strategy in the prevention of early-life programming of metabolic and reproductive dysfunction.


Approach to optic neuritis: An update.
Over the past few years, there has been remarkable development in the area of optic neuritis. The discovery of new antibodies has improved our understanding of the pathology of the disease. Antiaquaporin4 antibodies and antimyelin oligodendrocytes antibodies are now considered as distinct entities of optic neuritis with their specific clinical presentation, neuroimaging characteristics, treatment options, and course of the disease. Similarly, there has been a substantial change in the treatment of optic neuritis which was earlier limited to steroids and interferons. The development of new immunosuppressant drugs and monoclonal antibodies has reduced the relapses and improved the prognosis of optic neuritis as well as an associated systemic disease. This review article tends to provide an update on the approach and management of optic neuritis.


Evaluation of gene induction of drug-metabolizing enzymes and transporters in primary culture of human hepatocytes using high-sensitivity real-time reverse transcription PCR.
In the present study, the induction of drug-metabolizing enzymes and transporters was evaluated by analyzing mRNA expression in human hepatocytes after exposure to various compounds. The compounds tested included typical enzyme inducers, rifampicin and omeprazole, and controls. All experiments were performed in the presence of 0.1% DMSO. Analysis was performed by the real-time reverse-transcription polymerase chain reaction method (RT-PCR) in the presence of TaqMan probes using an ABI PRISM 7700 Sequence Detector system. A new analytic method to quantify mRNA levels in small numbers of human hepatocytes has been developed for phase I enzymes, phase II enzymes, and transporters. The levels of CYP1A1, CYP2B6, CYP2C8, CYP3A4, CYP3A5, ADH3, and ABCG1 mRNA in human hepatocytes increased after exposure to rifampicin. The levels of CYP1A1, CYP2B6, CYP3A4, CYP3A5, and ABCG1 mRNA recovered after a change to media without rifampicin. The levels of CYP1A1, CYP1A2, CYP1B1, ALDH3, and ALDH6 mRNA increased after exposure to omeprazole, and recovered after a change to media without omeprazole. On the other hand, the levels of ADH3 and ABCB4 mRNA decreased after exposure to omeprazole, and recovered after a change to media without omeprazole. In conclusion, these results demonstrate the applicability of quantitative real-time RT-PCR to the evaluation of the gene induction and recovery of drug-metabolizing enzymes and transporters after exposure to drugs in human hepatocytes.


The interaction of endosulfan with the Collembolan, Proisotoma minuta (Tullberg): toxicity, the effects of sub-lethal concentrations and metabolism.
An increased level of the Collembolan, Proisotoma minuta Tullberg was found in the cotton-growing areas of New South Wales, Australia. They were regularly exposed to endosulfan, a highly insecticidal compound. Toxicity, sub-lethal effects and metabolism of endosulfan were studied in P minuta that had been successfully maintained in a plaster of Paris and charcoal mixture substrate with freeze-dried yeast as a food. The 168-h LD50 values were 0.011, 0.049 and 0.055 mg liter(-1) for alpha- and beta-endosulfan and endosulfan sulfate, respectively. When P minuta were exposed to non-lethal concentrations of the endosulfans, egg production was inhibited. On recovery from the toxic effects of the endosulfans they resumed production of viable eggs. Conversion of alpha- and beta-endosulfan to endosulfan sulfate was found and the endosulfan sulfate could be further metabolized. The rate of metabolism of alpha-endosulfan was greater than that of beta-endosulfan and the product of endosulfan sulfate metabolism was not identified.


Micronutrient supplementation in maintenance haemodialysis patients enhances activity of antioxidant enzymes.
Haemodialysis patients are exposed to high levels of oxidative stress, perhaps contributing to increased rates of cardiovascular and malignant disease. In this context, the body's defence mechanisms against oxidative insult, including activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), are known to be deranged. This randomised double-blind study assessed the effects of a novel micronutrient cocktail containing physiological doses of antioxidant vitamins and trace minerals on antioxidant enzyme activity in maintenance haemodialysis. Thirty-seven patients were randomised to receive placebo or micronutrient. SOD and GPx activity was analysed at baseline and after 6 months of treatment. SOD levels did not change in the treatment group but fell significantly (p=0.0443) in controls, while activity of GPx remained unchanged in controls but rose significantly (p=0.0123) in treated patients. These results are consistent with a beneficial effect of the cocktail on antioxidant enzyme activity and may contribute to an indication for large-scale studies to assess clinical outcome measures.


[Acute hypoxic hypoxia increases lactate concentration in amniotic fluid of rabbits on 27-28th day of pregnancy].
We evaluated the influence of hypoxic hypoxia on lactate, creatinine and urea concentrations in the amniotic fluid (AF) of rabbits on 27-28th day of pregnancy. Rabbits were randomly sudivided into two groups: experimental (n=9) and control (n=6). Rabbits of experimental groups were placed in a hypoxic chamber containing 10±2% oxygen and 90±2% nitrogen for 1 h and then were euthanized, AF was extracted from the amniotic sacs via disposable syringe. Acute hypoxic hypoxia had no effect on the AF volume, increased (1.4-fold) lactate, (1.3-fold) creatinine and (1.1-fold) urea concentrations in AF. In contrast to animals of the control group, lactate concentration in the groups with hypoxic hypoxia correlated with the creatinine (r=0.71, p<0.0001, n=35) and urea concentrations in the AF (r=0.81, p<0.0001, n=35). These results suggest that acute hypoxic hypoxia in late pregnancy causes changes in the biochemical composition of AF; these changes are characterized by high lactate concentrations, and the fetus and uterus can be the source of increased lactate level in AF.


Exercise testing induces fatal thromboembolism from mechanical mitral valve.
Thromboembolism is still one of the most important complications of prosthetic heart valves. Embolism to a major coronary branch is rare, but acute proximal occlusions can be fatal, even when the coronary arteries are otherwise normal and intervention is rapid. We report a fatal complication of an exercise test in a patient who had a St. Jude bileaflet mitral valve. After an exercise test, a 42-year-old woman with a mechanical prosthetic valve had a severe hemodynamic collapse with acute ST segment changes. Coronary angiography showed a totally occluded left main coronary artery with TIMI grade 0 to 1 flow. Rapid injection of contrast material and the passage of a floppy guidewire through the thrombus restored a TIMI grade 3 flow. Angiography showed no coronary atherosclerostic involvement. Despite successful coronary reperfusion, intra-aortic balloon counterpulsation, and intensive medication, the patient died. This case demonstrates that exercise testing should be applied with great caution in patients with prosthetic valves, and only after a careful evaluation of valve function. We recommend transesophageal echocardiography prior to exercise testing in these patients.


A new thinking: extended application of genomic selection to screen multiomics data for development of novel hypoxia-immune biomarkers and target therapy of clear cell renal cell carcinoma.
Increasing evidences show the clinical significance of the interaction between hypoxia and immune in clear cell renal cell carcinoma (ccRCC) microenvironment. However, reliable prognostic signatures based on a combination of hypoxia and immune have not been well established. Moreover, many studies have only used RNA-seq profiles to screen the prognosis feature of ccRCC. Presently, there is no comprehensive analysis of multiomics data to mine a better one. Thus, we try and get it. First, t-SNE and ssGSEA analysis were used to establish tumor subtypes related to hypoxia-immune, and we investigated the hypoxia-immune-related differences in three types of genetic or epigenetic characteristics (gene expression profiles, somatic mutation, and DNA methylation) by analyzing the multiomics data from The Cancer Genome Atlas (TCGA) portal. Additionally, a four-step strategy based on lasso regression and Cox regression was used to construct a satisfying prognostic model, with average 1-year, 3-year and 5-year areas under the curve (AUCs) equal to 0.806, 0.776 and 0.837. Comparing it with other nine known prognostic biomarkers and clinical prognostic scoring algorithms, the multiomics-based signature performs better. Then, we verified the gene expression differences in two external databases (ICGC and SYSU cohorts). Next, eight hub genes were singled out and seven hub genes were validated as prognostic genes in SYSU cohort. Furthermore, it was indicated high-risk patients have a better response for immunotherapy in immunophenoscore (IPS) analysis and TIDE algorithm. Meanwhile, estimated by GDSC and cMAP database, the high-risk patients showed sensitive responses to six chemotherapy drugs and six candidate small-molecule drugs. In summary, the signature can accurately predict the prognosis of ccRCC and may shed light on the development of novel hypoxia-immune biomarkers and target therapy of ccRCC.


Design and initial operation of a two-color soft x-ray camera system on the Compact Toroidal Hybrid experiment.
A multi-camera soft x-ray diagnostic has been developed to measure the equilibrium electron temperature profile and temperature fluctuations due to magnetohydrodynamic activity on the Compact Toroidal Hybrid experiment. The diagnostic consists of three separate cameras each employing two 20-channel diode arrays that view the same plasma region through different beryllium filter thicknesses of 1.8 μm and 3.0 μm allowing electron temperature measurements between 50 eV and 200 eV. The Compact Toroidal Hybrid is a five-field period current-carrying stellarator, in which the presence of plasma current strongly modifies the rotational transform and degree of asymmetry of the equilibrium. Details of the soft x-ray emission, effects of plasma asymmetry, and impurity line radiation on the design and measurement of the two-color diagnostic are discussed. Preliminary estimates of the temperature perturbation due to sawtooth oscillations observed in these hybrid discharges are given.


[Serologic evaluation of the molecular forms of choriogonin during the course of pregnancy].
Antigenous (antibody binding) activity in vitro and disaggregating (absolute and relative) activity of choriogonin in the urine were studied simultaneously during pregnancy by means of the serologic tests--antibody neutralization and red cell disaggregation. The time course of choriogonin activity in the urine, which reflects variations in the molecular parameters of choriogonin in pregnancy indicates that it may be detected in the urine in the form of isohormones. Variations in the molecular parameters of choriogonin during pregnancy differ from those in its antibody binding activity. Application of serodiagnostic approaches may be valuable in determining the time course of the molecular parameters of hormones.


[Results of combined chemotherapy and local ophtalmic therapy of children with intraocular retinoblastoma].
Until recently chemotherapy in retinoblastoma was used as adjuvant therapy after enucleation in cases with extraretinal spread of the disease (weal extension, orbital extension, neoplastic infiltrates of the optic nerve at resection line, intracranial metastasis and generalized disease). Recent experience has proved that use of chemotherapy for intraocular retinoblastoma before local treatment (so called "chemoreduction") has allowed not only to decrease the number of enucleations and indications for external beam irradiation or limit the extension of local therapy; but also to increase the chances for vision preservation and to decrease the risk of severe complications. Twenty children aged 0,5-96 months (with lesions in 29 eyes) in whom intraocular retinoblastoma was diagnosed between January 1996 and June 2000, were the subject of this study. Among 29 children, in 15 (52%) stage V according to Reese-Ellsworth was established. Enucleation before chemotherapy was necessary in 9 cases, and in two more children the eye had to be removed after 1-2 courses of chemotherapy. In 11 remaining children (with 18 involved eyes) VEC chemotherapy combined with delayed local therapy (cryotherapy, photocoagulation, brachytherapy) was employed. Out of 18 treated cases enucleation could be avoided in 13 (72%), including 12 qualified as Reese-Ellsworth stage II or I. No eye with stage V could be saved. First-line chemotherapy combined with local treatment should be standard treatment for intraocular retinoblastoma groups I and II. More effective therapy is required for advanced cases particularly for Reese-Ellsworth eye group V.


XVI(th) QTLMAS: simulated dataset and comparative analysis of submitted results for QTL mapping and genomic evaluation.
A common dataset was simulated and made available to participants of the XVI(th) QTL-MAS workshop. Tasks for the participants were to detect QTLs affecting three traits, to assess their possible pleiotropic effects, and to evaluate the breeding values in a candidate population without phenotypes using genomic information. Four generations consisting of 20 males and 1000 females were generated by mating each male with 50 females. The genome consisted of 5 chromosomes, each of 100 Mb size and carrying 2,000 equally distributed SNPs. Three traits were simulated in order to mimic milk yield, fat yield and fat content. Genetic (co)variances were generated from 50 QTLs with pleiotropic effects. Phenotypes for all traits were expressed only in females, and were provided for the first 3 generations. Fourteen methods for detecting single-trait QTL and 3 methods for investigating their pleiotropic nature were proposed. QTL mapping results were compared according to the following criteria: number of true QTL detected; number of false positives; and the proportion of the true genetic variance explained by submitted positions. Eleven methods for estimating direct genomic values of the candidate population were proposed. Accuracies and bias of predictions were assessed by comparing estimated direct genomic values with true breeding values. The number of true detections ranged from 0 to 8 across methods and traits, false positives from 0 to 15, and the proportion of genetic variance captured from 0 to 0.82, respectively. The accuracy and bias of genomic predictions varied from 0.74 to 0.85 and from 0.86 to 1.34 across traits and methods, respectively. The best results in terms of detection power were obtained by ridge regression that, however, led to a large number of false positives. Good results both in terms of true detections and false positives were obtained by the approaches that fit polygenic effects in the model. The investigation of the pleiotropic nature of the QTL permitted the identification of few additional markers compared to the single-trait analyses. Bayesian and grouped regularized regression methods performed similarly for genomic prediction while GBLUP produced the poorest results.


Multiplanar and three-dimensional multi-detector row CT of thoracic vessels and airways in the pediatric population.
Multi-detector row computed tomography (CT) has changed the approach to imaging of thoracic anatomy and disease in the pediatric population. At the author's institution, multi-detector row CT with multiplanar and three-dimensional reconstruction has become an important examination in the evaluation of systemic and pulmonary vasculature and the tracheobronchial tree. In some clinical situations, multi-detector row CT with reformatted images is obviating conventional angiography, which is associated with higher radiation doses and longer sedation times. Although multi-detector row CT with multiplanar and three-dimensional reconstruction is expanding the applications of CT of the thorax, its role as a diagnostic tool still needs to be better defined. The purposes of this article are to describe how to perform multi-detector row CT with multiplanar and three-dimensional reconstruction in young patients, to discuss various reconstruction techniques available, and to discuss applications in the evaluation of vascular and airways diseases.


Barsine paraprominens sp. nov. (Lepidoptera, Erebidae, Arctiinae, Lithosiini) from China, with notes on four new records.
New information of the genus Barsine Walker, 1854 is provided. A new species, Barsine paraprominens Huang Wang sp. nov. is described from Pailong, SE Xizang. Four species: B. pseudomactans Volynkin Černý, 2016, B. anomala (Elwes, 1890), B. pseudocardinalis Volynkin Černý, 2017 and B. ustrina Černý, 2009 are recorded as new to China. The female genitalia of B. ustrina are described for the first time. Adults and genitalia of all species mentioned are illustrated.


Synaptogenesis Is Modulated by Heparan Sulfate in Caenorhabditis elegans.
The nervous system regulates complex behaviors through a network of neurons interconnected by synapses. How specific synaptic connections are genetically determined is still unclear. Male mating is the most complex behavior in Caenorhabditis elegans It is composed of sequential steps that are governed by > 3000 chemical connections. Here, we show that heparan sulfates (HS) play a role in the formation and function of the male neural network. HS, sulfated in position 3 by the HS modification enzyme HST-3.1/HS 3-O-sulfotransferase and attached to the HS proteoglycan glypicans LON-2/glypican and GPN-1/glypican, functions cell-autonomously and nonautonomously for response to hermaphrodite contact during mating. Loss of 3-O sulfation resulted in the presynaptic accumulation of RAB-3, a molecule that localizes to synaptic vesicles, and disrupted the formation of synapses in a component of the mating circuits. We also show that the neural cell adhesion protein NRX-1/neurexin promotes and the neural cell adhesion protein NLG-1/neuroligin inhibits the formation of the same set of synapses in a parallel pathway. Thus, neural cell adhesion proteins and extracellular matrix components act together in the formation of synaptic connections.


Sexual Abuse is Associated with Negative Health Consequences among High-risk Men who have Sex with Men.
This study evaluated whether a history of sexual abuse could differentiate negative health consequences among men who have sex with men (MSM; N=148) enrolled in a risk counseling program. Over half (51.4%) reported an experience of sexual abuse. A history of sexual abuse was associated with increased psychological distress, increased rates of alcohol (AOR = 2.91; p < .01) and/or drug abuse (AOR = 2; p < .01) treatment, increased risk of housing instability (AOR = 2.13; p < .05), and increased risk for suicidality (AOR = 4.3; p < .001). Findings demonstrate that screening for sexual abuse may be useful in determining the service needs of high-risk MSM.


An audit of the tetanus immunisation status of plastic surgery trauma and burns patients.
This study audits the tetanus immunisation management of plastic surgery trauma patients by their referring Accident and Emergency departments, and compares this to nationally published guidelines. We assessed 269 burns and trauma patients, referred from across South Wales, using a questionnaire together with their Accident and Emergency notes or letter. The precise question(s) that had been asked regarding the tetanus immunisation status of the patient, and the immunisation management based on the results of those questions, were recorded. The accurate tetanus immunisation status of the patient was established, the wound was assessed and further management was given as indicated. Only 16 patients had been asked whether they had received a course of tetanus, and 41 patients were not questioned about their tetanus immunisation status by the referring Accident and Emergency department. As a consequence of more accurate questioning, 73 patients (27%) required further action after their arrival in the Plastic Surgery unit. This audit has demonstrated that the management of tetanus immunoprophylaxis in plastic surgery trauma patients cannot be confidently left to the referring Accident and Emergency department but should form an integral part of the treatment at the admitting unit.