Monoclonal antibody to a human osteogenic sarcoma cell line.
Monoclonal antibodies against a human osteogenic sarcoma cell line were prepared by production of a somatic cell hybrids between the spleen cells from U-393OS--immunized mice and the mouse myeloma cells SP2/0. From 7 producing and well-growing clones only one--B-0S12--produced antibodies, reactive preferentially with osteosarcoma cells as identified by binding second antibodies and 125I-labeled Protein A. This antibody was tested against a panel of normal and tumor cell targets to determine the pattern of the antigen detected. The monoclonal antibody reacted strongly against U-3930S cells and another human sarcoma in vitro and more weakly against human fibroblasts, peripheral lymphocytes, red blood cells and was negative against mouse fibroblasts. When tested against a panel of unrelated human tumor cell lines, B-0S12 antibody was positive with melanoma cells and negative with cells from bladder, cervix and mammary carcinoma. These cross reactions suggested, that the antibody is reactive with a protein, expressed on different tumor types. This protein is not expressed on the cell surface and is probably associated with cytoskeleton, as revealed by immunofluorescence experiments. Western-blot analysis of a cytoskeletal preparation of U-3930S cells suggests, that B-0S12 antibody recognizes a protein with Mr 55 kD. Further studies are needed to characterize the molecules, carrying the epitope, identified by this monoclonal antibody.


Report of the workshop on the use of chemoprophylaxis in the control of leprosy held in Amsterdam, The Netherlands on 14 December 2006.
In recent years a number of field trials have been carried out to assess the efficacy of rifampicin chemoprophylaxis for the prevention of leprosy in contacts of leprosy patients. Results from these trials are now being analysed and published. The aim of this one-day workshop was to review current evidence and discuss potential future courses of action with regard to the use of chemoprophylaxis to prevent leprosy. During the morning session the current evidence for the contribution that chemoprophylaxis may make to leprosy prevention was presented, both the results from trials (abstracts in section 1) and the outcome of modelling (abstract in section 2); in addition presentations were given on different aspects of the use of antibiotics for chemoprophylaxis (abstracts in section 3). The afternoon was devoted to discussions, a summary of which is presented in section 4 of this report. The conclusions and recommendations are given in section 5.


Selective increase in hydrogen peroxide resistance of a coagulase-positive staphylococcus.
Staphylococcus culture 105B was serially treated with 0.05% hydrogen peroxide at 54.4 C or without hydrogen peroxide at this temperature to determine changes in resistance to these conditions and in catalase activity of the surviving populations. Resistance of the final surviving populations to H(2)O(2) treatment and to heat treatment without H(2)O(2) was 5.6 and 4.5 times greater, respectively, than the parent culture. Catalase activities of the cell-free extracts of survivors of the H(2)O(2) treatments and of the heat treatments were 33.56 and 2.69 times greater, respectively, than the control. The untreated control cultures grew in Peptonized Milk (Difco), but addition of sodium pyruvate to the medium was necessary to support growth of survivors.


The emerging field of polygenic risk scores and perspective for use in clinical care.
Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes and cancer. Genome-wide association studies (GWAS) have been invaluable in identifying single-nucleotide polymorphisms (SNPs) associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article, we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: informing population screening programs, guiding therapeutic interventions, refining risk for families at high risk, and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also highlighted.


Only one out of the three strong ribosomal binding sites of the early region of bacteriophage T7 exhibits high translational efficiency in fragments of about 30 base pairs.
Within the early region of bacteriophage T7 three genes, 0.3, 1 and 1.3, are most efficiently expressed. They belong to the strongest initiation signals of Escherichia coli. In the T7 wild-type situation the proteins are produced with a molar ratio of gene 1:1.3:0.3 protein = 1:3.9:9.7. DNA fragments of about 30 base pairs comprising the ribosomal binding sites (RBS) of these genes were synthesized and cloned into derivatives of the pDS1 vector ribosomal binding sites (RBS) of these genes were synthesized and cloned into two derivatives of the pDS1 vector just upstream of the mouse dihydrofolate reductase gene. Although all tested RBS fragments contained an initiation triplet, a Shine-Dalgarno sequence and some nucleotides upstream and downstream of this region, only the gene 1.3 RBS fragment showed high efficiency whereas those of genes 0.3 and 1 were at the border of significance. The amount of synthesized mRNA was about the same for all three constructs. A major influence of vector-derived sequences on the RBS activity could be ruled out. The high translational activity of the short 1.3 gene RBS seems to be largely due to its primary structure. The other two RBSs studied require much longer sequences for high activity.


Normal haematological and biochemical values for the swamp buffalo (Bubalus bubalis) in Australia.
Blood samples were collected from 24 immature male, 55 immature female and 99 mature female water buffalo kept at an experimental farm in the Northern Territory. Haematological analysis was performed on blood collected in dipotassium--ethylene diamine tetra acetic acid while biochemical analysis was performed on serum and plasma (for glucose) samples. Haematological values of mature buffalo were similar to those recorded for swamp buffalo in Malaysia. Blood cell appearances were similar to those reported for adult Indian river buffalo though values recorded for red cell components were higher. Statistical analysis revealed no significant differences between immature male and female buffalo. Red cell components, eosinophils, total plasma and serum proteins, albumin, gamma globulins, inorganic phosphate and the enzyme gamma-glutamyl transferase were significantly higher for mature female buffalo when compared to immature females. Reasons for the differences were not fully determined but the effect of age and nutritional status in combination with a variable period of domestication were considered.


Reducing Exact Two-Component Theory for NMR Couplings to a One-Component Approach: Efficiency and Accuracy.
The self-consistent and complex spin-orbit exact two-component (X2C) formalism for NMR spin-spin coupling constants [ J. Chem. Theory Comput. 17, 2021, 3874-3994] is reduced to a scalar one-component ansatz. This way, the first-order response term can be partitioned into the Fermi-contact (FC) and spin-dipole (SD) interactions as well as the paramagnetic spin-orbit (PSO) contribution. The FC+SD terms are real and symmetric, while the PSO term is purely imaginary and antisymmetric. The relativistic one-component approach is combined with a modern density functional treatment up to local hybrid functionals including the response of the current density. Computational demands are reduced by factors of 8-24 as shown for a large tin compound consisting of 137 atoms. Limitations of the current ansatz are critically assessed for Sn, Pb, Pd, and Pt compounds, i.e. the one-component treatment is not sufficient for tin compounds featuring a few heavy halogen atoms.


Fibrinogen is associated with EGFR mutation status and lymphatic metastasis in non-small cell lung cancer.
In the previous decade, tyrosine kinase inhibitors (TKIs) have demonstrated significant effects in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. However, sufficient tumor tissue for genetic testing cannot always be obtained in clinical settings. The present study evaluated whether fibrinogen may assist in predicting the EFGR mutation status in patients with NSCLC. Between January 2010 to December 2013, 303 patients with NSCLC underwent EGFR mutation testing. Plasma fibrinogen was acquired prior to treatment, and the associations between fibrinogen, EGFR mutation status and clinical features were assessed. A multivariate analysis and a receiver operator characteristic curve analysis were performed to identify the potential value of fibrinogen in predicting EGFR mutation status. The proportion of patients with hyperfibrinogenemia was significantly higher in N2 and N3 stages compared with N0 and N1 stages, 45.2 and 56.5 vs. 29.2 and 36.0%, respectively (P=0.001), and higher in the M1 stage compared with the M0 stage, 47.9 vs. 35.2%, respectively (P=0.025) (Stages according to the American Joint Committee of Cancer, 7th edition). Plasma fibrinogen levels were significantly lower in patients with EGFR mutations compared with the wild-type EGFR gene, 2.95 g/l (range, 0.84 -8.61 g/l) vs. 3.57 g/l (range, 1.38-7.44 g/l), respectively (P<0.001). In the multivariate analysis, logistic regression was utilized and the fibrinogen odds ratio (OR), 2.5, confidence intervals (CI) 1.53-4.51 (P<0.001) and smoking status OR 5.07, CI 3.01-8.53 (P<0.001), for which the area under the curve was 0.75, were revealed to be independent predictive factors. Hyperfibrinogenemia is associated with metastasis of the distant organs, but also metastasis of the lymphatic tissue. In addition, a multivariate model based on fibrinogen and smoking history may be used as a predictive marker of EGFR mutation status in patients with NSCLC.


Antibody responses to recombinant and plasma derived hepatitis B vaccines.
The antibody response to hepatitis B surface antigen (anti-HBs) induced in 25 recipients of a recombinant hepatitis B vaccine derived from yeast was compared with that induced in 25 recipients of a vaccine prepared from hepatitis B surface antigen (HBsAg) derived from plasma. Anti-HBs affinity and specificity were compared using assays of antibody affinity with two different antigens, a complex of the major polypeptide of HBsAg (p25; molecular weight 25 000 daltons) covalently linked to its glycosylated form (gp30) prepared from native purified HBsAg, and a cyclical synthetic peptide representing amino acid residues 139-147 of the major polypeptide of HBsAg and known to represent a major part of an a determinant. There was no difference in anti-HBs affinity or molar antigen binding sites of the antibody measured with either antigen between the two groups. All subjects in both groups produced antibody that bound to the gp30/p25 complex antigen, whereas 22 of the recipients of the plasma derived vaccine compared with 24 of those receiving the yeast derived vaccine produced antibodies that bound to the cyclical synthetic peptide 139-147. These results support the finding of similar levels of anti-HBs, measured by commercial solid phase radioimmunoassay, in the two vaccine groups after three doses of vaccine. These results show no significant difference in the quantity, quality, or specificity of the anti-HBs response induced by the recombinant hepatitis B vaccine and the plasma derived hepatitis B vaccine.


Presence of the organ-specific 'microsomal' autoantigen on the surface of human thyroid cells in culture: its involvement in complement-mediated cytotoxicity.
The presence of organ-specific cell surface-reactive antibodies in sera of patients with autoimmune thyroid diseases (ATD) has been detected by indirect immunofluorescence on viable blood group O normal thyroid cultures. The cell surface determinants involved in this reaction have been identified as the thyroid 'microsomal' antigen which is thus also represented on the outer surface of the plasma membrane. The reactivity persists when F(ab')2 fragments from positive sera are used. Non-thyroid cells present in the monolayers, as well as human adrenal or fibroblast cultures, do not show positive staining. Human thyroid cells progressively lose both cell surface and intracytoplasmic antigenic components during the first week of culture. The exposure and reactivity of this antigen on the cell surface do not depend upon unmasking effects of proteolytic enzymes used for dispersal of the cells. The 'microsomal' antigen on the cell surface is also involved in the complement-mediated cytotoxic effect of sera from ATD patients on freshly dispersed thyroid cells. Thyroglobulin antibodies failed to stain viable thyroid monolayers, even when these were previously incubated with purified human thyroglobulin, indicating that this protein or possible receptors for it cannot be detected on the cell surface under these conditions. Similarly, some thyrotoxicosis sera containing thyroid-stimulating but not microsomal antibodies, gave negative reactions on viable cultures.


[Survey of fungemia cases during the past seventeen years at Teikyo University Hospital].
Fungi were isolated from 642 cases (3.5%) of 18,403 blood samples at Teikyo University Hospital during the 17-years period between 1979 and 1995. The number of fungemia cases began to increase around 1985, reached a peak in 1988, and since then, it has been gradually decreasing. The fungal species of isolates were: (1) Candida albicans in 224 cases (34.9%), (2) C. parapsilosis in 149 cases (23.2%), (3) C. tropicalis in 87 cases (13.6%), (4) C. glabrata in 65 cases (10.1%), (5) Hansenula anomala in 58 cases (9.0%), (6) C. guilliermondii in 24 cases (3.7%), (7) C. famata in 14 cases (2.1%), (8) Trichosporon beigelii in 11 cases (1.7%), (9) C. inconspicua in 5 cases (0.8%) and C. lusitaniae in 5 cases (0.8%), and other yeasts in 33 causes (5.1%). The number of isolates of C. albicans has been decreasing since 1989, concomitant with the clinical introduction of fluconazole in this hospital. However, the number of fluconazole-insusceptible fungi such as non-albicans Candida and Trichosporon spp. has increased. Fungemia cases infected concomitantly or sequentially with two or more different fungal species have been found occasionally since 1983 and have shown a high mortality rate. The spectrum of the causative organisms of fungemia appears to be, at least, partly influenced, by the usage of antifungal agents, particularly fluconazole.


Long-term feeding of formulas high in linolenic acid and marine oil to very low birth weight infants: phospholipid fatty acids.
Red blood cell (RBC) phospholipids of infants fed human milk compared with formula have more arachidonic acid (AA) and docosahexanoic acid (DHA). The addition of low levels of marine oil to infant formula with 0.6 to 2.0% alpha-linolenic acid (LLA, 18:3n-3) prevented declines in DHA in formula-fed infants; however, the feeding trials were short (4 to 6 wk), LLA concentrations were low compared with current formulas (3.0 to 5.0% LLA), and the formulas were unstable. Trials with stable formulas were necessary to determine if dietary DHA could maintain phospholipid DHA after discharge from the hospital and, in fact, if it was necessary with higher intakes of LLA. The results of acute (4 wk) and extended (to 79 wk postconception) feeding of such formulas on RBC and plasma phospholipid AA and DHA are reported here. Control formulas were identical to commercially available formulas. Experimental formulas differed only in the addition of small amounts of marine oil. DHA in RBC and plasma phosphatidylethanolamine (PE) declined during four weeks of feeding but not if marine oil provided DHA (0.2% or 0.4%) and plasma phospholipid AA (g/100 g) decreased with time and marine oil feeding. Extended feeding with marine oil accounted for half the DHA in RBC and plasma phosphatidylethanolamine at equilibrium; however, RBC (g/100 g) and plasma AA (g/100 g; mg/L plasma) decreased progressively until late infancy and were depressed further by marine oil.(ABSTRACT TRUNCATED AT 250 WORDS)


[Relation of mechanical noise in the rat papillary muscle to the level of its contraction].
The existence of mechanical noise (MN) has been demonstrated in isolated papillary muscles of rats at rest. The mean amplitude of the MN was about 1 mg, the mean frequency 1.5 Hz (t 22 degrees C). A good agreement was found between the MN amplitude and the contracture level of the muscle. However, during long contractures, the correlation between the noise and contracture magnitude was disturbed. There was no relationship between the MN amplitude and contracture magnitude during exposures inducing metabolic alterations (hypoxia, NaCN) and upsetting the work of the sarcoplasmic reticulum (caffeine). It is believed that the MN amplitude is in a good agreement with the contracture magnitude and, therefore, with the concentration of intracellular Ca2+, if the sarcoplasmic reticulum and contractile elements of the cells are intact.


Recent self-harm and psychological measures in the emergency department.
The assessment of self-harm risk is a common, difficult, and perplexing task for many physicians, especially those working in emergency departments (ED). Attempts have been made to determine objective methods for assessing patients with suicidal ideation or self-harm though there is still a lack of knowledge about objective assessments of these patients. A study was conducted where 181 suicidal patients were enrolled in two EDs within the city of Edmonton, Canada. Initial interviews were conducted in the ED which collected basic demographics and medical history as well as psychometric measures including the Beck Hopelessness Scale, Barratt Impulsiveness Scale, Brief Symptom Inventory, Drug Abuse Screening Test 10, and CAGE questionnaire. The results of these measures were compared between those who presented to the ED with self-harm and those who presented only with ideation. Those with recent self-harm scored lower on many of the scales and subscales of distress and impulsivity measured compared to those with no recent self-harm. Possible explanations for this difference include differences in psychological traits between the two groups and possible cathartic effects of self-harm. The lower scores obtained by those that present with self-harm may complicate attempts to use psychometric tools to determine future self-harm risk.


Overuse wrist injuries in adolescent platform and springboard divers.
To investigate overuse wrist injuries in adolescent divers using magnetic resonance imaging (MRI). The bilateral wrists (76 wrists) of 38 professional divers were examined by MRI; 42 wrists with pain were placed in the symptomatic group, and 34 wrists without pain were placed in the asymptomatic group. Two experienced radiologists assessed the wrist injuries. Chi‑square test was used to compare the difference in injuries between the two groups. Subchondral osteosclerosis was observed in 47.62% of symptomatic wrists and 52.94% of asymptomatic wrists. Distal radial epiphyseal plate injury was detected in 42.86% of symptomatic wrists and 11.76% of asymptomatic wrists. Triangular fibrocartilage complex injury was observed in 19.04% of symptomatic wrists and 8.82% of asymptomatic wrists. Bursae around the wrist were observed in 21.42% of symptomatic wrists and 17.64% of asymptomatic wrists. The incidence of distal radial epiphyseal plate injury was higher in the symptomatic group than in the asymptomatic group (P = 0.007), however, other injuries were not statistically different between the two groups (P > 0.05). This study demonstrated that adolescent divers had various wrist injuries, and distal radial epiphyseal plate injury was more common in the symptomatic wrist; these injuries show no specific clinical symptoms and are easily overlooked.


Quantification of wild-type mitochondrial DNA and its 4.8-kb deletion in rat organs.
Oxidative damage to mitochondrial DNA (mtDNA) is considered a major contributor in aging. An age-dependent increase of oxidative damage and of the quantity of partially deleted mtDNA was reported for several rat and human organs. Here, a systematic investigation of ten different tissues and organs of 20-months-old rats was performed. The amount of mtDNA and age-dependent 4.8 kb deletion (delta mtDNA4834) was determined by competitive polymerase chain reaction, along with the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSHPx). The data were related to the corresponding metabolic rates. MtDNA content was highest in heart and lowest in spleen. delta mtDNA4834 was detected in all ten tissues and organs, and its amount was highest in liver and lowest in intestine. In heart, lung, muscle, and bone-marrow the deletion could not be quantified because of a point mutation, an A-->T transition at position 8107. Activities of SOD and GSHPx were highest in liver and lowest in intestinal mucosa. A negative correlation between mtDNA content and delta mtDNA4834, and a positive correlation between metabolic rate, GSHPx, and the deletion was found. These results suggest that the occurrence of delta mtDNA4834 in rat is related to oxidative stress.


[Studies on herpes simplex virus thymidine kinase gene and GCV system for treatment of human bladder carcinoma].
To investigate the antitumor effect of herpes simplex virus thymidine kinase (HSV-TK) gene/ganciclovir (GCV) system on human bladder cancer cells (T24), a retroviral vector with the gene (pLXSN-TK) was transduced into the packaging cell line PA317. A nude mouse model with human T24 was established to examine the in vivo efficacy. The animals were randomly assigned to two treatment groups and two control groups. Treatment I and Treatment II were given in situ injection of virus suspension and PA317/TK respectively, followed by treatment with GCV for 14 days. Control I and Control II were given in situ injection of same volume of normal saline and PA317/TK respectively, followed by treatment with GCV and with normaly physiologic saline respectively for 14 days. The weight and the volume of tumor were measured. HSV-TK mRNA expression was determined by hybridization in situ. Cell apoptosis was evaluated by flow cytometry (FCM) and termininal deoxynucleofidyl transferase-mediated dUTP nick end labelling (TUNEL) technique. The results showed: (1) In vivo, the retrovirus transferred HSV-TK gene can be transduced into human bladder cancer cell T24. The tumors in T24 mice with TK gene transduced were much smaller than those in other groups. (2) After treatment with HSV-TK/GCV, the phenomenon of bladder ceancer cell apoptosis was more conspicuous as compared with that of other groups. Therefore, HSV-TK/GCV system can suppress the growth of T24 in vivo and may relate to "bystander effect". It could be a valuable therapy for human bladder cancer.


Application of a cephalometric method to the temporomandibular joint in patients with or without alteration in the orientation of the mandibular condyle axis.
In a prior study, the spatial relationship of the mandibular condyle was studied through a cephalogram based on laminographies of the temporomandibular joint (TMJ). The present method was developed with the aim of analyzing TMJ morphology and the spatial relationship of the mandibular head within the mandibular fossa, considering references far from these structures, as they may suffer shape alterations. This study was conducted in view of the importance of the study of morphology and the hard structures relationship, which constitutes the temporomandibular joint. Its purpose is to validate a new TMJ cephalogram method by analyzing joints with and without alterations in the orientation of the condylar axis growth. Sixty joints were studied through laminographies in maximal occlusion, examining those joints with and without alterations in the orientation of the axis during condylar growth for subsequent analysis. Results showed that those joints were in a posterior position and rotation of the mandibular head, and that they presented a greater inclination in the articular eminence compared to joints without alterations in the axis orientation. Moreover, a new cephalometric method could be validated, demonstrating that changes in the condylar axis orientation imply pathology; they could also be correlated with changes in the condylar position and in the glenoid fossa morphology.


Early-onset severe preeclampsia by first trimester pregnancy-associated plasma protein A and total human chorionic gonadotropin.
This study aims to evaluate the relationship between early-onset severe preeclampsia and first trimester serum levels of pregnancy-associated plasma protein A (PAPP-A) and total human chorionic gonadotropin (hCG). The association between early-onset severe preeclampsia and abnormal levels of first trimester PAPP-A and total hCG in maternal serum were measured in a sample of singleton pregnancies without chromosomal defects that had integrated prenatal serum screening in 2009 and 2010 (n = 129,488). Logistic binomial regression was used to estimate the relative risk (RR) of early-onset severe preeclampsia in pregnancies with abnormal levels of first trimester PAPP-A or total hCG as compared with controls. Regardless of parity, women with low first trimester PAPP-A or high total hCG were at increased risk for early-onset severe preeclampsia. Women with low PAPP-A (multiple of the median [MoM] ≤ the 10th percentile in nulliparous or ≤ the 5th percentile in multiparous) or high total hCG (MoM ≥ the 90th percentile in nulliparous or ≥ the 95th percentile in multiparous) were at more than a threefold increased risk for early-onset severe preeclampsia (RR, 4.2; 95% confidence interval [CI], 3.0-5.9 and RR, 3.3; 95% CI, 2.1-5.2, respectively). Routinely collected first trimester measurements of PAPP-A and total hCG provide unique risk information for early-onset severe preeclampsia.


Experimental realization of directed percolation criticality in turbulent liquid crystals.
This is a comprehensive report on the phase transition between two turbulent states of electroconvection in nematic liquid crystals, which was recently found by the authors to be in the directed percolation (DP) universality class [K. A. Takeuchi, Phys. Rev. Lett. 99, 234503 (2007)]. We further investigate both static and dynamic critical behaviors of this phase transition, measuring a total of 12 critical exponents, 5 scaling functions, and 8 scaling relations, all in full agreement with those characterizing the DP class in 2+1 dimensions. Developing an experimental technique to create a seed of topological-defect turbulence by pulse laser, we confirm in particular the rapidity symmetry, which is a basic but nontrivial consequence of the field-theoretic approach to DP. This provides a clear experimental realization of this outstanding truly out-of-equilibrium universality class, dominating most phase transitions into an absorbing state.


The NPC1L1 Gene Exerts a Notable Impact on the Reduction of Low-Density Lipoprotein Cholesterol in Response to Hyzetimibe: A Factorial-Designed Clinical Trial.
Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of NPC1L1 gene variation on LDL-C reduction. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the NPC1L1 gene expression and the reduction of LDL-C. Results: In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (-23.99%) than either the GG (-16.45%, p < 0.01) or GC (-13.02%, p < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. -45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%. Conclusion: The g1679C > G SNP in the NPC1L1 gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351].


[Graphology in the psychological approach of candidates for esthetic surgery. Report of 45 cases].
45 patients considering cosmetic surgery underwent two graphological tests; the first prior to their operation, the second approximately six months afterwards. The results of these tests show that the patients have a number of elements in common depending on the type of operation performed and reveal several psychological aspects specific to subjects likely to envisage cosmetic surgery. However, the second graphological analysis showed no significant changes in any of the patients. The tests are simple and easily accepted by prospective subjects and enable a better psychological approach between patient and practicians.


Three-body dynamics in a (1+1) -dimensional relativistic self-gravitating system.
The results of our study of the motion of a three particle, self-gravitating system in general relativistic lineal gravity is presented for an arbitrary ratio of the particle masses. We derive a canonical expression for the Hamiltonian of the system and discuss the numerical solution of the resulting equations of motion. This solution is compared to the corresponding nonrelativistic and post-Newtonian approximation solutions so that the dynamics of the fully relativistic system can be interpreted as a correction to the one-dimensional Newtonian self-gravitating system. We find that the structure of the phase space of each of these systems yields a large variety of interesting dynamics that can be divided into three distinct regions: annulus, pretzel, and chaotic; the first two being regions of quasiperiodicity while the latter is a region of chaos. By changing the relative masses of the three particles we find that the relative sizes of these three phase space regions changes, and that this deformation can be interpreted physically in terms of the gravitational interactions of the particles. Furthermore, we find that many of the interesting characteristics found in the case where all of the particles share the same mass also appear in our more general study. We find that there are additional regions of chaos in the unequal mass system which are not present in the equal mass case. We compare these results to those found in similar systems.


Pro-inflammatory cytokines negatively regulate PPARγ mediated gene expression in both human and murine macrophages via multiple mechanisms.
PPARγ is a lipid activated transcription factor that connects lipid metabolism and immune function. It is known that anti-inflammatory cytokines, such as IL-4 that mediates the differentiation of alternatively activated macrophages, positively modulate PPARγ at three levels: by (1) increasing its expression (2), initiating a complex formation with STAT6 enhances its transcriptional activity and (3) increasing endogenous ligand production. On the other hand, PPARγ is known to inhibit inflammatory processes via transrepression. However, the impact of a pro-inflammatory cytokine milieu on PPARγ transcriptional activity in macrophages is less understood. We hypothesized that pro-inflammatory cytokines, such as IFNγ and TNFα negatively regulate PPARγ activity and sought to test this within human and murine macrophage models using both global and single target gene expression analysis. We found that IFNγ/TNFα inhibited PPARγ expression in human CD14+ monocytes derived macrophages and mouse bone marrow derived macrophages, but not in macrophages originating from CD34+ stem cells or Thp-1 monocytic cells. Irrespective of the model system, the ability of PPARγ to regulate gene expression was inhibited. Moreover, we demonstrated that in Thp-1 cells PPARγ in vitro DNA binding remained unchanged following IFNγ/TNFα pre-treatment. Taken together, our data suggest that pro-inflammatory conditions inhibit PPARγ activity at the gene expression level and propose two, mutually not exclusive models as mechanisms: (1) the level of PPARγ itself is down-regulated by the cytokines leading to loss of function, while (2) PPARγ itself remains associated with the DNA though unable to initiate gene expression. These findings support that inflammatory conditions skew the lipid sensing function of macrophages, further contributing to the vicious circle of metabolic disorders.


A novel methodological approach for the analysis of host-ligand interactions.
Traditional analysis of drug-binding data relies upon the Scatchard formalism. These methods rely upon the fitting of a linear equation providing intercept and gradient data that relate to physical properties, such as the binding constant, cooperativity coefficients and number of binding sites. However, the existence of different binding modes with different binding constants makes the implementation of these models difficult. This article describes a novel approach to the binding model of host-ligand interactions by using a derived analytical function describing the observed signal. The benefit of this method is that physically significant parameters, that is, binding constants and number of binding sites, are automatically derived by the use of a minimisation routine. This methodology was utilised to analyse the interactions between a novel antitumour agent and DNA. An optical spectroscopy study confirms that the pentacyclic acridine derivative (DH208) binds to nucleic acids. Two binding modes can be identified: a stronger one that involves intercalation and a weaker one that involves oriented outer-sphere binding. In both cases the plane of the bound acridine ring is parallel to the nucleic acid bases, orthogonal to the phosphate backbone. Ultraviolet (UV) and circular dichroism (CD) data were fitted using the proposed model. The binding constants and the number of binding sites derived from the model remained consistent across the different techniques used. The different wavelengths at which the measurements were made maintained the coherence of the results.


Induction of apoptosis by Se-MSC in U937 human leukemia cells through release of cytochrome c and activation of caspases and PKC-delta: mutual regulation between caspases and PKC-delta via a positive feedback mechanism.
Se-methylselenocysteine (Se-MSC) has been shown to possess potent chemopreventive and anti-tumor properties. However, its exact mechanism of action is still not well understood. The present study investigated the mechanism of Se-MSC on the induction of apoptosis using U937 human leukemia cells. Se-MSC induced dose- and time-dependent apoptosis of U937 cells as assessed by flow cytometry analysis, DNA fragmentation, and proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP). Se-MSC increased time- and dose-dependent cytochrome c accumulation in the cytosol, which was greatly inhibited by overexpression of Bcl-2, suggesting that the apoptotic effect by Se-MSC in U937 cells is mitochondrial-dependent. Se-MSC also induced activation of caspases, followed by proteolytic cleavage of PKC-delta. The Se-MSC-induced apoptosis required activities of caspases since pretreatment of a pan-caspase inhibitor z-VAD-fmk greatly suppressed the Se-MSC-induced apoptosis as well as proteolytic cleavage of PKC-delta, suggesting activation of caspases is critical for the Se-MSC-induced apoptosis, and caspases lie upstream of PKC-delta. The Se-MSC-induced apoptosis of U937 cells also required activity of PKC-delta because pretreatment of rottlerin, a specific PKC-delta inhibitor greatly blocked the Se-MSC-induced apoptosis as well as processing and activities of caspases, suggesting activation of PKC-delta is also important for the Se-MSC-induced apoptosis of U937 cells, and PKC-delta lies upstream of caspases. Together, our data suggest the apoptotic mechanism by Se-MSC in U937 cells may be related to cytochrome c release from the mitochondria, and mutual activation between caspases and PKC-delta via a positive feedback mechanism, which may potentiate the apoptotic action by Se-MSC in U937 cells.


Cold-preservation of pancreatic beta cells.
Clinical islet transplantation requires graft preservation conditions with a minimal loss in viable beta cells. The present study examines whether rat pancreatic beta cells survive a 96 h storage period at 4 degrees C. In a single cell viability assay, less than 20% viable cells were counted after 48 h storage in physiological HAM's F10 medium; cell survival was better in the high potassium solutions UW or Collins and further improved by supplementing Collins with albumin and benzamidine (CAB-77% viability after 96 h). Suspended beta cell aggregates were also well preserved during 4 days in CAB-4 degrees C as judged from DNA recovery and electron microscopy. After cold-storage in CAB, beta cells exhibited a higher insulin content than after culture in HAM's F10 at 20 degrees or 37 degrees C, but their capacity for subsequent insulin synthesis and release was comparable. When isolated islets were stored in CAB-4 degrees C for 96 h, they yielded slightly higher numbers of dissociated cells than after culture in HAM's F10 at 20 degrees C. Implantation of cold stored islets from 2 donor pancreata corrected hyperglycemia in streptozotocin-diabetic rats. It is concluded that rat beta cells can be stored in a supplemented Collins solution for at least 4 days at 4 degrees C, with preservation of initial cell number, hormone content and glucose responsiveness. During short-term periods, this new storage condition is at least equivalent to cultures at 20 degrees or 37 degrees C. Further studies are needed to assess any advantage for long-term storage of islet cell grafts.


Deviant peer affiliation and antisocial behavior: interaction with Monoamine Oxidase A (MAOA) genotype.
Although genetic and environmental factors are separately implicated in the development of antisocial behavior (ASB), interactive models have emerged relatively recently, particularly those incorporating molecular genetic data. Using a large sample of male Caucasian adolescents and young adults from the National Longitudinal Study of Adolescent Health (Add Health), the association of deviant peer affiliation, the 30-base pair variable number tandem repeat polymorphism in promoter region of the monoamine oxidase-A (MAOA) gene, and their interaction, with antisocial behavior (ASB) was investigated. Weighted analyses accounting for over-sampling and clustering within schools as well as controlling for age and wave suggested that deviant peer affiliation and MAOA genotype were each significantly associated with levels of overt ASB across a 6-year period. Only deviant peer affiliation was significantly related to covert ASB, however. Additionally, there was evidence suggestive of a gene-environment interaction (G × E) where the influence of deviant peer affiliation on overt ASB was significantly stronger among individuals with the high-activity MAOA genotype than the low-activity genotype. MAOA was not significantly associated with deviant peer affiliation, thus strengthening the inference of G × E rather than gene-environment correlation (rGE). Different forms of gene-environment interplay and implications for future research on ASB are discussed.


Vanadium (V) is reduced by the 'as isolated' nitrogenase Fe-protein at neutral pH.
Orthovanadate has been investigated in the presence of the nitrogenase Fe-protein. Electron paramagnetic resonance (EPR) spectra demonstrate that vanadium (V) is reduced by the reduced Fe-protein to vanadium (IV) which then probably binds to the nucleotide binding site in place of the Mg2+ which is normally present. In contrast, the oxidized Fe-protein is unable to reduce vanadate. In this case vanadate has potential for use as a phosphate analogue where it acts as transition state mimic for hydrolysis.


Effect of synthetic gonadotropin-releasing hormone (GnRH) in a patient with the "fertile eunuch" syndrome.
A patient with isolated LH deficiency ("fertile eunuch" syndrome) was given synthetic gonadotropin releasing hormone (GnRH) by a single intravenous injection and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and dihydrotestosterone were measured. A significant rise in both gonadotropins was found after GnRH and the increase was similar to that reported for normal men. No significant change was noted in the serum androgen levels. The patient was re-tested with another single intravenous injection after a 6-h infusion of GnRH two days later. The rise in serum Fsh and LH levels during the infusion was greater than with the initial bolus. A further increase in LH but not FSH concentration was noted when a 150 mug bolus was given at the end of the infusion. Acute (4 day) treatment with human chorionic gonadotropin (hCG) resulted in an increase in the serum testosterone and dihydrotestosterone levels to those observed in normal adult males. The "fertile eunuch" syndrome thus appears to be a hypothalamic disorder. It is consistent with the concept of more than one hypothalamic factor controlling gonadotropin secretion. Other possibilities would be deficient or defective production of a releasing factor affecting one or both gonadotropins. The lack of a definite response of serum androgens to GnRH would appear to be secondary to a decreased number of differentiated Leyding cells.


Anakinra in the Treatment of Patients with Refractory Scleritis: A Pilot Study.
This study aimed to evaluate the safety and efficacy of anakinra for severe and refractory scleritis. Ten patients with severe (i.e. at least 2 ocular relapses per year despite treatment) and refractory [i.e. at least to one disease modifying antirheumatic drugs (DMARDS)] scleritis were treated with anakinra (100 mg/day subcutaneously). Scleritis was associated with inflammatory systemic diseases in 60% of cases. The remission rate defined the primary outcome. Ninety percent of patients were complete responders with a mean follow-up of 19.4 months after starting anakinra. The corticosteroids daily dose decreased from 18.3 ± 4.1 mg to 4.2 ± 4.9 mg, (p < 0.05), at initiation of anakinra and at end of follow-up, respectively. Associated immunosuppressants were stopped in all cases except one. Side effects were observed in 4 patients who did not need anakinra withdrawal. This pilot study suggests the efficacy of anakinra in patients with refractory scleritis.


The Health Care Ethics Consultant, edited by Françoise Baylis.
The Health Care Ethics Consultant marks a stage in the development of ethics consultancy. Ethics consultancy is a manifestation of a newly secularized society in which a new discipline has developed to fill a gap created by the combination of the diminishing influence of traditional moral authorities and the growth of new problems associated with the development of new technology and changes in society and culture. The stated primary objective of the book is to focus attention on an immediate practical problem: the role and responsibilities, the education and training, and the certification and accreditation of health ethics consultants. An edited collection of articles, the book originated as a research project financed by the Social Sciences and Humanities Research Council of Canada, undertaken by a Strategic Research Network which included faculty members from Dalhousie University, McGill University, the University of Toronto, McMaster University and the University of Calgary.


Polymyositis/dermatomyositis and interstitial lung disease: a new therapeutic approach with T-cell-specific immunosuppressants.
Interstitial lung disease (ILD) is a common complication of polymyositis (PM) and dermatomyositis (DM), and accounts for a significant proportion of their morbidity and mortality because of the resistance to therapeutic agents including corticosteroids. Its pathogenic mechanism is not known, but several studies have provided findings implicating that T-cells, especially activated CD8+ cells, may play essential roles, and thus could be therapeutic targets in this disease. To test this hypothesis, we began clinical investigation of the efficacy of T-cell-specific immunosuppressants, cyclosporine (CsA) and FK506, in PM/DM patients with ILD. In our retrospective nationwide multi-center study compiling a total of 53 patients, a combination of CsA and corticosteroids resulted in favorable early and long-term outcome in the majority of patients except for DM patients with acute ILD. In this subset, those who received the combination as an initial therapy had better survival than those who initially received corticosteroids alone. FK506 has a similar mode of action but is up to 100-fold more potent than CsA in vitro, and has been used in more refractory ILD cases. We next reviewed 5 PM/DM patients with ILD who failed on various immunosuppressants including CsA and were subsequently treated with FK506 in our hospital, and found that 3 improved promptly, 1 gradually and steadily, and another case responded slowly after prednisolone dose was increased. None developed adverse effects. In summary, these T-cell targeted therapies have a potential to be the cornerstone of the treatment for ILD in PM/DM patients. The combination therapy with CsA and corticosteroids may be efficacious especially when used early. FK506 may be advantageous even in refractory cases to CsA. These findings indicate that further investigation is warranted. Currently, prospective investigation of FK506 is underway.


A STUDY OF SOME FACTORS AFFECTING THE MORTALITY RATE IN DIFFUSE PERITONITIS.
The results of a retrospective analysis of the records of 665 consecutive patients with diffuse peritonitis emphasize the considerable effect age and causal lesion have on the prognosis. The comparison of results of any innovations in the treatment of diffuse peritonitis cannot be assessed unless these factors are fully taken into account. The fallacy of comparing overall mortality figures is demonstrated. The high mortality rate for diffuse peritonitis associated with diverticulitis is noted.


[HPLC fingerprinting of total glycosides of Swertia franchetiana].
To establish a sensitive and specific HPLC method for controlling the quality of total glycosides from Swertia franchetiana H. Smith. HPLC method was applied for quality and quantitative assessment of the pharmaceutical extracts from Swertia franchetiana H. Smith. The preparation of sample, the HPLC column, mobile phase, elution mode (isocratic or gradient) and gradient program were optimized in order to obtain HPLC profile. The HPLC system consisted of a SPD-1OAvp pump, SPD-M1OAVP photodiode-array detector (PAD), SIL-10ADVP auto injector. Data were acquired and processed with the CLASS-VP6.1 workstation. HPLC analysis was performed on a Kromasil C18 column (250 mm x 4. 6 mm ID, 5 microm) with methanol and water as mobile phase. The column temperature was set up at 40 degrees C and the flow-rate was 1 mL x min(-1). The reference solution of chemical standards and sample were injected into HPLC system, separately. The HPLC chromatographic fingerprinting of the total glycosides, showing 16 characteristic peaks which were partitioned into three parts: one peak in 0-10 min of retention time, nine peaks containing main 1-7 peaks in 10-15 min of retention time, 6 peaks in 15-30 min of retention time, was established from 10 lots of their products. By comparison of the retention time and the on-line UV spectra and their molecule weights of chemical standards, peak 1-7 were identified as swertiamarin (1), gentiopicroside (2), sweroside (3), isoorientin (4), swertisin (5), isoswertisin (6) and swetianolin (7), respectively. The ratios of peak area between 1-16 were in their extent. Moreover, comparison of the HPLC profiles of the total glycosides, the extracts prepared using another process and the plant indicated that they were closely related to each other. The HPLC profiles and quantitative assessment of the total glycosides from Swertia franchetiana H. Smith with high specificity can be used to control their quality and assure lot to lot consistency.


A comparative study of the ultrastructure of microvilli in the epithelium of small and large intestine of mice.
A comparative analysis of the fine structure of the microvilli on jejunal and colonic epithelial cells of the mouse intestine has been made. The microvilli in these two locations demonstrate a remarkably similar fine structure with respect to the thickness of the plasma membrane, the extent of the filament-free zone, and the characteristics of the microfilaments situated within the microvillous core. Some of the core microfilaments appear to continue across the plasma membrane limiting the tip of the microvillus. The main difference between the microvilli of small intestine and colon is in the extent and organization of the surface coat. In the small intestine, in addition to the commonly observed thin surface "fuzz," occasional areas of the jejunal villus show a more conspicuous surface coat covering the tips of the microvilli. Evidence has been put forward which indicates that the surface coat is an integral part of the epithelial cells. In contrast to the jejunal epithelium, the colonic epithelium is endowed with a thicker surface coat. Variations in the organization of the surface coat at different levels of the colonic crypts have also been noted. The functional significance of these variations in the surface coat is discussed.


[A prospective protocol increases oral anticoagulant prescription in patients with chronic, nonvalvular atrial fibrillation].
Observational studies have shown that oral anticoagulants (OAC) prescription is suboptimal in patients with nonvalvular atrial fibrillation (NVAF). Our objective was to evaluate the usefulness of a prospective protocol for increasing OAC usage in these patients. From 1 February 2000 until 31 October 2002 we enrolled all patients with chronic NVAF seen in two outpatient cardiology clinics, excluding candidates for cardioversion. Each patient was studied to identify cardioembolic risk factors (CERF) and contraindications for OAC. Anticoagulation was suggested to all patients with > or =2 CERF and without contraindications for OAC. The decision to prescribe OAC was made by the physician in charge when there was only one CERF. 721 patients fulfilled the inclusion criteria. Mean age was 73 +/- 8 years; 44% were men. In most cases NVAF was related with hypertension (57%), followed by no structural heart disease (25%) or ischemic heart disease (9%). The most frequent CERFs were hypertension (66%), age > or =75 years (45%) and diabetes (24%). A total of 663 patients had > or =1 CERF (92%), and 125 (19%) of these presented at least one contraindication for OAC. Of the 538 remaining patients (90%), 485 (67% of the whole series) were treated with anticoagulation. Of the patients with > or =2 CERF and without contraindications for OAC, 95% were treated. A prospective protocol for use in the outpatient cardiology clinic allows to prescribe OAC in a large percentage of patients with NVAF.


Hydrophobic molecular similarity from MST fractional contributions to the octanol/water partition coefficient.
The use of a recently proposed hydrophobic similarity index for the alignment of molecules and the prediction of their differences in biological activity is described. The hydrophobic similarity index exploits atomic contributions to the octanol/water transfer free energy, which are evaluated by means of the fractional partitioning scheme developed within the framework of the Miertus-Scrocco-Tomasi continuum model. Those contributions are used to define global and local measures of hydrophobic similarity. The suitability of this computational strategy is examined for two series of compounds (ACAT inhibitors and 5-HT3 receptor agonists), which are aligned to maximize the global hydrophobic similarity using a Monte Carlo-simulated protocol. Indeed, the concept of local hydrophobic similarity is used to explore structure-activity relationships in a series of COX-2 inhibitors. Inspection of the 3D distribution of hydrophobic/hydrophilic contributions in the aligned molecules is valuable to identify regions of very similar hydrophobicity, which can define pharmacophoric recognition patterns. Moreover, low similar regions permit to identify structural elements that modulate the differences in activity between molecules. Finally, the quantitative relationships found between the pharmacological activity and the hydrophobic similarity index points out that not only the global hydrophobicity, but its 3D distribution, is important to gain insight into the activity of molecules.


Subgenomic promoter recognition by the norovirus RNA-dependent RNA polymerases.
The replication enzyme of RNA viruses must preferentially recognize their RNAs in an environment that contains an abundance of cellular RNAs. The factors responsible for specific RNA recognition are not well understood, in part because viral RNA synthesis takes place within enzyme complexes associated with modified cellular membrane compartments. Recombinant RNA-dependent RNA polymerases (RdRps) from the human norovirus and the murine norovirus (MNV) were found to preferentially recognize RNA segments that contain the promoter and a short template sequence for subgenomic RNA synthesis. Both the promoter and template sequence contribute to stable RdRp binding, accurate initiation of the subgenomic RNAs and efficient RNA synthesis. Using a method that combines RNA crosslinking and mass spectrometry, residues near the template channel of the MNV RdRp were found to contact the hairpin RNA motif. Mutations in the hairpin contact site in the MNV RdRp reduced MNV replication and virus production in cells. This work demonstrates that the specific recognition of the norovirus subgenomic promoter is through binding by the viral RdRp.


Frequency offset estimation for nonlinear frequency division multiplexing with continuous spectrum modulation.
Carrier frequency offset (CFO) estimation is very important for the optical fiber communications and has been studied widely in linear coherent systems, while only a few works have been reported for nonlinear Fourier transform (NFT) based systems. In continuous spectrum (CS) modulation nonlinear frequency division multiplexing (CS-NFDM) systems, frequency offset (FO) has a great influence on its performance, requiring an improved frequency offset estimation (FOE) method. We found that the oversampling rate R0 adopted in NFDM to ensure the accuracy of the NFT and inverse NFT (INFT) calculations, would cause the estimation accuracy of the traditional FFT-FOE method to decrease by R0 times. Moreover, CS-NFDM signals with higher baud rate require more subcarriers and then result in an oversampling factor greater than 16. This makes the traditional FFT-FOE method be ineffective to use the common training sequence (TS) overhead to meet the FOE error requirement of CS-NFDM system. Therefore, a modified FOE method based on FFT assisted by TS and autocorrelation has been proposed. The theoretical analysis and simulation results show that the proposed method is applicable to CS-NFDM system, no matter what modulation format is used. For 512 subcarriers, with a high rate of 70GBaud and the TS length of 8192, the proposed method can obtain a minimum FO estimation error about 0.1 MHz, which is better than the other two typical FFT-FOE and Schmidl & Cox methods. In addition, the proposed method can save at least 87.5% and 50% overhead. Thus, the proposed method has obvious improvement for CS-NFDM system with requiring high oversampling rate.


Regulation of the Target of Rapamycin and Other Phosphatidylinositol 3-Kinase-Related Kinases by Membrane Targeting.
Phosphatidylinositol 3-kinase-related kinases (PIKKs) play vital roles in the regulation of cell growth, proliferation, survival, and consequently metabolism, as well as in the cellular response to stresses such as ionizing radiation or redox changes. In humans six family members are known to date, namely mammalian/mechanistic target of rapamycin (mTOR), ataxia-telangiectasia mutated (ATM), ataxia- and Rad3-related (ATR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), suppressor of morphogenesis in genitalia-1 (SMG-1), and transformation/transcription domain-associated protein (TRRAP). All fulfill rather diverse functions and most of them have been detected in different cellular compartments including various cellular membranes. It has been suggested that the regulation of the localization of signaling proteins allows for generating a locally specific output. Moreover, spatial partitioning is expected to improve the reliability of biochemical signaling. Since these assumptions may also be true for the regulation of PIKK function, the current knowledge about the regulation of the localization of PIKKs at different cellular (membrane) compartments by a network of interactions is reviewed. Membrane targeting can involve direct lipid-/membrane interactions as well as interactions with membrane-anchored regulatory proteins, such as, for example, small GTPases, or a combination of both.


Oxford-Liverpool Inventory of Feelings and Experiences: reliability in an experimental population.
Further to the recent development of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE), a short multidimensional schizotypy questionnaire, the present study set out to identify the reliability of all scales of this questionnaire within the same population. Participants were required to complete the O-LIFE on two separate occasions, whilst taking part in latent inhibition and negative priming experiments. All scales correlated highly, thus lending further support to the reliability of this time efficient questionnaire.


Synthesis, characterization, and relative stabilities of self-assembled monolayers on gold generated from bidentate n-alkyl xanthic acids.
A series of self-assembled monolayers (SAMs) on gold were generated by the adsorption of n-alkyl xanthic acids (NAXAs) having the general formula CH3(CH2)nOCS2H (n = 12-15). The structural features of these SAMs were characterized by optical ellipsometry, contact angle goniometry, polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS), and X-ray photoelectron spectroscopy (XPS). This series of xanthate SAMs were compared to SAMs generated from the corresponding n-alkanethiols and aliphatic dithiocarboxylic acids (ADTCAs). The collected data indicate that the NAXAs generate densely packed and well-ordered monolayers. The contact angles of hexadecane on the xanthate monolayers exhibited a large "odd-even" effect similar to that produced by the ADTCA SAMs. The relative stability of these bidentate xanthate SAMs was evaluated by monitoring the changes in ellipsometric thicknesses and wettability as a function of time under various conditions. The results demonstrate that SAMs formed from NAXAs are much less stable than analogous n-alkanethiolate and ADTCA SAMs.


Ki-67 expression in vulvar carcinoma.
The proliferative activity of invasive squamous cell carcinoma of the vulva was examined using a Ki-67 equivalent monoclonal antibody (MIB1), which gives a strong immunoreaction in paraffin-embedded tissue. Quantitation of Ki-67 immunostaining was accomplished by image analysis. Ki-67 immunostaining revealed two general patterns of reactivity in vulvar tumors: (a) a diffuse distribution of Ki-67 positive nuclei within the tumor mass and (b) a localized distribution of Ki-67 positive nuclei staining predominantly basilar components of tumor aggregates. The distribution of localized and diffuse patterns did not differ significantly between various clinicopathologic categories (age, histologic type and grade, FIGO stage, and lymph node status). However, the survival times for patients with a diffuse Ki-67 labelling pattern tended to be shorter than those for patients with a localized pattern. Survival curves based on the median positive nuclear area (PNA) calculated by image analysis did not differ significantly. Thus, the pattern of Ki-67 immunostaining, rather than the percentage of PNA, may have prognostic significance in vulvar squamous cell carcinoma.


[Diagnosis of vascular complications at the puncture site after cardiac catheterization].
Cardiac catheterization is increasingly used for the diagnosis or treatment of coronary artery disease. Previous studies that revealed the incidence of complications such as arteriovenous fistula and pseudoaneurysm were based on retrospective analysis of cohorts referred to vascular surgery. This study was designed to determine the incidence of arteriovenous fistula and pseudoaneurysm after percutaneous transluminal angiography. All 557 consecutive patients undergoing cardiac catheterization were examined by ultrasonography from March 1, 2001 to April 1, 2002, to investigate the occurrence of arteriovenous fistula and pseudoaneurysm at the puncture site. Pseudoaneurysm was found in 16 patients (2.9%), and arteriovenous fistula in 12 patients (2.2%). Pseudoaneurysm in 7 patients (43.8%) and arteriovenous fistula in 6 patients (50.0%) were diagnosed only by ultrasonic examination. There were more female patients (9 patients, 56.3%) than male with pseudoaneurysm (p < 0.01). The puncture site was located after the division of the deep femoral artery and superficial femoral artery in all patients with complications. Ultrasonic examination was useful for diagnosis of complications such as arteriovenous fistula and pseudoaneurysm after cardiac catheterization.


Use of clinical characteristics to predict spirometric classification of obstructive lung disease.
There is no consensus on how to define patients with symptoms of asthma and chronic obstructive pulmonary disease (COPD). A diagnosis of asthma-COPD overlap (ACO) syndrome has been proposed, but its value is debated. This study (GSK Study 201703 [NCT02302417]) investigated the ability of statistical modeling approaches to define distinct disease groups in patients with obstructive lung disease (OLD) using medical history and spirometric data. Patients aged ≥18 years with diagnoses of asthma and/or COPD were categorized into three groups: 1) asthma (nonobstructive; reversible), 2) ACO (obstructive; reversible), and 3) COPD (obstructive; nonreversible). Obstruction was defined as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity <0.7, and reversibility as a post-albuterol increase in FEV1 ≥200 mL and ≥12%. A primary model (PM), based on patients' responses to a health care practitioner-administered questionnaire, was developed using multinomial logistic regression modeling. Other multivariate statistical analysis models for identifying asthma and COPD as distinct entities were developed and assessed using receiver operating characteristic (ROC) analysis. Partial least squares discriminant analysis (PLS-DA) assessed the degree of overlap between groups. The PM predicted spirometric classifications with modest sensitivity. Other analysis models performed with high discrimination (area under the ROC curve: asthma model, 0.94; COPD model, 0.87). PLS-DA identified distinct phenotypic groups corresponding to asthma and COPD. Within the OLD spectrum, patients with asthma or COPD can be identified as two distinct groups with a high degree of precision. Patients outside these classifications do not constitute a homogeneous group.


How we do it: employment of listening-development criteria during assessment of infants who use cochlear implants.
There are currently no formal, standardized procedures for assessing speech processing and perception during infancy. This lack of tools makes interpretation of infant data challenging. This article describes how our clinical research center established listening-development criteria for infants with cochlear implants. The listening-development criteria incorporate programming, audiometric, and parent-report measures to estimate adequate audibility of the speech signal prior to the infants' inclusion in research protocols. This paper operationally defines the listening-development criteria, discusses its importance, and presents data from 10 infants who met the listening criteria on average after 6 months of device use.


Kidney stone formation and antioxidant effects of Cynodon dactylon decoction in male Wistar rats.
The antioxidant capacity impairs in kidney and urinary bladder of animals with stone disease. Herbal medicine can improve the antioxidant condition of renal tissue. Cynodon dactylon (C. dactylon) is a medicinal plant with antioxidative and diuretic properties and different preparations of this plant have shown promising effects in stone disease. Assessment of the whole plant decoction to prevent kidney stone disease as well as its antioxidant effects was the aim of this paper. Fifty male Wistar rats were randomly divided into 5 experimental groups (n=10). One group was left without treatment and four groups received ethylene glycol (1% v/v) in drinking water for 6 weeks. Three doses of Cynodon dactylon aqueous decoction (12.5, 50 and 200 mg/kg BW) were added to the drinking water of groups 3-5. Finally, water intake, 24-hour urine volume, MDA, total thiol concentration and FRAP value were measured in the serum and kidney tissues. The CaOx depositions were evaluated by hematoxylin and eosin staining. Compared to the ethylene glycol-treated group, 200 mg/kg C. dactylon, lowered stone incidents, decreased urine volume, increased FRAP/g Cr (43%) and thiol content (p<0.05) with no significant alteration of water intake, MDA decreased significantly compared to C. dactylon 12.5 (p<0.01). Kidney weight increased and body weight decreased in ethylene glycol-treated group compared to the control group (p<0.05). A minimum dose of 200 mg/kg C. dactylon reduced stone formation and simultaneously increased total antioxidant power of serum and preserved MDA content and water.


A Pilot Genome-Wide Association Study Identifies Potential Metabolic Pathways Involved in Tinnitus.
Tinnitus, the perception of an auditory phantom sound in the form of ringing, buzzing, roaring, or hissing in the absence of an external sound source, is perceived by ~15% of the population and 2.5% experiences a severely bothersome tinnitus. The contribution of genes on the development of tinnitus is still under debate. The current manuscript reports a pilot Genome Wide Association Study (GWAS) into tinnitus, in a small cohort of 167 independent tinnitus subjects, and 749 non-tinnitus controls, who were collected as part of a cross-sectional study. After genotyping, imputation, and quality checking, the association between the tinnitus phenotype and 4,000,000 single-nucleotide polymorphisms (SNPs) was tested followed by gene set enrichment analysis. None of the SNPs reached the threshold for genome-wide significance (p < 5.0e-8), with the most significant SNPs, situated outside coding genes, reaching a p-value of 3.4e-7. By using the Genetic Analysis of Complex Traits (GACT) software, the percentage of the variance explained by all SNPs in the GWAS was estimated to be 3.2%, indicating that additive genetic effects explain only a small fraction of the tinnitus phenotype. Despite the lack of genome-wide significant SNPs, which is, at least in part, due to the limited sample size of the current study, evidence was found for a genetic involvement in tinnitus. Gene set enrichment analysis showed several metabolic pathways to be significantly enriched with SNPs having a low p-value in the GWAS. These pathways are involved in oxidative stress, endoplasmatic reticulum (ER) stress, and serotonin reception mediated signaling. These results are a promising basis for further research into the genetic basis of tinnitus, including GWAS with larger sample sizes and considering tinnitus subtypes for which a greater genetic contribution is more likely.


A new method of obtaining zygotes in Saccharomyces cerevisiae.
Experiments leading to a simple method of mass zygote formation in Saccharomyces cerevisiae are described. This method ordinarily requires only about 3 h of incubation, and consistently yielded 55-65% zygotes in seven different crosses among six different strains. Matings involving one strain required about 4 h of incubation but otherwise the results were comparable.


[Interleukin-6 content in the blood serum and bile duct in patients with obturative jaundice of different origin].
There were examined 19 patients with nontumoral disease and 13--with hepatopancreatoduodenal zone organs tumor. In nontumoral disease interleukin-6 (IL-6) was revealed in 83.3% of patients in the blood serum and in 88.9%--in ductal bile; in nontumoral impassability of biliary ducts IL-6 was revealed in the blood serum in 53.8% of patients, in ductal bile--in 87.5%. It was established, that bilirubinemia degree did not correlate with IL-6 content in the blood serum, but was directly influenced by its concentration in ductal bile.


[Manifestations and prognosis of congenital diaphragmatic hernia].
We conducted a retrospective examination of the data of 36 patients with congenital diaphragm defects detected at an early stage or even before birth. The course of pregnancy, pregnancy risks, prenatal findings, mode of delivery, clinical parameters, prenatal, perinatal and postnatal procedures, findings at surgery and surgical therapy were analyzed with respect to the patients' outcome. The following factors were seen to influence the prognosis: associated anomalies, prenatal diagnosis, maturity for age, weight, Apgar score, the size of the defect and the extent of the pulmonary hypoplasia (and--linked to this--the patient's cardiorespiratory condition prior to surgery), and possibly sex. The mortality of patients surviving until surgery became possible was 28%. Our standard procedure in case of diaphragm defects known before birth is primary intubation before the child's first spontaneous breath. We also consider the practice of delaying surgery until stabilization has been achieved and especially in the incubator on the ward the course of action with the fewest complications at present from the patient's point of view.


Glatiramer acetate-induced acute hepatotoxicity in an adolescent with MS.
Glatiramer acetate (GA), a synthetic copolymer, is a frequently used first-line treatment for relapsing-remitting multiple sclerosis (RRMS). Probable autoimmune hepatotoxicity during GA treatment has been reported,(1-4) but GA hepatotoxicity in the absence of positive autoimmune markers has not previously been described. Here, we report GA-induced hepatotoxicity in a pediatric patient with multiple sclerosis (MS).


The relation between gray matter morphology and divergent thinking in adolescents and young adults.
Adolescence and early adulthood are developmental time periods during which creative cognition is highly important for adapting to environmental changes. Divergent thinking, which refers to generating novel and useful solutions to open-ended problems, has often been used as a measure of creative cognition. The first goal of this structural neuroimaging study was to elucidate the relationship between gray matter morphology and performance in the verbal (AUT; alternative uses task) and visuo-spatial (CAT; creative ability test) domain of divergent thinking in adolescents and young adults. The second goal was to test if gray matter morphology is related to brain activity during AUT performance. Neural and behavioral data were combined from a cross-sectional study including 25 adolescents aged 15-17 and 20 young adults aged 25-30. Brain-behavior relationships were assessed without a priori location assumptions and within areas that were activated during an AUT-scanner task. Gray matter volume and cortical thickness were not significantly associated with verbal divergent thinking. However, visuo-spatial divergent thinking (CAT originality and fluency) was positively associated with cortical thickness of the right middle temporal gyrus and left brain areas including the superior frontal gyrus and various occipital, parietal, and temporal areas, independently of age. AUT brain activity was not associated with cortical thickness. The results support an important role of a widespread brain network involved in flexible visuo-spatial divergent thinking, providing evidence for a relation between cortical thickness and visuo-spatial divergent thinking in adolescents and young adults. However, studies including visuo-spatial divergent thinking tasks in the scanner are warranted.


Optimization of cavity size for spatial confined laser-induced breakdown spectroscopy.
Spatial confinement with a small cavity is known to enhance the signal intensity of laser-induced breakdown spectroscopy. In this study, the optical emission intensity and signal stability in terms of the relative standard deviation of laser-induced plasmas generated from brass samples with and without the presence of small cylindrical cavities were carefully investigated. The cylindrical cavities were prefabricated by drilling on a set of aluminum plates with variable diameters and heights, which were then placed near the sample surface. Both plasma emission intensity and stability were influenced by cavity diameter and height. With increased cavity diameter from 1.5 mm to 6 mm, the emission intensity of the confined plasma initially increased and then decreased. Furthermore, if a suitable cavity size was selected, both line intensity and stability of the confined plasma emission improved. Based on these observed signal characters with varying cavities, the optimized cavity size for the best signal quality of the laser-induced plasma emission on brass sample was obtained.


Severity of E. coli mastitis is mainly determined by cow factors.
Intramammary infections of dairy cows with Gram-positive bacteria such as Staphylococcus aureus (major cause of mastitis) have received a lot of attention because of their major economic impact on the dairy farm through production losses induced by an increase in somatic cell count. Management strategies, including greater awareness for efficient milking and hygienic measures, have limited the spread of Gram-positive bacteria and resulted in a significant decrease of proportion of S. aureus isolates and subclinical mastitis worldwide. Other organisms such as coliform subspecies and Streptococcus uberis, both environmental bacteria that cause clinical mastitis, have received less attention. Escherichia coli causes inflammation of the mammary gland in dairy cows around parturition and during early lactation with striking local and sometimes severe systemic clinical symptoms. This disease affects many high producing cows in dairy herds and may cause several cases of death per year in the most severe cases. It is well known that bacterial, cow and environmental factors are interdependent and influence mastitis susceptibility. Many studies, executed during the last decade, indicate that the severity of E. coli mastitis is mainly determined by cow factors rather than by E. coli pathogenicity. During E. coli mastitis, the host defense status is a cardinal factor determining the outcome of the disease. Today, we know that the neutrophil is a key factor in the cows' defense against intramammary infection with E. coli. Effective elimination of the pathogen by neutrophils is important for the resolution of infection and the outcome of E. coli mastitis. This review is a compilation of some major findings over the last 15 years concerning mainly host factors that modulate and influence neutrophil function and the mammary inflammatory reaction. The individual chapters address: virulence factors of E. coli strains, how neutrophils kill E. coli, connection between endotoxins, tumor necrosis factor-alpha and nitric oxide, severity classification of E. coli mastitis, lifespan of neutrophils, host factors that influence severity, tissue damage and production loss.


Convenient synthesis of oligodeoxynucleotides containing 2'-deoxy-6-thioinosine.
A facile synthesis of oligodeoxynucleotides (ODN) containing 2'-deoxy-6-thioinosine (dI6S) based on the convertible nucleoside O6-phenyl-2'-deoxyinosine is presented. After standard solid-phase DNA synthesis and removal of the cyanoethyl protecting groups with DBU treatment with aqueous sodium hydrogen sulfide introduces the sulfur functionality, deprotects the other nucleobases and cleaves the ODN from the solid support in a one-pot reaction. In addition, the extinction coefficient of 2'-deoxy-6-thioinosine is determined by enzymatic fragmentation of the resulting ODN in the presence of adenosine deaminase.


Shrinking hydrogel-DNA spots generates 3D microdots arrays.
This report describes a straightforward approach for the achievement of sub-100 micrometers size hydrogel dots supporting DNA immobilization. Hydrogel-DNA spots are arrayed and UV-crosslinked on PolyShrink, an innovative polymer material having the remarkable property of isotropically shrinking under high temperature. Curing the microarray enables then spot miniaturization, resulting in 6 µm thick and 60 µm wide hydrogel dots in which oligonucleotides are immobilized in a 3D hydrophilic environment. The probe immobilization within the hydrogel network and its capacity to detect targets specifically and quantitatively is demonstrated using chemiluminescent as well as colorimetric detection techniques. The hydrogel material improves probe accessibility within the spot, leading to an enhanced sensitivity.


Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation.
Bcl6 is required for CD4 T cell differentiation into T follicular helper cells (Tfh). In this study, we examined the role of IL-6 in early processes of in vivo Tfh differentiation, because the timing and mechanism of action of IL-6 in Tfh differentiation have been controversial in vivo. We found that early Bcl6(+)CXCR5(+) Tfh differentiation was severely impaired in the absence of IL-6; however, STAT3 deficiency failed to recapitulate that defect. IL-6R signaling activates the transcription factor STAT1 specifically in CD4 T cells. Strikingly, we found that STAT1 activity was required for Bcl6 induction and early Tfh differentiation in vivo. IL-6 mediated STAT3 activation is important for downregulation of IL-2Rα to limit Th1 cell differentiation in an acute viral infection. Thus, IL-6 signaling is a major early inducer of the Tfh differentiation program unexpectedly mediated by both STAT3 and STAT1 transcription factors.


Demonstration of proteinase inhibitors cystatin A, B and C in breast cancer and in cell lines MCF-7 and ZR-75-1.
Polyclonal rabbit antibodies to endogenous natural inhibitors of cysteine proteinases (cystatins) were used for their immunohistochemical demonstration in samples of breast cancers and in two breast cancer derived cell lines (MCF-7 and ZR-75-1). The influence of estrogen stimulation on the expression of these inhibitors was also studied. The results showed that all cystatins tested can be found equally inside carcinomatous cells or in surrounding connective tissue, as well as in both cell lines examined. Further, the expression of inhibitors can be regulated by estrogen, and a certain role of cystatins in the regulation of the mitotic activity and differentiation of mammary cells can be supposed.


[Personality pathological traits and brain metabolites as predictors of non-abstinence in addicts with personality disorders].
Differences in pathological personality traits and disturbances in brain metabolites between non consumers, abstinent and non abstinent consumers were assessed. Participants (n=113) aged between 18-45 years with personality disorder (PD) were diagnosed with clinical interview and scales for depression, anxiety, impulsivity and dimensions of personality pathology. Brain metabolites were analyzed with magnetic resonance spectroscopy. Data were analyzed with ANOVA and multiple comparisons. Abstinent and non-abstinent differentiated from non-consumers in emotional deregulation, inhibition, and restricted expression; abstinent and non-abstinent differentiated from each other in self-aggression, dissocial behaviour, conduct disorder, stimulus seeking and intimacy problems. N-Acetyl Aspartate and creatine values were lower between non-abstinent in prefrontal, anterior cingulate cortex, cerebellar vermis and superior corona radiata. For abstinent, choline levels were greater in cerebellar vermis and n-acetyl aspartate were lower in dorso-lateral prefrontal and anterior cingulated cortex and insula. Regarding personality traits, insecure attachment, narcissism, lability, self-aggression and anxiety characterize consumers and abstinent, while suspiciousness, rejection and character hardness are found in consumers (non-abstinent and abstinent). Compulsive traits, unplanned body impulsiveness and lack of control in emotional regulation predominated in non-abstinent and participants with co-morbidities. Detachment and inhibition predominate in alcohol abuse disorder and narcissistic traits in substance abuse.


The importance of critical thinking skills in disaster management.
The adverse circumstances occasioned by disasters rarely remain static but rather continue to evolve, temporally and spatially, rendering preplanned response operations uncertain, at best, and ineffectual, at worst. As such, disaster management professionals need to think critically to implement response strategies best suited to the circumstances at hand, with the best available information. This paper provides an overview of critical thinking, and its importance in helping leaders provide order to the chaos often associated with disaster response and recovery efforts. Critical thinking skills include the ability to identify and define a problem, recognise assumptions, evaluate arguments, and apply inductive and deductive reasoning to draw conclusions from the available information. Understanding and improving a leader's critical thinking skills helps to provide a sense of confidence, trust and authority during a community-wide crisis. As such, emergency management professionals must continually enhance their critical thinking skills.


Design and implementation of a nursing clinical decision support system to promote guideline adherence.
This article describes the development and implementation of a nursing clinical decision support system that prompts nurses to place mechanically ventilated patients in a semirecumbent position in the absence of contraindications. A literature review is provided regarding (1) ventilator-associated pneumonia and recommendations from expert panels to maintain mechanically ventilated patients in a semirecumbent position (unless contraindicated) and (2) clinical decision support systems. Use of clinical decision support systems has primarily been developed for physicians; however, there is growing interest in expanding this technology to nurses working in the clinical area. Despite recommendations from organizations such as the Center for Disease Control and Prevention to maintain mechanically ventilated patients in a head-elevated position, there is evidence that the practice is not adequately adhered to. Therefore, a nursing clinical decision support system (in the form of a reminder) that prompts nurses to adhere to this recommendation was designed and implemented.


The Association of Serum Leptin with Mortality in Older Adults.
Elevated levels of serum leptin are associated with increased adiposity and production of pro-inflammatory cytokines. Both cytokines and body adiposity have been shown to predict cardiovascular events and mortality. The primary objective of the present study is to explore the associations between serum leptin and all-cause mortality and mortality from cardiovascular disease (CVD) over a span of 10 years, controlling for body adiposity and proinflammatory cytokines. The Health, Aging and Body Composition (Health ABC) study is a prospective cohort of 3,075 older adults aged 70 to 79 years. This analysis includes 2,919 men and women with complete serum leptin and vital status data. Data on all-cause mortality and incident cardiovascular events (including Coronary Heart Disease and Congestive Heart Failure) were collected over 10 years of follow-up (mean 8.4 years). Women with leptin in quartile 2 and 3 were at lower risk of all-cause mortality, and those with leptin in quartile 2 were at lower risk of mortality from CVD as compared to women with lowest leptin values when adjusted for age, race, site, years of education, alcohol use, smoking, and physical activity. When these associations were additionally adjusted for body fat, C-reactive protein and pro-inflammatory cytokines, women with leptin values in quartile 3 were at lower risk of all-cause mortality and women with leptin in quartile 2 and 3 were at lower risk of mortality from CVD than women with lowest leptin values. These associations were not significant among men after adjusting for body fat and cytokines. The present study suggests that moderately elevated concentrations of serum leptin are independently associated with lower risk of all-cause mortality and CVD-related mortality among older women. Among men, serum leptin is not associated with reduced risk of all-cause and CVD mortality after controlling for body fat and cytokines.


Treatment of chlamydia and gonorrhea infections during the COVID-19 pandemic using provisional Centers for Disease Control guidance.
The COVID-19 pandemic created new challenges in controlling the transmission of sexually transmitted diseases (STDs), forcing the Centers for Disease Control and Prevention (CDC) to temporarily modify recommendations. As rapid COVID-19 testing emerged, supplies for similar testing platforms, specifically Chlamydia trachomatis and Neisseria gonorrhoeae, became compromised. The local community was identified as having the highest rate of chlamydia infections in North Carolina. Concerns regarding disease transmission within the community were amplified as the project site began experiencing a critical shortage of chlamydia and gonorrhea testing kits. This quality improvement (QI) project, conducted in an emergency department, located in an underserved area with high STD infection rates, offered a prioritized approach to STD testing and treatment during a critical time with limited testing capabilities. Program analysis evaluated the management of 227 patients preintervention and 218 patients postintervention with confirmed or suspected infection, using a testing and treatment algorithm to identify and treat those most likely to be infected while preserving testing supplies for those at higher risk for complications from infections. Test utilization decreased by 25% (p-value = .003 via t-test), whereas a significant improvement in empiric treatment, increasing from 59% (133/227) to 73% (158/218), was also observed (p-value = .002 via chi-square analysis). Results suggest that a testing and treatment algorithm for providers can successfully guide testing and treatment decisions, reducing onward transmission and preserving supplies for those more likely to experience complications from chlamydia and gonorrhea infections.


The Elmslie-Trillat procedure: evaluation in patellar dislocation and subluxation.
The Elmslie-Trillat procedure for correction of patello-femoral malalignment was evaluated in 27 knees in 22 patients with an average followup of 42 months (minimum of 24 months). Preoperative and postoperative pain and activity levels were recorded for all knees. The quadriceps angle was recorded in 22 knees preoperatively and in 19 knees postoperatively. Good or excellent results were obtained in 81% overall and in 91% of those knees with patella alta. The postoperative quadriceps angle (Q-angle) correlated with the result. Correction of 10 degrees or less was always associated with a good or excellent result. In contrast, all patients with a fair or poor result had Q-angles at 15 degrees or greater. The preoperative Q-angle did not correlate with the eventual result. We concluded that inadequate medial displacement of the anterior tibial tuberosity may lead to unsatisfactory results and that this may be avoided by intraoperative measurement of the Q-angle; that significant distal advancement of the tibial tuberosity is not required in patella alta; and that correction of the Q-angle to 10 degrees or less correlates with a good or excellent result from the Elmslie-Trillat procedure for treatment of patella subluxation and dislocation.


Reduction in circulating pro-angiogenic and pro-inflammatory factors is related to improved outcomes in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega-3 fish oil.
Pancreatic cancer is a rapidly progressive disease which is often only amenable to palliative treatment. Few patients respond to palliative chemotherapy, so surrogate markers indicating which patients are likely to respond to treatment are required. There is a well-established link between pro-inflammatory circulating cytokines and growth factors (CAF), and the development of neoplasia. Agents that may modulate these factors are of interest in developing potential novel therapeutic applications. As part of a single-arm phase II trial in patients with advanced pancreatic cancer (APC) treated with gemcitabine and intravenous (i.v.) omega-3 rich lipid emulsion (n-3FA), serum samples were analysed for 14 CAF using a multiplex cytokine array. Baseline serum concentrations were correlated with overall (OS) and progression-free survival (PFS), and changes in concentration correlated with time and outcomes for CAF responders were analysed. Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) concentrations reduced significantly with treatment over time. Low baseline interleukin (IL)-6 and -8 were correlated with improved OS. PDGF responders showed a tendency towards improved OS and FGF responders a significantly improved PFS. Treatment with gemcitabine plus i.v. n-3FA may reduce concentrations of CAF which may be associated with an improved outcome. Baseline IL-6 and -8 may be surrogate markers for outcome in patients with APC treated with this regimen.


Characterization of Major and Clinically Relevant Non-Major Bleeds in the APEX Trial.
Background Among medically ill patients treated with thromboprophylaxis, betrixaban was not associated with an increase in major bleeding compared with enoxaparin, but an increase in clinically relevant non-major (CRNM) bleeding was observed. The aim of this analysis is to describe the severity and clinical consequences of major and CRNM bleeding in the APEX trial. Methods The APEX trial randomized 7,513 hospitalized acutely ill medical patients to receive either enoxaparin for 6 to 14 days or betrixaban for 35 to 42 days. Subjects receiving a concomitant strong p-glycoprotein inhibitor or with creatinine clearance <30 mL/min were administered a reduced dose of study drug. Results A total of 25 (0.7%) and 21 (0.6%) major bleeds occurred in the betrixaban and enoxaparin arms, respectively ( p = NS) and a total of 91 (2.5%) and 38 (1.0%) CRNM bleeds occurred in the betrixaban and enoxaparin arm ( p < 0.001), respectively. Most major bleeds were considered moderate or severe and most CRNM bleeds were considered mild and moderate ( p = NS). One fatal major bleed occurred in each treatment arm. Rates of major or CRNM bleeds resulting in new or prolonged hospitalization (major: 44.0 vs. 28.6%; CRNM: 12.1 vs. 21.1%) or study treatment interruption or cessation (major: 72.0 vs. 71.4%; CRNM: 71.3 vs. 68.4%) were similar between treatment arms ( p = NS). Conclusions In the APEX trial, CRNM bleeds were mild or moderate in nature and had less of a clinical impact than major bleeds. The severity and clinical sequela of bleeds in the betrixaban arm were comparable to those in the enoxaparin arm. Clinical Trial Registration URL: http://www.clinicaltrials.gov .; Unique identifier: NCT01583218.


The conversion of L-phenylalanine into benzoic acid on the thylakoid membrane of higher plants.
The conversion of L-phenylalanine into benzoic acid and other aromatic carboxylic acids was investigated in Nasturtium officinale (watercress), Astilbe chinensis, and Hydrangea macrophylla in vivo and in vitro. Comparative feeding experiments with radioactively labelled L-phenylalanine and cinnamic acid administered to intact leaf discs of A. chinensis indicated a rapid formation of benzoic acid from L-phenylalanine, whereas cinnamic acid was a poor precursor. Using a pulse-chase labelling technique followed by a fractionation of the tissue into subcellular components, chloroplasts could be identified as the predominant, if not exclusive, site of benzoic acid formation in A. chinensis. Experiments in vitro with chloroplasts and thylalkoids of N. officinale, H. macrophylla, and A. chinensis demonstrate the capacity of thylakoid membranes to catalyze the degradation of L-phenylalanine to benzoic acid. The results obtained upon stimultaneous incubation with [4'-3H]L-phenylalanine and [3-14C]cinnamic acid lead to the hypothesis that the reaction of L-phenylalanine to benzoic acid proceeds via a cinnamic acid pool which is different from that of soluble cinnamic acid.


Relevance of apolipoproteins in the development of fatty liver and fatty liver-related peripartum diseases in dairy cows.
Most metabolic diseases in dairy cows occur during the peripartum period and are suggested to be derived from fatty liver initially developed during the nonlactating stage. Fatty liver is induced by hepatic uptake of nonesterified fatty acids that are released in excess by adipose tissues attributable to negative energy balance. The fatty accumulation leads to impairment of lipoprotein metabolism in the liver, and the impairment in turn influences other metabolic pathways in extrahepatic tissues such as the steroid hormone production by the corpus luteum. Detailed understanding of the impaired lipoprotein metabolism is crucial for elucidation of the mechanistic bases of the development of fatty liver and fatty liver-related peripartum diseases. This review summarizes results on evaluation of lipoprotein lipid and protein concentrations and enzyme activity in cows with fatty liver and those with ketosis, left displacement of the abomasum, milk fever, downer syndrome and retained placenta. Obtained data strongly suggest that decreases in serum concentrations of apolipoprotein B-100, apolipoprotein A-I and apolipoprotein C-III, a reduction in activity of lecithin:cholesterol acyltransferase and induction of haptoglobin and serum amyloid A are intimately related to the development of fatty liver and fatty liver-related diseases. Moreover, determination of the apolipoprotein concentrations and enzyme activity during the peripartum period is useful for early diagnoses of these diseases.


Glass transition temperature of glucose, sucrose, and trehalose: an experimental and in silico study.
Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of models of different amorphous carbohydrates (glucose, sucrose, and trehalose) as a function of temperature. Plots of specific volume vs temperature exhibit a characteristic change in slope when the amorphous systems change from the glassy to the rubbery state. The intersection of the regression lines of data below (glassy state) and above (rubbery state) the change in slope provides the glass transition temperature (T(g)). These predicted glass transition temperatures are compared to experimental T(g) values as obtained from differential scanning calorimetry measurements. As expected, the predicted values are systematically higher than the experimental ones (about 12-34 K) as the cooling rates of the modeling methods are about a factor of 10(12) faster. Nevertheless, the calculated trend of T(g) values agrees exactly with the experimental trend: T(g)(glucose) < T(g)(sucrose) < T(g)(trehalose). Furthermore, the relative differences between the glass transition temperatures were also computed precisely, implying that atomistic molecular dynamics simulations can reproduce trends of T(g) values in amorphous carbohydrates with high quality.