Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC).
The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period. A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between January 1995 and December 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, clinical and pathological stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Four hundred thirty-five GBC cases were identified: 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28-100). Pathology: 88% adenocarcinoma, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy. One hundred thirty-six of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections (N = 123), 8 (6.5%) received adjuvant chemotherapy, 8 (6.5%) chemoradiation alone and 8 (6.5%) both chemoradiation and systemic chemotherapy. Median overall survival for the cohort was 10.3 months (95% CI 8.8-11.8) with a median follow up of 26.6 months. The median survival for those presenting with stage Ia-III disease was 12.9 months (95% CI 11.7-15.8 months) and 5.8 months (95% CI 4.5-6.7) for those presenting with stage IV disease. Median survival was 15.7 months (95% CI 12.4-18.4) for those discovered incidentally at laparoscopic cholecystectomy. For those who underwent re-exploration, median survival was 14.6 months (95% CI 12.6-18.3) if residual disease was present, and 72 months (95% CI 34 to infinity) if no evidence of disease. The median survival for those who received adjuvant therapy was 23.4 months (95% CI 15.7-47). GBC is commonly diagnosed incidentally (47%). Re-exploration reveals a high incidence of residual disease (74%). Median survival is better for patients who have no evidence of disease on re-exploration (72 months) compared to those with residual disease detected (P < 0.0001). Overall prognosis is poor. Although we did not observe a survival benefit for those who received adjuvant therapy, the study did not have sufficient power to address this question. In addition, the number of patients who received adjuvant therapy was small with marked heterogeneity in clinical and therapeutic details, precluding any definitive conclusions being drawn. Prospective randomized trials of adjuvant therapy are needed in this disease.


A novel proteochemometrics model for predicting the inhibition of nine carbonic anhydrase isoforms based on supervised Laplacian score and k-nearest neighbour regression.
Carbonic anhydrases (CAs) are essential enzymes in biological processes. Prediction of the activity of compounds towards CA isoforms could be evaluated by computational techniques to discover a novel therapeutic inhibitor. Studies such as quantitative structure-activity relationships (QSARs), molecular docking and pharmacophore modelling have been carried out to design potent inhibitors. Unfortunately, QSAR does not consider the information of target space in the model. We successfully developed an in silico proteochemometrics model that simultaneously uses target and ligand descriptors to predict the activities of CA inhibitors. Herein, a strong predictive model was built for the prediction of protein-ligand binding affinity between nine human CA isoforms and 549 ligands. We applied descriptors obtained from the PROFEAT webserver for the proteins. Ligands were encoded by descriptors from PaDEL-Descriptor software. Supervised Laplacian score (SLS) and particle swarm optimization were used for feature selection. Models were derived using k-nearest neighbour (KNN) regression and a kernel smoother model. The predictive ability of the models was evaluated by an external validation test. Statistical results (Q2ext = 0.7806, r2test = 0.7811 and RMSEtest = 0.5549) showed that the model generated using SLS and KNN regression outperformed the other models. Consequently, the selectivity of compounds towards these enzymes will be predicted prior to synthesis.


Sociologic study of food habits--a review. II. Differentiation, accessibility and solidarity.
The process of changing food habits is more complex than would appear to most nutritionists; it involves much more than the collection of information. Change must be studied from a multidisciplinary, chiefly a sociologic, point of view, since the food habits of families within a community are formed in a matrix of human relationships. Three major variables are presented and discussed: (a)differentiation, the capacity to process information; (b)accessibility, the measured distance between a family and an information source; and (c)solidarity, the ability of a family group to react cohesively to proposed change. To effect change in his dietary habits, an individual needs his family's cooperation. The nutritionist will do well to rely on the findings of social scientists if proposed changes in family food habits are to be implemented.


The American Society of Anesthesiologists Practice Parameter Methodology.
The methodology used during the development of American Society of Anesthesiologists evidence-based practice parameters, from conceptualization through final adoption of the documents, is described. Features of the methodology include the literature search, review and analysis, survey development and application, and consolidation of the full body of evidence used for preparing clinical practice recommendations. Anticipated risks of bias, validation of the process, and the importance of the documents for clinical use are discussed.


Quantitative nuclear magnetic resonance (QNMR) spectroscopy for assessing the purity of technical grade agrochemicals: 2,4-dichlorophenoxyacetic acid (2,4-D) and sodium 2,2-dichloropropionate (Dalapon sodium).
Comparison of quantitative NMR spectroscopy (QNMR) with chromatographic methods such as gas chromatography (GC) or high-pressure liquid chromatography (HPLC) for the determination of the purity of and impurities in technical grade agrochemicals, 2,4-dichlorophenoxyacetic acid (2,4-D), 1, and Dalapon sodium (sodium 2,2-dichloropropionate), 10, has revealed that QNMR is more precise and accurate than the chromatographic methods. Quantitative impurity profiling of technical grade 1 is rapid and accurate using 600 MHz (1)H NMR. Extra dispersion at the relatively high frequency allowed full assignment of the NMR spectrum of 1 and its related organic impurities in technical samples. The percentage purity of 1 was measured by the difference QNMR method, which involves summing the amounts of impurities and subtracting from 100%. Results are superior in consistency to those obtained by chromatographic methods. The percentage purity of Dalapon sodium, 10, in technical grade batches is readily obtained by (1)H QNMR, using either the difference method or the internal standard method, using dimethyl sulfone (DMSO2) internally as a reference material, that is chemically unrelated to the analyte. The latter method also allows the simultaneous identification and quantification of impurities, many of which are either not accessible to or detectable by the chromatographic methods. Uncertainty budgets for the QNMR method are presented and demonstrate that the major contributors to uncertainty lie in the weighing of the chemicals and in purity of the standard reference material prior to the QNMR experiment.


Phase I Study of Definitive Radio-chemotherapy with Cisplatin, 5-Fluorouracil and Cetuximab for Unresectable Locally Advanced Esophageal Cancer.
Prognoses of patients receiving radio-chemotherapy with 5-fluorouracil (5-FU) and cisplatin for unresectable esophageal cancer may be improved with the addition of cetuximab. This phase I study aimed to define the maximum tolerated dose of 5-FU when combined with cisplatin, cetuximab and radiotherapy. Treatment included 59.4 Gy of radiotherapy concurrently with two courses of cisplatin (20 mg/m2, d1-4) and 5-FU (dose level 0: 500 mg/m2, dose level 1: 750 mg/m2, d1-4; dose level 2: 1,000 mg/m2, d1-4), followed by two courses of chemotherapy. Cetuximab was given for 14 weeks (400 mg/m2 loading dose followed by 250 mg/m2 weekly). At dose level 1 (n=3) and 2 (n=3), no patient experienced a dose-limiting toxicity. Minor treatment modifications were due to organization or request by physicians/patients. At dose level 2, only five grade 3 adverse events occurred. Dose level 2 appears safe and is used in a subsequent randomized phase II study.


Electronegative low-density lipoprotein. A link between apolipoprotein B misfolding, lipoprotein aggregation and proteoglycan binding.
Subendothelial retention of lipoproteins is considered the first step in the development of atherosclerosis, but the molecular mechanisms involved are poorly understood. Recent findings on the atherogenic properties of a minor electronegative fraction of LDL (LDL(-)) could contribute to a better understanding of this process. Circular dichroism, Trp-fluorescence and two-dimensional nuclear magnetic resonance have shown that apolipoprotein B (apoB) in LDL(-) has an abnormal, misfolded conformation. Immunochemical analysis revealed a different conformation, mainly in the N-terminal and C-terminal extremes. These alterations contribute to the high susceptibility to aggregation of LDL(-). Moreover, LDL(-) can seed the aggregation of native LDL, suggesting an amyloidogenic character that has been attributed to the amphipathic helix cluster in the α2-domain. A phospholipase C (PLC)-like activity associated to LDL(-) seems to play a major role in the LDL(-)-induced aggregation. The aggregation of LDL(-) increases its binding to proteoglycans because of the abnormal conformation of the N-terminal extreme of apoB. LDL(-) could play a relevant role in atherogenesis by acting as a priming factor that stimulates lipoprotein aggregation. This process, which appears to be mediated by a PLC-like activity intrinsic to LDL(-), increases the binding of LDL to proteoglycans and could promote subendothelial retention of these lipoproteins.


Post-transfusion purpura: an enigma of alloimmunization.
A patient with post-transfusion purpura is reported. This female patient, sensitized by previous blood transfusion, developed symptomatic thrombocytopenia seven days after a second blood transfusion. A platelet antibody, which had anti-P1A1 specificity, was identified by 51Cr-release assay and by indirect immunofluorescence. Hemorrhage stopped abruptly after plasma exchange therapy. Thrombocytopenia did not recur when the patient was further challenged with P1A1-positive blood and plasma. Anti-P1A1 antibody, detectable by immunofluorescence but not by complement-dependent platelet cytoxicity, persisted in high titer for at least one year after recovery. The heterogeneity and pathogenesis of this clinical syndrome are discussed.


H5N1 Avian Influenza Pre-pandemic Vaccine Strains in China.
To prepare the 4 candidate vaccine strains of H5N1 avian influenza virus isolated in China. Recombinant viruses were rescued using reverse genetics. Neuraminidase (NA) and hemagglutinin (HA) segments of the A/Xinjiang/1/2006, A/Guangxi/1/2009, A/Hubei/1/2010, and A/Guangdong/1/2011 viruses were amplified by RT-PCR. Multibasic amino acid cleavage site of HA was removed and ligated into the pCIpolI vector for virus rescue. The recombinant viruses were evaluated by trypsin dependent assays. Their embryonate survival and antigenicity were compared with those of the respective wild-type viruses. The 4 recombinant viruses showed similar antigenicity compared with wild-type viruses, chicken embryo survival and trypsin-dependent characteristics. The 4 recombinant viruses rescued using reverse genetics meet the criteria for classification of low pathogenic avian influenza strains, thus supporting the use of them for the development of seeds and production of pre-pandemic vaccines.


Systematic analysis of enzyme-catalyzed reaction patterns and prediction of microbial biodegradation pathways.
The roles of chemical compounds in biological systems are now systematically analyzed by high-throughput experimental technologies. To automate the processing and interpretation of large-scale data it is necessary to develop bioinformatics methods to extract information from the chemical structures of these small molecules by considering the interactions and reactions involving proteins and other biological macromolecules. Here we focus on metabolic compounds and present a knowledge-based approach for understanding reactivity and metabolic fate in enzyme-catalyzed reactions in a given organism or group. We first constructed the KEGG RPAIR database containing chemical structure alignments and structure transformation patterns, called RDM patterns, for 7091 reactant pairs (substrate-product pairs) in 5734 known enzyme-catalyzed reactions. A total of 2205 RDM patterns were then categorized based on the KEGG PATHWAY database. The majority of RDM patterns were uniquely or preferentially found in specific classes of pathways, although some RDM patterns, such as those involving phosphorylation, were ubiquitous. The xenobiotics biodegradation pathways contained the most distinct RDM patterns, and we developed a scheme for predicting bacterial biodegradation pathways given chemical structures of, for example, environmental compounds.


Evolutionary genomics: is Buchnera a bacterium or an organelle?
The first genome sequence of an intracellular bacterial symbiont of a eukaryotic cell has been determined. The Buchnera genome shares features with the genomes of both intracellular pathogenic bacteria and eukaryotic organelles, and it may represent an intermediate between the two.


Identification of an Overlooked Halogen-Bond Synthon and Its Application in Designing Fluorescent Materials.
Research on new supramolecular synthons facilitates the progress of materials design. Herein, the ability of sp2 carbonyl oxygen atoms to act as halogen-bond acceptors was established through cocrystallization. Four sets of carbonyl compounds, including aldehydes, ketones, esters, and amides, were selected as halogen-bond acceptors. In the absence of strong hydrogen bonds, 14 out of 16 combinations of halogen-bond donors and acceptors could form cocrystals, whereby the supramolecular synthon C=O⋅⋅⋅X acts as the main interaction. Further, the geometric parameters of the C=O⋅⋅⋅X interaction were statistically revealed on the basis of the crystallographic database. The bifurcated interaction mode that has been observed in other halogen-bond synthons rarely occurs in the case of C=O⋅⋅⋅X. The robustness of C=O⋅⋅⋅X makes its application in crystal engineering possible and opens up new opportunities in designing multicomponent fluorescent materials, as indicated by multicolor emission of cocrystals D through C=O⋅⋅⋅X interactions.


Cyclopean flash-lag illusion.
Possible physiological mechanisms to explain the flash-lag effect, in which subjects perceive a flashed item that is co-localized with a moving item as trailing behind the moving item, have been found within the retina of lower species, and in the motor pathways of humans. Here, we demonstrate flash-lag employing "second-order" moving and flashed stimuli, defined solely by their binocular-disparity, to circumvent any possible "early" contributions to the effect. A significant flash-lag effect was measured with cyclopean stimuli composed entirely of correlated random dot patterns. When the disparity-defined moving stimulus was replaced with a luminance-defined one, potentially engaging retinal mechanisms, the magnitude of the measured effect showed no significant change. Thus, in primates, though retinal mechanisms may contribute, flash-lag must be explained through cortical processes.


Differential effects of scopolamine and amphetamine on microcomputer-based performance tests.
Scopolamine (1.0 mg) and d-amphetamine (10 mg) were administered alone and in combination to 16 subjects (medical students), randomly assigned to testing sessions in a fully crossed-over (Latin square) within-subjects design. After being practiced to stability, 9 performance tests from a menu of portable microcomputer-based tests were administered double-blind over 4 weekly treatments (including a placebo). Differential effects of drugs on performance were found. Motor and perceptual speed tests appeared enhanced by d-amphetamine and not degraded by scopolamine. Two of the five cognitive tests showed reductions with scopolamine. The findings are discussed in connection with using a menu of performance tests that can have diagnostic significance for assessment of drug treatments. The effects of scopolamine in this study and others are considered in terms of a model which implies that magnitude of performance deficit depends on performance type (cognitive, motor, self-report) and dosage level. Applying the model, we offer the following summary: below 0.15 mg scopolamine is without any effect; below 0.50 mg, the effect is limited, but can be revealed by some sensitive, complex performance tests and self-report; above 1.0 mg, the effect is likely to impact on operational efficiency.


Cysticercosis of the tongue.
Cysticercosis is a condition where man forms the intermediate host for the proglottids of Taenia solium. The common sites of cysticercosis are brain, skeletal muscle and subcutaneous tissues, but they can be found at any site. An unusual case of lingual cysticercosis is being reported.


Molecular markers for human placental investigation.
The human placenta is a source for a variety of growth factors, hormones, and other proteins. The cellular source of the proteins can be best determined by immunohistochemistry. Furthermore, immunohistochemistry can also be used to identify a specific cell type and to differentiate it from other types of cells. Thus, there is the need for specific markers of those cell types that are present in the placenta. In this chapter, the basic protocols for the identification of proteins in a tissue section are described. This chapter focuses on methods that are available in the majority of laboratories, and therefore concentrates on methods that are used together with light microscopy.


Does midtrimester delta OD450 of amniotic fluid reflect severity of Rh disease?
Thirty-two patients with Rh-immunized pregnancies had amniocenteses between 16 and 20 weeks' gestation. Serial amniotic fluid values of delta optical density at 450 nm were studied to predict the severity of Rh disease. A value greater than 0.15 indicated severe Rh immunization. Values less than 0.09 indicated mild or no Rh disease; delta optical density at 450 nm between 0.09 and 0.15 require further evaluation to determine the trend. Midtrimester amniocentesis is a simple technique that helps to determine which patients may or may not require fetal blood sampling.


A meta-analytic review of behavior modeling training.
A meta-analysis of 117 studies evaluated the effects of behavior modeling training (BMT) on 6 training outcomes, across characteristics of training design. BMT effects were largest for learning outcomes, smaller for job behavior, and smaller still for results outcomes. Although BMT effects on declarative knowledge decayed over time, training effects on skills and job behavior remained stable or even increased. Skill development was greatest when learning points were used and presented as rule codes and when training time was longest. Transfer was greatest when mixed (negative and positive) models were presented, when practice included trainee-generated scenarios, when trainees were instructed to set goals, when trainees' superiors were also trained, and when rewards and sanctions were instituted in trainees' work environments.


[Epileptic spasms without hypsarrhythmia showing astatic seizures in clusters].
It is difficult to differentiate astatic seizures among atonic, myoclonic and tonic seizures without the help of ictal polygraphic recordings. We described a girl with epilepsy presenting periodic astasia caused by epileptic spasms. Her seizures had occurred in clusters since 1-year and 7-month of age. Her interictal electroencephalogram (EEG) showed intermittent diffuse (poly) spike (s) and wave discharges, without a trace of hypsarrhythmia. She had a diagnosis of epilepsy with myoclonic-astatic seizures at a previous hospital, and her seizures had been resistant to multiple antiepileptic agents. After she was referred to our hospital, the ictal video-EEG recordings were made before and after ACTH administration, which revealed that her astatic seizures were epileptic spasms with presumed cortical origin. We should carefully evaluate the astatic seizures during early childhood which may be an atypical presentation of epileptic spasms.


Changes in luteinizing hormone receptors in the granulosa and theca layers of the ovarian follicle during follicular maturation in the Japanese quail.
Attempts were made to reveal changes in number and affinity of LH receptors in the avian ovary during the course of the final maturation of follicles. First, we characterized the hormone binding properties of LH receptors in ovarian follicles of the Japanese quail by incubating a crude plasma membrane preparation of follicle layer with radioiodinated chicken LH prepared by a recently devised method. Specific LH receptors with common binding properties were detected in both granulosa and theca layers of large preovulatory follicles. The binding affinity of the receptors in the quail ovary to chicken LH (Ka: 2.9-17.2 x 10(9) M-1) was similar to that of gonadal LH receptors of other vertebrates. Optimal temperature and pH for the binding of chicken LH to the receptors of quail were also similar to those reported for LH receptors of mammals. Secondly, we compared the bindings of chicken LH to the receptors in the follicular layers of the largest three follicles. Specific binding to the crude plasma membrane preparation of the theca layer differed slightly between the third and second largest follicles, but decreased abruptly to about one-third in the largest follicle that was expected to ovulate within 24 hr. This change was explained mainly by a decrease in the number of receptors. The specific binding of chicken LH to receptors in the granulosa layer did not differ significantly among the largest three follicles.(ABSTRACT TRUNCATED AT 250 WORDS)


Community services for people with intellectual disabilities and mental health problems.
This review will examine the most recently published studies of community services for people with intellectual disabilities and mental health problems. There is a continuing lack of evidence regarding these community-based services. Few studies have been published at all whilst even fewer still have reported outcomes in any detail. Recent studies have attempted to evaluate assertive community treatment for this service user group; however, they have been unsuccessful owing to inconsistency about what an assertive community treatment service should be for people with intellectual disabilities. An evidence base is urgently needed for these community-based services. Research should utilize the opinions of service users and their carers as well as professionals and focus on those people with intellectual disabilities and more severe mental health problems. It may be more fruitful to examine the components of community-based services rather than use the terminology of specific models such as assertive community treatment. The service components considered to be essential need first to be identified using a systematic methodology and then evaluated using a broad range of outcomes.


Draping and associated equipment for indwelling catheter manipulation by hospital staff: an assessment of attitudes and adequacy.
To address the usability and safety aspects of current equipment for indwelling urinary catheter (IDC) manipulation, by assessing the attitudes of doctors and nurses to infection control, occupational health and environmental waste, and the perceived adequacy of available catheter packs, particularly drapes, when performing such manipulations. A self-administered survey instrument was created using an online database and completed by doctors and nurses. The survey covered basic demographics and experience with IDC, attitudes to infection control, occupational health and safety, and the environment, as well as adequacy of current equipment in containing spillage of urine and/or blood. In all, 87 doctors and 228 nurses completed 315 of 350 (90%) surveys. Doctors and nurses were concerned about infection control, occupational health and safety issues, and environmental waste. Incidents involving spillage of urine and/or blood often go unreported. There were no differences between nurses and doctors having specialist training in urology or experience (P > 0.05). The second major finding is that available catheter packs, particularly drapes, when manipulating IDCs, are inadequate and spillage is likely. These findings were more pronounced in doctors and those with urology training (P < 0.05). The attitudes of health professionals involved with IDC manipulations are consistent with other fields, as is the under-reporting of episodes of contamination by bodily fluids. The current equipment, particularly drapes, are inadequate for containing urine and blood, leading to infection control, occupational health, environmental and cost implications.


A clinical trial of the American Heart Association step one diet for treatment of hypercholesterolemia.
Although diet therapy is the primary treatment for hypercholesterolemia, a trial to determine the effectiveness of the new American Heart Association Step One Diet (AHA diet) in lowering cholesterol has to our knowledge never been carried out. A clinical trial was conducted to assess the plasma lipids response and adherence to the AHA diet in 120 men and women with hypercholesterolemia. All subjects were advised to follow the AHA diet for 18 weeks. After 6 weeks of the AHA diet intervention, there were modest but significant reductions in plasma total cholesterol (-2.6%) and low-density lipoprotein (LDL) cholesterol (-3.5%), but no further significant reductions were observed thereafter. Rather, there was a tendency to return to and even exceed baseline levels of total cholesterol and LDL cholesterol over the subsequent 12 weeks, in spite of the subjects' reported continued adherence to the AHA diet and maintenance of weight loss throughout the entire study period. Nevertheless, 51% of the subjects had experienced improvement (-0.2% to -26.3%) in their plasma LDL cholesterol levels by the end of the study. A probable reason for the limited response of the diet was low baseline levels in intake of saturated fat and cholesterol by participants. The subjects who were older and had higher levels of plasma LDL cholesterol and total fat intake at baseline experienced better plasma LDL cholesterol response to the AHA diet. Thus, practicing physicians should consider assessing the baseline dietary fat and cholesterol intake of patients with hypercholesterolemia before starting the AHA diet, since patients may already be following a relatively prudent self-selected diet. Additional dietary gains in lipid management might well require a more severe restriction of dietary fats and cholesterol. Long-term efficacy of the AHA diet should also be evaluated clinically with periodic lipid profiles.


The effect of NADPH-oxidase inhibitor apocynin on cognitive impairment induced by moderate lateral fluid percussion injury: role of inflammatory and oxidative brain damage.
Traumatic brain injury (TBI) is a devastating disease that commonly causes persistent mental disturbances and cognitive deficits. Although studies have indicated that overproduction of free radicals, especially superoxide (O2(-)) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a common underlying mechanism of pathophysiology of TBI, little information is available regarding the role of apocynin, an NADPH oxidase inhibitor, in neurological consequences of TBI. Therefore, the present study evaluated the therapeutic potential of apocynin for treatment of inflammatory and oxidative damage, in addition to determining its action on neuromotor and memory impairments caused by moderate fluid percussion injury in mice (mLFPI). Statistical analysis revealed that apocynin (5mg/kg), when injected subcutaneously (s.c.) 30min and 24h after injury, had no effect on neuromotor deficit and brain edema, however it provided protection against mLFPI-induced object recognition memory impairment 7days after neuronal injury. The same treatment protected against mLFPI-induced IL-1β, TNF-α, nitric oxide metabolite content (NOx) 3 and 24h after neuronal injury. Moreover, apocynin treatment reduced oxidative damage (protein carbonyl, lipoperoxidation) and was effective against mLFPI-induced Na(+), K(+)-ATPase activity inhibition. The present results were accompanied by effective reduction in lesion volume when analyzed 7days after neuronal injury. These data suggest that superoxide (O2(-)) derived from NADPH oxidase can contribute significantly to cognitive impairment, and that the post injury treatment with specific NADPH oxidase inhibitors, such as apocynin, may provide a new therapeutic approach to the control of neurological disabilities induced by TBI.


Long non-coding RNAs as novel therapeutic targets in cancer.
Thanks to impressive technology advancements, pervasive expression of non-coding RNAs (ncRNAs) has been recently identified in the genome of numerous cancers. Long ncRNAs (lncRNAs) belong to a new class of ncRNAs including tens of thousands different species. A fraction of these molecules shows a striking cancer-enriched expression pattern, suggesting an essential role in tumor cells and, possibly, a utility in therapeutic terms. This review aims at summarizing current knowledge for the identification and validation of lncRNAs as therapeutics targets in tumors. Both in-silico and wet-biology resources are presented in relation to the many challenges that the scientific community still needs to address in terms of lncRNA identification, stratification, patient personalization, drug delivery and toxicity.


A generalization of Birchs theorem and vertex-balanced steady states for generalized mass-action systems.
Mass-action kinetics and its generalizations appear in mathematical models of (bio)chemical reaction networks, population dynamics, and epidemiology. The dynamical systems arising from directed graphs are generally non-linear and difficult to analyze. One approach to studying them is to find conditions on the network which either imply or preclude certain dynamical properties. For example, a vertex-balanced steady state for a generalized mass-action system is a state where the net flux through every vertex of the graph is zero. In particular, such steady states admit a monomial parametrization. The problem of existence and uniqueness of vertex-balanced steady states can be reformulated in two different ways, one of which is related to Birch's theorem in statistics, and the other one to the bijectivity of generalized polynomial maps, similar to maps appearing in geometric modelling. We present a generalization of Birch's theorem, by providing a sufficient condition for the existence and uniqueness of vertex-balanced steady states.


Helicobacter pylori-infected macrophages induce Th17 cell differentiation.
Th17 cells represent a novel subset of CD4(+) T cells, which is associated with chronic inflammation. The present study evaluated Th17 cell responses to Helicobacter pylori infection in mouse model and CD4(+) T cell differentiation in response to H. pylori-infected macrophages. Th17 cells were observed in the H. pylori-infected gastric tissue. Co-culture of CD4(+) T cells with H. pylori-infected macrophages elevated IL-17 and IFN-γ secretion, up-regulated retinoid-related orphan receptor gamma t (RORγt) and T box expressed in T cells (T-bet) expression and increased the numbers of Th17 and Th1 cells. The expression of CD40, CD80, and CD86 and the secretion of IL-6, TGF-β1, IL-23, and CCL20 were significantly increased in H. pylori-stimulated macrophages. NF-κB pathway participated in the production of IL-6, IL-23, and CCL20 from macrophages in response to H. pylori, and inhibition of NF-κB pathway of macrophages resulted in less Th17 cell differentiation. Taken together, these results suggest that H. pylori induces Th17 cell differentiation via infected macrophages.


[Magnetohydrodynamic effects during blood movement].
Theoretical investigations of magnetohydrodynamic (MHD) effects in flowing blood are briefly reviewed in their formal and physiological aspects. It is shown that the great part of published works contain serious errors, as well as groundless practical propositions without any satisfactory explanation.


Gender roles, medical practice roles, and ob-gyn career choice: a longitudinal study.
This paper discusses follow-up data from physicians who were studied ten years earlier when they were medical students. Seventeen physicians were practicing ob-gyn, and 57 of the physicians studied had been interested in an ob-gyn career when they were medical students. At Time 1, women were more likely than men to be strongly interested in ob-gyn, but they were no more likely than men to be ob-gyn physicians at Time 2. The desire to have a surgical specialty was much more important to men than to women practitioners. Men ob-gyn practitioners were significantly more traditional in their sex-role outlook as medical students than were either women practitioners or women who had been strongly interested in the field but did not enter it. The data suggest that women ob-gyn physicians are more likely than their male peers to be egalitarian in their relationships with female patients.


[Peroperative localization of insuloma using staged portal vein insulin assay. Apropos of a case].
The diagnosis of insulinoma is easily done now but, in many cases, it is still difficult to locate it without the use of invasive procedures. With selective angiography and percutaneous transhepatic catheterization of the portal vein however, failure is reduced to about 4%. We report a case of a double localisation of insulinoma, revealed by an intraoperative catheterization of the splenic vein. The advantages of this method are discussed.


Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53.
The p53 tumor suppressor is found to be mutated and abundant in a wide variety of tumors. Within tumors showing rapid growth, the Type II isoform of hexokinase is also highly expressed to facilitate high rates of glucose catabolism, which in turn promote their rapid proliferation. We previously reported isolation of the proximal promoter of the Type II hexokinase gene from the highly glycolytic hepatoma AS-30D (Mathupala, S. P., Rempel, A., and Pedersen, P. L. (1995) J. Biol. Chem. 270, 16918-16925). Here, we show that a p53 protein, exhibiting two point mutations in its cDNA, is abundantly expressed in the AS-30D hepatoma. Co-expression studies showed that p53 overexpression significantly and reproducibly activated the Type II hexokinase promoter. Two functional p53 motifs were identified within this promoter by footprint and gel retardation analyses. Presence of functional p53 response elements on the Type II hexokinase promoter and the positive regulatory effect on the promoter by the mutant p53 indicates that in rapidly growing liver tumors, and perhaps in many other tumors as well, this highly abundant p53 protein plays a role in maintaining a high glycolytic rate. This is the first report of a possible link between loss of cell cycle control in rapidly growing cancer cells and their high glycolytic phenotype.


Trajectories of Anxiety Among Women with Breast Cancer: A Proxy for Adjustment from Acute to Transitional Survivorship.
Anxiety is one of the main components of distress among women with breast cancer (BC), particularly in the early stages of the disease. Changes in anxiety over time may reflect the process of adjustment or lack thereof. The process of adjustment in the traverse of acute to transitional stages of survivorship warrants further examination. To examine the trajectory of anxiety and the specific patterns that may indicate a lack of adjustment within 2 years following BC surgery, survey data from a 2-year prospective cohort study of 725 women with BC were analyzed by Mixture Growth Modelling and logistic regression and Analysis of Variance. A piece-wise growth curve displayed the best fit to the data, indicating a significant decrease in anxiety in the first year, followed by a slower rate of change during the second year. Four classes of trajectories were identified: High Stable, High Decrease, Mild Decrease, and Low Decrease. Of these, High Stable anxiety showed the most substantive indications of lack of adjustment. This subgroup was predominantly characterized by sociodemographic variables such as financial difficulties. Our results support an emphasis on the transitional nature of the stage that follows the end of primary active treatment and imply a need for supportive follow up care for those who display lack of adjustment at this stage.


Electrothermal assisted shoulder capsulorraphy--monopolar.
Monopolar electrothermal stabilization of the shoulder shows considerable promise as a treatment alternative in athletes and patients with recurrent instability. Range of motion is preserved, recovery is faster than with open procedures, there is little disruption or alteration of inherent anatomy, and, most importantly, results at 2 years appear comparable to other surgical procedures in high-demand populations. The procedure is technically easy to perform, and the complication rate is low. Success depends on surgeon's understanding of the applications of RF energy, the use of proper surgical technique, careful patient selection, attention to the rehabilitation program, and the patient's compliance with postoperative protocol. Long-term follow-up is necessary to determine if results for this procedure deteriorate over time, especially in patients with multidirectional instability.


Identification of novel ARF binding proteins by two-hybrid screening.
The ARF tumor suppressor protects us against cancer through protein-protein interactions in partially defined p53-dependent and p53-independent pathways. We performed a two-hybrid screen using ARF as bait and present the identification of several new ARF partners that may regulate its growth inhibitory signaling. The potential physiological roles of these novel ARF binding proteins in regulating ARF signaling are discussed.


Irosustat: a first-generation steroid sulfatase inhibitor in breast cancer.
Endocrine therapy is a key modality in the management of breast cancer, with current options for postmenopausal women including tamoxifen, aromatase inhibitors and fulvestrant. Unfortunately, in spite of these advances, many women still relapse or progress on endocrine therapy. Given that resistance (de novo or acquired resistance) is a major limiting factor in the use of endocrine therapy, additional endocrine therapies with novel methods of action are required. Steroid sulfatase, which is responsible for the conversion of estrone sulfate to estrone, as well as dehydroepiandrosterone sulfate to dehydroepiandrosterone, has been implicated in endocrine resistance. In this article, we summarize the preclinical and clinical data to support the potential role of steroid sulfatase in breast cancer, as well as the current data on the first available steroid sulfatase inhibitor named irosustat (STX64; 667 Coumate; BN83495), and discuss its potential clinical development.


Estimation of copy number in polyploid plants: the good, the bad, and the ugly.
Genetic studies in polyploid plants rely heavily on the collection of data from dominant marker loci. A dominant marker locus is a locus for which only the presence or absence of an observable (dominant) allele is recorded. Before these marker loci can be used for genetic exploration, the number of copies of a dominant allele carried by a parent (copy number) must be determined for each marker locus. Copy number in polyploids is estimated using a hypothesis testing procedure. The performance of this estimation procedure has never been evaluated. In this paper, I quantify whether the highly sought after single-copy markers can be accurately identified, if the performance of the estimation procedure improves with increasing sample size, and whether the estimation procedure is capable of accurately estimating the copy number of high copy markers. I found that the probability of incorrectly estimating copy number is quite low and that more data can actually reduce the accuracy of the estimation procedure when the testing assumptions are violated. Fortunately, when a significant result is obtained, it is almost always correct. The challenge often is in obtaining a significant result.


Continual catheter administration of an elemental diet in infants and children.
Elemental diet offers a safe, simple, widely applicable technique for providing nutritional support in infants and children, thus protecting them against the hazards of malnutrition. Continual catheter administration of elemental diet provides an avenue of nutritional support free of many of the complications associated with total parenteral nutrition. Although mechanical and metabolic complications were avoided by rigid protocol compliance in our group of over 150 patients, further metabolic studies may suggest minor compositional changes providing a more optimal diet for premature and newborn infants.


Effect of alkaline pH on the activity of rat liver phenylalanine hydroxylase.
The pH optimum of rat liver phenylalanine hydroxylase is dependent on the structure of the cofactor employed and on the state of activation of the enzyme. The tetrahydrobiopterin-dependent activity of native phenylalanine hydroxylase has a pH optimum of about 8.5. In contrast, the 6,7-dimethyltetrahydropterin-dependent activity is highest at pH 7.0. Activation of phenylalanine hydroxylase either by preincubation with phenylalanine or by limited proteolysis results in a shift of the pH optimum of the tetrahydrobiopterin-dependent activity to pH 7.0. Activation of the enzyme has no effect on the optimal pH of the 6,7-dimethyltetrahydropterin-dependent activity. The different pH optimum of the tetrahydrobiopterin-dependent activity of native phenylalanine hydroxylase is due to a change in the properties of the enzyme when the pH is increased from pH 7 to 9.5. Phenylalanine hydroxylase at alkaline pH appears to be in an altered conformation that is very similar to that of the enzyme which has been activated by preincubation with phenylalanine as determined by changes in the intrinsic protein fluorescence spectrum of the enzyme. Furthermore, phenylalanine hydroxylase which has been preincubated at an alkaline pH in the absence of phenylalanine and subsequently assayed at pH 7.0 in the presence of phenylalanine shows an increase in tetrahydrobiopterin-dependent activity similar to that exhibited by the enzyme which has been activated by preincubation with phenylalanine at neutral pH. Activation of the enzyme also occurs when m-tyrosine or tryptophan replace phenylalanine in the assay mixture. The predominant cause of the increase in activity of the enzyme immediately following preincubation at alkaline pH appears to be the increase in the rate of activation by the amino acid substrate. However, in the absence of substrate activation, phenylalanine hydroxylase preincubated at alkaline pH displays an approximately 2-fold greater intrinsic activity than the native enzyme.


Investigating effects of high cellulase concentration on the enzymatic hydrolysis of the sisal cellulosic pulp.
The goal of this study was to investigate how the use of high concentration of cellulase may impact the properties of the substrate and the reaction medium during the enzymatic hydrolysis of the sisal pulp. Enzyme concentration of 0.9 mL g-1 was considered for hydrolysis of a sisal cellulosic substrate, and the results were compared with previous ones using 0.5 mL g-1 as cellulase concentration. Nonhydrolyzed pulps and the liquors were withdrawn from the reaction medium and characterized by scanning electron microscopy, crystallinity index, average molar mass, length/thickness, and high-performance liquid chromatography (HPLC). The results indicated that the enzyme/substrate ratio impacted crystallinity variations during the reaction and the induction period for exoglucanase action. The concentration of 0.9 mL g-1 led to a glucose yield (98%, an almost quantitative conversion) higher than 0.5 mL g-1 (89%). Aiming to gain information on the post-burst phase (after 15 h), 1 g of sisal pulp was added, and the results demonstrated that the enzymes remained active, which can counterbalance the higher cost due to the use of high enzymes concentrations. This study deepened the understanding of the enzymatic hydrolysis of sisal cellulosic pulp, and the findings may also benefit investigations on other pulps.


Opinions about potential causes and triggers of intimate partner violence against women: a population-based study among married men from Kermanshah city, Iran.
This cross-sectional study forms part of a community-based social diagnosis in an Iranian city where different community members were approached regarding their opinions about what can cause and trigger intimate partner violence against women (IPVAW). The study deals with the opinions of married men and looks for patterns of opinions and how those patterns relate to individual socio-demographic characteristics. It also discusses opinions expressed concerning the consequences of IPVAW. A workplace-based convenient sample of men from Kermanshah city filled in a standardised, self-administered questionnaire (n = 480, response rate 93%). By means of cluster analysis, four patterns of answers emerged: (1) regarding most items proposed as potential causes or triggers (33.3% of respondents); (2) not regarding them as potential causes or triggers (18.9%); (3) being ambivalent about their role (20.3%); (4) having mixed opinions but mainly not regarding them as potential causes and triggers (27.4%). Being less educated and a blue-collar worker were prominent attributes of those men inclined not to agree with the potential role played in IPVAW by the items proposed (class 2). Moreover, individual ethnicity and perpetration of non-physical violence against one's spouse had very little association with the patterns observed.


[Correction factors for central corneal thickness in Goldmann applanation tonometry].
For many years researchers have discussed which corneal parameters can influence the measurement of intraocular pressure (IOP). As a substantial parameter, the central corneal thickness (CCT) is assumed; however, different measuring methods - including Goldmann applanation tonometry (GAT), dynamic contour tonometry (DCT), and corneal compensated pressure measured with the ocular response analyzer (IOPcc) - may lead to a completely different dependence on corneal thickness. In a study approved by the ethics commission, the anterior chamber of 92 eyes of cataract patients and 85 eyes of glaucoma patients with very different CCT measurements was cannulized before surgery (cataract operation or trabeculectomy), and the IOP values were measured simultaneously with a pressure absorber and with GAT (Perkins tonometer) at different pressure values. The individual measurements exhibited an extraordinarily wide dispersion. In both groups, weak correlations of the difference between GAT and IOP values with the CCT were found (correction factors of 0.95 mmHg/100 microm CCT at pressure level 20 mmHg, 1.2 mmHg/100 microm CCT at pressure level 30 mmHg, and 1.7 mmHg/100 microm CCT at pressure level 40 mmHg). Measurement of CCT is valuable for prognostic assessment of glaucoma, but not for correction factors for corneal thickness.


[Predictors of treatment duration for inpatients with mental disorders--a systematic literature review].
In a systematic literature review we examined patient-related predictors of inpatient treatment duration for mental disorders. The databases Medline, Embase, Psyndex, PsycINFO and EBMR were systematically reviewed for studies in the years 1990-2009 regarding treatment duration of inpatients with ICD-10 diagnoses F3-F6. Also, their methodological quality was evaluated. Twenty-one studies examining 28 predictors (sociodemographic, clinical) were included. Longer treatment durations were found for patients living alone and with higher levels of initial symptom severity, duration of mental disorder, number of previous treatments, work absenteeism, and comorbidity. Obsessive-compulsive, eating and personality disorders were treated longer than depressive, anxiety, somatoform, and adjustment disorders. Results for age, gender, education, and profession were inconsistent. The studies included heterogeneous analyses, treatments, and patients. Despite their sufficient methodical quality, these results are only tentative.


Impact of residual mitral regurgitation after MitraClip implantation.
MitraClip (MC) is an alternative treatment for mitral regurgitation (MR). Although residual MR is common after MC, little was known about the impact of residual MR after MC. We examined 255 consecutive patients who underwent MC. The primary endpoint was the composite endpoint including all-cause death, left ventricular (LV) assist device, and mitral valve surgery. Procedure failure defined as unsuccessful MC implantation (n=6) and residual MR ≥3+ (n=19) was associated with worse outcomes including the primary endpoint and all-cause death than those with acute procedure success (APS) defined as residual MR 2+ (n=125) or 1+ (n=105). Among patient with APS, background characteristics including age, MR etiology, heart failure severity, and LV function were not different. Although MR grade and NT-pro BNP level at 6months after MC were higher in patients with residual MR 2+, there was no significant difference in the incidence of the primary endpoint and all-cause death. Subanalysis showed that the primary endpoint occurred more frequently in patients with MR 2+ in patients with LV ejection fraction ≤40%, chronic kidney disease, and baseline NYHA-class IV. Procedure failure was associated with adverse outcomes after MC. Among patients with APS, residual MR 2+ was not significantly associated with overall worse outcomes than residual MR 1+. However, residual MR 2+ was associated with poorer prognosis in patients with impaired LV function, renal dysfunction, and severe heart failure, suggesting that the optimal endpoint of MC procedure should be individualized according to each patient's baseline characteristic.


Cortical thickness of superior frontal cortex predicts impulsiveness and perceptual reasoning in adolescence.
Impulsiveness is a pivotal personality trait representing a core domain in all major personality inventories. Recently, impulsiveness has been identified as an important modulator of cognitive processing, particularly in tasks that require the processing of large amounts of information. Although brain imaging studies have implicated the prefrontal cortex to be a common underlying representation of impulsiveness and related cognitive functioning, to date a fine-grain and detailed morphometric analysis has not been carried out. On the basis of ahigh-resolution magnetic resonance scans acquired in 1620 healthy adolescents (IMAGEN), the individual cortical thickness (CT) was estimated. Correlations between Cloninger's impulsiveness and CT were studied in an entire cortex analysis. The cluster identified was tested for associations with performance in perceptual reasoning tasks of the Wechsler Intelligence Scale for Children (WISC IV). We observed a significant inverse correlation between trait impulsiveness and CT of the left superior frontal cortex (SFC; Monte Carlo Simulation P<0.01). CT within this cluster correlated with perceptual reasoning scores (Bonferroni corrected) of the WISC IV. On the basis of a large sample of adolescents, we identified an extended area in the SFC as a correlate of impulsiveness, which appears to be in line with the trait character of this prominent personality facet. The association of SFC thickness with perceptual reasoning argues for a common neurobiological basis of personality and specific cognitive domains comprising attention, spatial reasoning and response selection. The results may facilitate the understanding of the role of impulsiveness in several psychiatric disorders associated with prefrontal dysfunctions and cognitive deficits.


Chemoresistance to doxorubicin and cisplatin in a murine cell line. Analysis of P-glycoprotein, topoisomerase II activity, glutathione and related enzymes.
Resistance to antineoplastic drugs has often been associated with P-glycoprotein overexpression, this certainly being not the sole mechanism. In order to characterize resistance to doxorubicin and cisplatin, we have analysed P-glycoprotein expression, topoisomerase II activity, glutathione and related enzymes in murine leukemic cells (doxorubicin or cisplatin-resistant). The doxorubicin-resistant cells contained P-glycoprotein, showed lower activities of glutathione S-transferase well as of glutathione reductase and topoisomerase II. The modifications observed in the most cisplatin-resistant cell line were a higher activity of glutathione S-transferase isoenzyme pi and topoisomerase II. These results suggest that drug uptake, glutathione metabolism as well as topoisomerase II activity are all characteristic of multidrug resistance.


Migrainous stroke.
Twenty-two patients with acute migraine-associated stroke were prospectively evaluated; 91% were female, and 23% had a prior history of presumed migrainous stroke. The incidences of major stroke risk factors and mitral valve prolapse were no higher for the study group than for the general population of similar age. Computed tomography, magnetic resonance imaging, or radionucleotide scanning of the brain was performed on all patients, and demonstrated ischemic or hemorrhagic infarction in 12 (55%). Cerebral arteriography revealed abnormalities related to the acute stroke in five (42%) of 12 cases overall, and in four (67%) of six studies performed within 72 hours of stroke onset; one patient (8%) suffered significant complications from arteriography. Although a variety of processes, alone or in combination, may contribute to migrainous stroke, extracranial and/or intracranial vasospasm appears to play a major role in at least some cases.


Late onset of exercise induced focal ventricular tachycardia originating from the ventricular end of an A-V accessory pathway after elimination of conduction.
The authors report the unique case of remote onset of exercise induced focal ventricular tachycardia in a 40-year old male patient that originated from the ventricular end of an accessory atrioventricular pathway 18 months after a successful ablation. There was no residual conduction across the pathway after the first ablation. The ventricular tachycardia (VT) was mapped to and successfully ablated at the same site where the ventricular end of the pathway was previously ablated. The VT morphology was similar to that of the pre-excited QRS beats noted before. Thus far, in all reported cases of accessory pathway related automaticity there was intact conduction over the pathway or acute injury to it. To the best of our knowledge a case similar to our patient is not yet reported.


Revision of failed shoulder arthroplasty: epidemiology, etiology, and surgical options.
Our aim was to analyze the epidemiology, etiologies, and revision options for failed shoulder arthroplasty from 2 tertiary centers. From 1993 to 2013, 542 failed arthroplasties were revised in 540 patients (65% women): 224 hemiarthroplasties (HAs, 41%), 237 anatomic total shoulder arthroplasties (TSAs, 44%) and 81 reverse total arthroplasties (RSAs, 15%). Data about patients, pathology, and reintervention procedures, as well as intraoperative data, were analyzed from our 2 local registries that prospectively captured all the revision procedures. Patients had an average follow-up period of 8.7 years. The revision rate was 12.7% for HAs, 6.7% for TSAs, and 3.9% for RSAs. HAs were revised earlier (33 ± 40 months) than RSAs (47 ± 150 months) and TSAs (69 ± 61 months). Glenoid failure was a major cause of reintervention: erosion in HAs (29%) or loosening in TSAs (37%) and RSAs (24%). Instability was another major cause of reintervention: 32% in RSAs, 20% in TSAs, and 13% in HAs. Humeral implant loosening led to revision in 10% of RSAs, 6% of HAs, and 6% of TSAs. Multiple reinterventions were required in 21% of patients, mainly for instability (26%) and/or infection (25%). The final implant was an RSA in 48%, especially when associated with cuff insufficiency, instability, and/or bone loss. Final reimplantation was possible in 90% of cases, with the remaining 10% treated with a resection or spacer. Glenoid failure and instability are the most common causes of revision. Soft-tissue insufficiency and/or infection results in multiple revisions. Surgeons must recognize all complications so that they can be addressed at the first revision operation and avoid further reinterventions. RSA was the most common final revision implant.


Flow-volume curve in the diagnosis and follow-up of intrathoracic airway obstruction.
Spirometry is an easy method to measure lung function and to show pathophysiology. It assists not only to determine the severity of bronchial obstruction in asthma but also to differentiate the characteristics of the intrathoracic diseases narrowing the central airways. Different types of benign and malignant tumors of the trachea may cause emergence of symptoms of airway obstruction. Herein a patient who had been initially diagnosed with asthma but later on shown to have intratracheal myofibroblastic tumor is presented. The importance of flow-volume curve in both initial diagnosis of the mass and in the detection of recurrence is discussed.


A 3' cis-regulatory region controls wingless expression in the Drosophila eye and leg primordia.
The precise regulation of wingless (wg) expression in the Drosophila eye disc is key to control the anteroposterior and dorsoventral patterning of this disc. Here, we identify an eye disc-specific wg cis-regulatory element that functions as a regulatory rheostat. Pannier (Pnr), a transcription factor previously proposed to act as an upstream activator of wg, is sufficient to activate the eye disc enhancer but required for wg expression only in the peripodial epithelium of the disc. We propose that this regulation of wg by Pnr appeared associated to the development of the peripodial epithelium in higher dipterans and was added to an existing mechanism regulating the deployment of wingless in the dorsal region of the eye primordium. In addition, our analysis identifies a separate ventral disc enhancer that lies adjacent to the eye-specific one, and thus altogether, they define a 1-kb genomic region where disc-specific enhancers of the wg gene are located.


Prevalence and Correlates of Unhealthy Alcohol and Drug Use Among Men Who Have Sex with Men Prescribed HIV Pre-exposure Prophylaxis in Real-World Clinical Settings.
Pre-exposure prophylaxis (PrEP) is effective in preventing HIV acquisition among men who have sex with men (MSM). However, little is known about unhealthy substance use among MSM initiating PrEP in real-world settings. Unhealthy substance use is a risk factor for HIV acquisition and non-adherence to treatment, and may also impact PrEP use. MSM who were prescribed PrEP from 2015 to 2017 at clinics in Providence, Rhode Island and New Haven, Connecticut were recruited to participate in a prospective observational study. Structured clinical assessments were used to assess demographics, HIV risk behaviors, and unhealthy alcohol (alcohol use disorders identification test [AUDIT]-C scores ≥ 4) and drug use (use of any drugs in the past 3 months). Bivariate and multivariate analyses were performed to determine demographics and behaviors associated with unhealthy alcohol and drug use. Among 172 MSM initiating PrEP, 64% were white and 40% were 25-34 years old. Participants reported a median of 3 (IQR 2-7) sexual partners in the last 3 months; 20% reported an HIV positive partner. Unhealthy alcohol and any drug use were reported by 54 and 57%, respectively, and 76% reported at least one of the two. The majority of drug use reported was marijuana and poppers (41 and 26% of participants, respectively). Relative to those without unhealthy alcohol use, unhealthy alcohol use was independently associated with any drug use (adjusted odds ratio [AOR] = 2.57, 95% CI 1.32-5.01). Frequent drug use was associated with younger age (< 25 years, AOR 4.27, 95% CI 1.51-12.09). Unhealthy alcohol use is common among MSM taking PrEP. Drug use other than marijuana and poppers was uncommon among our cohort. Further efforts may be needed to understand the influence of unhealthy alcohol and other substance use on PrEP outcomes and to engage MSM who use drugs for PrEP.


Effects of delay in administration of potassium cardioplegia to the isolated rat heart.
Ischemic injury to the heart in the period between aortic cross-clamping and administration of cardioplegic solution was evaluated in the normothermic rat heart model. After isolation and control perfusion with oxygenated Krebs-Henseleit bicarbonate buffer, the hearts were given lactated Ringer's cardioplegic solution (30 mEq of K+ per liter) for 2 minutes at three different intervals following aortic clamping: no delay, 2-minute delay, and 5-minute delay. Thereafter, the hearts were left unperfused and the time to initiation of ischemic contracture was recorded. Adenosine triphosphate (ATP) and creatine phosphate levels were measured in all groups prior to and at the conclusion of cardioplegia administration. A 2-minute delay in the administration of cardioplegic solution resulted in significantly lower (p less than 0.001) ATP levels that were restored after 2 minutes of cardioplegia administration. Contracture times were not significantly altered. A 5-minute delay resulted in significantly shorter (p less than 0.001) contracture times and significantly lower (p less than 0.001) ATP levels that were not restored to preischemic levels by 2 minutes of cardioplegia administration. The fate of the myocardium may be insensitive to events that occur during the earliest moments of ischemia provided that rapid administration of oxygenated potassium cardioplegia follows the ischemic period and restores preischemic high-energy phosphate stores. However, there is a critical ischemic time during the initial interval before cardioplegia that is associated with an impaired ability of the myocardium to tolerate subsequent ischemia.


Effect of aging and repeated intratracheal challenge on levels of cryptic and overt natural antibodies in poultry.
Natural antibodies (NAb) have been divided in 2 classes: overt and cryptic. Overt NAb can be detected in unfractionated normal sera of nonimmunized mammals and chickens. Cryptic NAb as described in mammals need an in vitro physical or biochemical treatment to be detected, which may reflect their biochemical modification in situ during inflammation or infection. We studied the effect of concurrent primary, secondary, and tertiary intratracheal (i.t.) challenges with lipopolysaccharide (LPS) and human serum albumin on levels of 2 cryptic NAb [i.e., NAb binding actin (ACT), or thyroglobulin (THYRO)] and levels of an overt NAb binding keyhole limpet hemocyanin (KLH). In addition, effect of aging of the birds on levels of NAb was taken into account. Presence and changes on the level of the cryptic antibodies directed to ACT and THYRO were expected after the i.t. challenges with LPS (and human serum albumin). However, levels of NAb binding ACT were only significantly enhanced by LPS after primary challenge, whereas levels of NAb binding THYRO were not affected by primary nor secondary challenges but were significantly decreased by LPS after the third immunization. On the other hand, no changes in the levels of overt NAb binding KLH were expected, but levels of NAb binding KLH were significantly enhanced after the primary and secondary challenges with LPS. Levels of all three NAb increased with aging, but the different challenges performed at 3 moments during aging did not significantly or consistently affect levels of the overt nor cryptic NAb. Our results suggest that chickens might react by overt NAb as well as cryptic NAb to an infection or inflammation rather than by cryptic NAb only. The relation between various types of NAb and i.t. immunization with antigen and LPS and aging is discussed.


The anticonvulsant action of propofol on epileptiform activity in rat hippocampal slices.
We used extracellular electrophysiological recordings from the CA1 region in rat hippocampal slices to investigate the effects of propofol on the field excitatory postsynaptic potential (fEPSP), population spike, and epileptiform activity induced by a Mg(2+)-free condition. Propofol depressed the population spike, fEPSP, and epileptiform activity. Both aminophylline, a nonselective adenosine receptor antagonist, and 8-cyclopentyl-1,3-dipropylxanthine, an A(1) receptor antagonist, significantly reduced the effect of propofol on fEPSP amplitude. However, 3,7-dimethyl-1-propagylxanthine, an A(2) receptor antagonist, did not alter the effect of propofol on fEPSP amplitude. Picrotoxin, a specific chloride channel blocker, partly reduced the effect of propofol on epileptiform activity, but bicuculline, a competitive gamma-aminobutyric acid(A) receptor antagonist, failed to antagonize it. Aminophylline significantly reduced the action of propofol on the epileptiform activity. The anticonvulsant action of propofol was partly reduced by 8-cyclopentyl-1,3-dipropylxanthine, whereas 3,7-dimethyl-1-propagylxanthine failed to affect it. Adenosine depressed the amplitude of fEPSPs in a dose-dependent manner, and propofol enhanced this inhibition. The results demonstrated that, in rat hippocampal slices, propofol inhibits epileptiform activity. In addition, adenosine neuromodulation through the A(1) receptor may contribute to the anticonvulsant action of propofol.


Interaction between an (-)-epigallocatechin-3-gallate-copper complex and bovine serum albumin: Fluorescence, circular dichroism, HPLC, and docking studies.
The interaction of copper complexed with (-)-epigallocatechin-3-gallate (EGCG) and bovine serum albumin (BSA) was investigated using fluorescence, circular dichroism (CD) spectroscopy, HPLC and protein-ligand docking. The fluorescence quenching efficiency of BSA by EGCG was enhanced after EGCG was complexed with copper, and the EGCG-Cu complex exhibited a higher apparent binding affinity (8.88 × 105 M-1) to BSA compared with EGCG alone (5.17 × 105 M-1). The CD experiment showed that both the EGCG-BSA and [EGCG-Cu]-BSA interactions resulted in the unfolding of the secondary structure of the protein. Results of competitive binding experiments confirmed that the location of EGCG and EGCG-Cu complex binding in BSA was site I. Furthermore, molecular modeling was used to identify the amino acid residue in site I and site II that play key roles in this binding interaction. The data suggest that most of the residues involved in the [EGCG-Cu]-BSA reaction belong to the subdomains IIa (site I) of BSA.


On the oxidation of the three-dimensional aromatics [B(12)X(12)](2-) (X=F, Cl, Br, I).
The perhalogenated closo-dodecaborate dianions [B12 X12 ](2-) (X=H, F, Cl, Br, I) are three-dimensional counterparts to the two-dimensional aromatics C6 X6 (X=H, F, Cl, Br, I). Whereas oxidation of the parent compounds [B12 H12 ](2-) and benzene does not lead to isolable radicals, the perhalogenated analogues can be oxidized by chemical or electrochemical methods to give stable radicals. The chemical oxidation of the closo-dodecaborate dianions [B12 X12 ](2-) with the strong oxidizer AsF5 in liquid sulfur dioxide (lSO2 ) yielded the corresponding radical anions [B12 X12 ](⋅-) (X=F, Cl, Br). The presence of radical ions was proven by EPR and UV/Vis spectroscopy and supported by quantum chemical calculations. Use of an excess amount of the oxidizing agent allowed the synthesis of the neutral perhalogenated hypercloso-boranes B12 X12 (X=Cl, Br). These compounds were characterized by single-crystal X-ray diffraction of dark blue B12 Cl12 and [Na(SO2 )6 ][B12 Br12 ]⋅B12 Br12 . Sublimation of the crude reaction products that contained B12 X12 (X=Cl, Br) resulted in pure dark blue B12 Cl12 or decomposition to red B9 Br9 , respectively. The energetics of the oxidation processes in the gas phase were calculated by DFT methods at the PBE0/def2-TZVPP level of theory. They revealed the trend of increasing ionization potentials of the [B12 X12 ](2-) dianions by going from fluorine to bromine as halogen substituent. The oxidation of all [B12 X12 ](2-) dianions was also studied in the gas phase by mass spectrometry in an ion trap. The electrochemical oxidation of the closo-dodecaborate dianions [B12 X12 ](2-) (X=F, Cl, Br, I) by cyclic and Osteryoung square-wave voltammetry in liquid sulfur dioxide or acetonitrile showed very good agreement with quantum chemical calculations in the gas phase. For [B12 X12 ](2-) (X=F, Cl, Br) the first and second oxidation processes are detected. Whereas the first process is quasi-reversible (with oxidation potentials in the range between +1.68 and +2.29 V (lSO2 , versus ferrocene/ferrocenium (Fc(0/+) ))), the second process is irreversible (with oxidation potentials ranging from +2.63 to +2.71 V (lSO2 , versus Fc(0/+) )). [B12 I12 ](2-) showed a complex oxidation behavior in cyclic voltammetry experiments, presumably owing to decomposition of the cluster anion under release of iodide, which also explains the failure to isolate the respective radical by chemical oxidation.


Single and dual mutations at positions 2058, 2503 and 2504 of 23S rRNA and their relationship to resistance to antibiotics that target the large ribosomal subunit.
To study mutations at positions A2058, A2503 and U2504 (Escherichia coli numbering) of 23S rRNA and their relationship to resistance to antibiotics that target the large ribosomal subunit. Single and dual mutations at positions 2058, 2503 and 2504 of 23S rRNA were introduced into a Mycobacterium smegmatis strain with a single functional rRNA operon. MICs of macrolide, pleuromutilin, phenicol, lincosamide and oxazolidinone antibiotics were determined for the engineered mutants. The doubling times of the mutant strains were measured to investigate how the introduced mutations affected growth rate. Single mutations A2058G, A2503U and U2504G and double mutations A2058G-A2503U and A2058G-U2504G were successfully introduced. The A2058G mutation resulted in various levels of resistance to macrolides and clindamycin. The A2503U and U2504G mutations conferred resistance to valnemulin, chloramphenicol, florfenicol and linezolid. In addition, the A2503U mutant showed reduced susceptibility to the 16-membered macrolides tylosin, spiramycin and josamycin, and the U2504G mutant exhibited decreased susceptibility to spiramycin and josamycin. Moreover, the dual mutations A2058G-A2503U and A2058G-U2504G had co-effects on resistance to 16-membered macrolides. 23S rRNA mutations A2058G, A2503U and U2504G play key roles in resistance to clinically useful antibiotics that target the large ribosomal subunit. Furthermore, the double mutations A2058G-A2503U and A2058G-U2504G have combined effects on resistance to 16-membered macrolides.


Computing and the cultures of proving.
This article discusses the relationship between mathematical proof and the digital computer from the viewpoint of the 'sociology of proof': that is, an understanding of what kinds of procedures and arguments count for whom, under what circumstances, as proofs. After describing briefly the first instance of litigation focusing on the nature of mathematical proof, the article describes a variety of 'cultures of proving' that are distinguished by whether the proofs they conduct and prefer are (i) mechanized or non-mechanized and (ii) formal proofs or 'rigorous arguments'. Although these 'cultures' mostly coexist peacefully, the occasional attacks from within one on another are of interest in respect to what they reveal about presuppositions and preferences. A variety of factors underpinning the diverse cultures of proving are discussed.


Residual vision in transition zones in patients with cerebral blindness.
Using high resolution perimetry in repeated sessions, we investigated 27 patients with homonymous visual field defects in order to detect islands of vision within the damaged area, and to determine color- and form-recognition abilities within these zones of residual vision. In most patients we found circumscribed areas within the "blind" field in which the stimulus was detected in about 50% of presentations. Only one patient had an island of vision greater than 5 degrees within the defective area. We also found an area of variable performance between the blind and the intact field. Borders of field defects were classified as being: (a) sharp (small transition zone), (b) medium, or (c) fuzzy (scattered deficits). We propose that transition zones are functional representations of partially spared neuronal structures in areas of the brain which are only partially injured.


Behavioral contrasts in twinships: stability and patterns of differences in childhood.
Semistructured interviews with 305 mothers of same-sex twins were conducted periodically over the course of the twins' first 6 years. During each of the interviews, the mothers were asked to contrast the twins on a variety of specific behaviors. From the body of reports, 5 ages and 16 behaviors were selected for analysis as most illustrative of the main developmental trends for intrapair differences and similarities. For each of the behaviors, intrapair contrasts were moderately stable across age spans as long as 18-36 months. A set of behaviors related to negative aspects of temperament and a set of behaviors related to sociability were obtained at 6 months and were replicated at later ages. Concordance rates for the identical twin pairs were uniformly higher than for the fraternal pairs, suggesting that genotypic similarity was associated with intrapair similarity for aspects of emotionality and sociability.


Pregnancy outcome in women who use opiates.
Opiate use in pregnancy is on the increase. There are a number of complications associated with this problem but current data from UK centres are sparse. A retrospective study. A North of England Hospital. Maternal and neonatal case records were studied and a standard data set completed. Maternal and neonatal outcomes were classified by the woman's drug usage at the end of pregnancy. One hundred and ten babies born to 108 women were studied and 41% had evidence of previous exposure to the hepatitis C virus. Women who took heroin in later pregnancy were significantly more likely than women who were stabilised on methadone to have a baby who needed morphine (40% versus 19%), had higher mean maximum neonatal abstinence scores (NAS) (5.8 versus 4.7) and stayed in the neonatal unit significantly longer (mean 17.2 days versus 11.8 days). There were two neonatal deaths and the overall rate of prematurity was 29%. The outcome for pregnancy in women who use opiates is complicated by high rates of prematurity and neonatal death. Women who used heroin in later pregnancy had babies who developed more severe NAS and needed a longer hospital stay than women who used only methadone.


Effect of treatment with the antioxidant alpha-lipoic (thioctic) acid on heart and kidney microvasculature in spontaneously hypertensive rats.
Endothelial cells represent an important vascular site of signaling and development of damage during ischemia, inflammation and other pathological conditions. Excessive reactive oxygen species production causes pathological activation of endothelium including exposure of cell to adhesion molecules. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) are members of the immunoglobulin super-family which are present on the surface of endothelial cells. These molecules represent important markers of endothelial inflammation. The present study was designed to investigate, with immunochemical and immunohistochemical techniques, the effect of treatment with (+/-)-alpha lipoic (thioctic) acid and its enantiomers on heart and kidney endothelium in spontaneously hypertensive rats (SHR). Arterial hypertension is accompanied by an increased oxidative stress status in the heart characterized by thiobarbituric acid reactive substances (TBARS) and nucleic acid oxidation increase. The higher oxidative stress also modifies adhesion molecules expression. In the heart VCAM-1, which was higher than ICAM-1 and PECAM-1, was increased in SHR. ICAM-1, VCAM-1 and PECAM-1 expression was significantly greater in the renal endothelium of SHR. (+/-)-Alpha lipoic acid and (+)-alpha lipoic acid treatment significantly decreased TBARS levels, the nucleic acid oxidation and prevented adhesion molecules expression in cardiac and renal vascular endothelium. These data suggest that endothelial molecules may be used for studying the mechanisms of vascular injury on target organs of hypertension. The effects observed after treatment with (+)-alpha lipoic acid could open new perspectives for countering heart and kidney microvascular injury which represent a common feature in hypertensive end-organs damage.


Triethanolamine zinc phosphite, (C6H13NO3)Zn2(HPO3): a templated network or a network of clusters?
(C6H13NO3)Zn2(HPO3) (I) displays an extended hybrid organic/inorganic structure in which the triethanolamine organic species acts as an anionic tetradentate ligand, rather than a typical protonated cationic template. Crystal data for I: Mr = 357.89, monoclinic, P2(1)/c (no. 14), a = 8.4216(4) angstroms, b = 9.9262(5) angstroms, c = 12.8494(6) angstroms, beta = 91.824(1) degrees, V = 1073.6(1) angstroms3, Z = 4.


[Effect of environmental factors and fishing effort allocation on catch of the Spotted Eagle Ray Aetobatus narinari (Rajiformes: Myliobatidae) in Southern Gulf of Mexico].
Aetobatus narinari represents a fisheries target in Southern Gulf of Mexico, and it is currently considered a Near Threatened species by the IUCN red list. The information available of this batoid fish includes some biological and fishery aspects; nevertheless, little is known about the factors influencing on fishing operations and catches. In order to evaluate the effect of environmental factors and the fishing effort allocation by vessels on the target fishery of A. narinari in this area, a daily basis sampling was carried out on four small-scale vessels, from January to July 2009 (the entire fishing season), in two fishing localities (Campeche and Seybaplaya). A total of 896 rays were recorded from 280 fishing trips. A General Linear Model was used to predict the factors effect on the probability that fishing operations occurred, and on the probability for captures of at least one or three or five rays per vessel-trip. The probability that fishing operations occurred off Campeche was predicted by the lunar cycle, with the highest probability in the new moon period (66%) and a probability smaller than 35% for the other periods. The probability that fishing operations occurred off Seybaplaya was predicted by wind velocity, with higher probabilities at low wind velocity than at high wind velocity, and a 50% probability of fishing operations at 12-15 km/h. Catch rates off Seybaplaya were predicted by the vessel's factor (the effect of fishing effort allocation), the North wind season and sea surface temperature. The probability for captures of at least one and three rays per vessel-trip was predicted by the vessel's factor and the North wind season. One vessel had higher catch probability (83% for at least one ray and 43% for at least three rays) than the others (69 and 70% for at least one ray and 26% for at least three rays), and during the North wind season the catch probability was higher (96% for at least one ray and 72% for at least three rays) than out of that season (68% for at least one ray and 21% for at least three rays). The probability for capture at least five rays per vessel-trip was predicted by the sea surface temperature and the North wind season. At 23 degrees C the catch probability was of 49% and the probability gradually diminished to 4% at 28 degrees C, and during the North wind season the catch probability was higher (40%) than out of that season (7%). This study shows that some environmental factors and fishermen perceptions and experience (fishing effort allocation) influence on the catch rate of A. narinari, and that these factors must be considered in future studies on elasmobranch fisheries, mainly when comparisons between catch rates among seasons or regions are analyzed.


Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4β-hydroxycholesterol.
The purpose of this study was to determine the 4β-hydroxycholesterol to cholesterol ratio in mothers and neonates at the time of birth and 4 months post-partum. 21 mothers and 22 neonates were recruited at the delivery ward at Karolinska University Hospital, Huddinge, Sweden. Blood samples taken from mothers and neonates at birth and 4 months post-partum were analysed for 4β-hydroxycholesterol and cholesterol. The median plasma concentration of 4β-hydroxycholesterol was higher in mothers at delivery (50 ng/mL) compared to healthy non-pregnant women (29 ng/mL). The pregnant women had a higher median cholesterol concentration (6.2 mmol/L) compared to healthy non-pregnant women (4.6 mmol/L) but this could only partly explain the increased 4β-hydroxycholesterol. The major cause is an increased CYP3A activity during pregnancy. The median 4β-hydroxycholesterol/cholesterol ratio·10(4) was elevated in mothers at time of birth compared to non-pregnant women (0.19 and 0.15, respectively) but decreased to 0.15 4 months post-partum. Neonates had a median 4β-hydroxycholesterol/cholesterol ratio·10(4) (0.19) comparable to adults already at birth, but lower 4β-hydroxycholesterol (12 ng/mL) and cholesterol (1.8 mmol/L) concentrations. Pregnancy leads to increased CYP3A enzyme activity as determined by the 4β-hydroxycholesterol/cholesterol ratio. Neonates have low 4β-hydroxycholesterol and cholesterol concentrations but similar total CYP3A activity as adults already at birth.


Tackling the child malnutrition problem: from what and why to how much and how.
There is strong economic evidence to invest in improving the economic status of young children, yet programs remain underresourced. Returns on investment in child nutrition in terms of improved health, better education outcomes and increased productivity are substantial, and cost estimates for effective programs are in the range of $2.8 to $5.3 billion. These amounts are modest when compared with total international development assistance or current spending on luxury goods in wealthy nations. New initiatives to redefine nutrition science and to apply innovative problem-solving technologies to the global nutrition problem suggest that steps are being taken to accelerate progress toward a malnutrition-free world.


Sheep as a new experimental host for Babesia divergens.
Babesia divergens was cultivated in sheep erythrocytes in RPMI 1640 supplemented with 10% Fetal Calf Serum (FCS) or sheep serum. In vitro cultures in sheep red blood cells were initiated with human erythrocytes infected in vitro with B. divergens Rouen 1987 or with gerbil blood infected with several isolates from bovine origin. After the first subcultures on sheep erythrocytes, a ten-fold multiplication of the parasites was obtained within 48 h. Erythrocytes from three splenectomized sheep were infected in vitro with B. divergens; when parasitaemia reached 10%, the animals were inoculated with homologous parasitized erythrocytes. All sheep expressed hyperthermia with a peak between the 6th and the 9th day post-infection (p-i) and a transitory parasitaemia 10 days p-i. In vitro primary cultures were performed on two of these sheep, demonstrating the parasite persistence at very low parasitaemia in the infected animals. Splenectomized sheep can be used as a new model for B. divergens chronic infection.


Pharmacological abnormality of kallikrein-kinin system in hypertension.
Until recently the possible role of vasodilator systems in the etiology of hypertension has been largely ignored, although deficiency of vasodilator influence could be more important than the presence of vasoconstriction in determining vascular tone. Lower concentrations of urinary kallikrein excretion have been widely indicated in clinical and in several experimental hypertensive situations. The reduced plasma kininogen levels may reflect either decreased synthesis compensating for a chronically reduced kinin generation or genetic abnormality leading to reduced plasma kininogen, which may be a predisposing factor in hypertension. An alternative possibly could be enhanced adrenergic control during hypertensive conditions which may cause reduction in prostaglandin and kallikrein-kinin systems. It has also been suggested that most of the pharmacological actions of the kallikrein-kinin system are mediated through prostaglandin formation. Thus, subnormal kallikrein-kininogen-kinin concentrations could be the cause of reduced vasodilating influence leading to both clinical and experimental hypertension.


Smiling emphasizes perceived distinctiveness of faces.
In this study, 114 Japanese observers (56 men and 58 women) rated the distinctiveness of 48 neutral faces and 48 smiling faces. Analysis showed smiling faces were rated as significantly more distinctive than neutral ones. Greater perceived distinctiveness provides an explanation for previous results that smiling faces are better remembered than faces with neutral expressions.


Uptake and intracellular fate of cholera toxin subunit b-modified mesoporous silica nanoparticle-supported lipid bilayers (aka protocells) in motoneurons.
Cholera toxin B (CTB) modified mesoporous silica nanoparticle supported lipid bilayers (CTB-protocells) are a promising, customizable approach for targeting therapeutic cargo to motoneurons. In the present study, the endocytic mechanism and intracellular fate of CTB-protocells in motoneurons were examined to provide information for the development of therapeutic application and cargo delivery. Pharmacological inhibitors elucidated CTB-protocells endocytosis to be dependent on the integrity of lipid rafts and macropinocytosis. Using immunofluorescence techniques, live confocal and transmission electron microscopy, CTB-protocells were primarily found in the cytosol, membrane lipid domains and Golgi. There was no difference in the amount of motoneuron activity dependent uptake of CTB-protocells in neuromuscular junctions, consistent with clathrin activation at the axon terminals during low frequency activity. In conclusion, CTB-protocells uptake is mediated principally by lipid rafts and macropinocytosis. Once internalized, CTB-protocells escape lysosomal degradation, and engage biological pathways that are not readily accessible by untargeted delivery methods.


[Tietze's syndrome].
The results of treatment of 14 patients (11 males and 3 females) with Tietze's syndrome are discussed. The patient's ages ranged from 22 to 56 years. Most of them were engaged in heavy physical work. The correct diagnosis was established before admission only in 9 patients. The complaints and clinical symptomatology were of the same type almost in all of the patients: pain and swelling in the region of the II-IV costal cartilages at the sternum or along the whole cartilaginous part of the ribs, in some cases pain was referred to the upper part of the shoulder girdle. Clinical and X-ray methods of examination failed to make recognition of the disease easier. The diagnosis was established on basis of scrupulous investigation of the complaints, the history of the disease, and the local clinical manifestations. Most patients were subjected to nonoperative treatment, 2 patients were treated by operation--resection of the hypertrophied cartilage. Local application of hydrocortisone and kenalog produced good results. Pain disappeared completely in 7, was relieved significantly in 5, and was not relieved at all in 2 patients.


Psychosocial Needs of Relatives of Trauma Patients.
In trauma care, the patient is the primary focus of attention. However, patients' relatives also need attention, for two main reasons. First, the support of relatives is an important factor in the convalescence of patients. Second, the trauma means a serious disruption of not only the life of patients, but also that of their relatives. The purpose of this study was to explore the needs of relatives of trauma patients, to what extent these needs are met by the support of social workers, and how relatives benefit from this support. The study was conducted in hospitals in The Netherlands. Needs were measured using the Dutch version of the Critical Care Family Needs Inventory. Results of in-depth interviews were used to develop a questionnaire to explore the type of social worker support and to what extent relatives benefit from this support. Findings show that trauma patients' relatives have a need for information, access to the patient and hospital staff, and psychosocial assistance. In most cases social workers supported relatives and relatives benefited from the support. To ensure that trauma patients' relatives receive the support they need, social workers should be involved in trauma care as the standard of good care.


Design, synthesis and evaluation of chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the treatment of Alzheimer's disease.
A series of chromone-2-carboxamido-alkylbenzylamines were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 49 displayed excellent inhibitory potency toward acetylcholinesterase (AChE), moderate anti-oxidative activity, selective biometal chelating, and possessed good inhibitory effects on self-induced and Cu(2+)-induced Aβ aggregation. Both kinetic analysis of AChE inhibition and molecular modeling study indicated that 49 was a mixed-type inhibitor, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. These results suggested that 49 might be a potential multifunctional agent for AD treatment.


Identification of uridine diphosphate glucuronosyltransferases involved in the metabolism and clearance of mycophenolic acid.
Mycophenolic acid, the active metabolite of the immunosuppressant and antiproliferative agent, mycophenolate mofetil, is primarily metabolized by glucuronidation to the inactive 7-O-glucuronide. Although the uridine diphosphate (UDP) 7-O-glucuronide is the principal excretion product of this drug, carboxyl-linked glucuronides have also been detected in vitro and in vivo. To identify human UDP glucuronosyltransferases that are active in the glucuronidation of mycophenolic acid, cDNAs encoding individual UDP glucuronosyltransferase forms have been expressed in cell culture, and the capacity of the expressed enzymes to use mycophenolic acid as a substrate has been assessed. Two UDP glucuronosyltransferase forms, UGT1A8 and UGT1A10, were active in the glucuronidation of mycophenolic acid. Both enzymes are predominantly expressed in the gastrointestinal tract and hence, may play a role in the metabolism of mycophenolic acid in the gastrointestinal tract and in the acquisition of resistance to the mito-inhibitory effects of this drug in cultured human colorectal carcinoma cell lines. The identities of the UDP glucuronosyltransferase forms that are mainly responsible for the glucuronidation of mycophenolic acid in the liver and kidney remain unknown; however, UGT1A9 may be important in this respect as the cDNA-expressed enzyme has some capacity to glucuronidate mycophenolic acid. Other UGT1A forms in the liver and kidney (UGT1A1, UGT1A3, UGT1A4, and UGT1A6) were inactive toward mycophenolic acid.


Expectorated tissue leading to diagnosis of renal adenocarcinoma.
Metastatic tumour to the tongue is extremely rare. We report a case of renal adenocarcinoma metastasis involving the right side of the base of the tongue with extension to the right vallecula in a 59-year-old man in which a piece of the metastatic lesion in the tongue was expectorated and was the first evidence of the primary tumour in the right kidney. Previously reported cases are reviewed.


Isolation of active recombinant XPG protein, a human DNA repair endonuclease.
Complementation group G of xeroderma pigmentosum (XP-G) is one of the most rare and phenotypically heterogeneous forms of this inherited disorder. XP-G patients vary from having a very mild defect in DNA repair to being severely affected, and a few cases are also associated with the neurological complications of Cockayne's syndrome. The XPG gene encodes an acidic protein with a predicted molecular mass of 133 kDa that confers normal UV resistance when expressed in XP-G cells. Here we report the isolation of full-length XPG as a soluble protein expressed from a recombinant baculovirus. The purified polypeptide corrects the DNA nucleotide excision repair defect of XP-G cell extracts in vitro, and it acts as a magnesium-dependent single-stranded DNA endonuclease. This is the first direct evidence for a human protein with properties that implicate it in the incision step of nucleotide excision repair.


Power and sensitivity of alternative fit indices in tests of measurement invariance.
Confirmatory factor analytic tests of measurement invariance (MI) based on the chi-square statistic are known to be highly sensitive to sample size. For this reason, G. W. Cheung and R. B. Rensvold (2002) recommended using alternative fit indices (AFIs) in MI investigations. In this article, the authors investigated the performance of AFIs with simulated data known to not be invariant. The results indicate that AFIs are much less sensitive to sample size and are more sensitive to a lack of invariance than chi-square-based tests of MI. The authors suggest reporting differences in comparative fit index (CFI) and R. P. McDonald's (1989) noncentrality index (NCI) to evaluate whether MI exists. Although a general value of change in CFI (.002) seemed to perform well in the analyses, condition specific change in McDonald's NCI values exhibited better performance than a single change in McDonald's NCI value. Tables of these values are provided as are recommendations for best practices in MI testing.


Transcriptional regulation of uncoupling protein-2 gene expression in L6 myotubes.
To increase the understanding of the transcriptional regulation of UCP2 gene expression in skeletal muscle cells, we examined the effect of all-trans-retinoic acid (tRA), a ligand (after the conversion to 9-cis-RA) of the retinoid X receptor (RXR), and linolenic acid, a polyunsaturated fatty acid and peroxisome proliferator-activated receptors (PPARs) ligand, on the expression of UCP2 mRNA in cultured L6 myotubes. UCP2 gene expression in L6 myotubes was confirmed by Northern blot analysis. The time- and concentration-dependency of tRA and linolenic acid on UCP2 gene expression was assessed by dot blot quantification. The mRNA levels of PPAR subtypes (alpha, gamma and delta) were determined by RT-PCR. tRA induced UCP2 gene expression in a time- and concentration-dependent manner. Similar to tRA, UCP2 mRNA was markedly increased by 0.5 mM linolenic acid. In L6 myotubes, PPARdelta mRNA was abundant, whereas PPARalpha mRNA was lower and PPARgamma mRNA was minimal. UCP2 mRNA expression in L6 myotubes is up-regulated by tRA and linolenic acid, possibly through a mechanism involving PPAR and RXRs.


An intense light source. The photoderm VL-flashlamp as a new treatment possibility for vascular skin lesions.
Up to now, vascular diseases were treated with various lasers, such as argon, pulsed dye, and copper vapor lasers, which can lead to side effects like hypopigmentations, hyperpigmentations, and scarring. We treated patients with vascular lesions with an incoherent intense light source, the PhotoDerm VL-flashlamp. The aim of the study was to test the effectiveness and safety of the PhotoDerm VL for vascular skin lesions. One hundred and twenty patients with facial or leg telangiectasias, spider nevi, erythrosis interfollicularis, and senile angiomas were treated with the PhotoDerm VL. In 73.6% of patients there was an immediate clearing, and in 84.3% a clearing after 1 month was found of leg telangiectasias up to 1 mm in diameter. Facial telangiectasias and erythrosis interfollicularis colli showed clearance up to 90%. Spider nevi and senile angiomas often only needed to be treated once. From our experience we conclude that the PhotoDerm VL is an excellent device to treat vascular lesions as there were hardly any side effects seen, however, the user needs a sufficient experience to get good results.