Assessing the metabolic effects of prednisolone in healthy volunteers using urine metabolic profiling.
Glucocorticoids, such as prednisolone, are widely used anti-inflammatory drugs, but therapy is hampered by a broad range of metabolic side effects including skeletal muscle wasting and insulin resistance. Therefore, development of improved synthetic glucocorticoids that display similar efficacy as prednisolone but reduced side effects is an active research area. For efficient development of such new drugs, in vivo biomarkers, which can predict glucocorticoid metabolic side effects in an early stage, are needed. In this study, we aim to provide the first description of the metabolic perturbations induced by acute and therapeutic treatments with prednisolone in humans using urine metabolomics, and to derive potential biomarkers for prednisolone-induced metabolic effects. A randomized, double blind, placebo-controlled trial consisting of two protocols was conducted in healthy men. In protocol 1, volunteers received placebo (n = 11) or prednisolone (7.5 mg (n = 11), 15 mg (n = 13) or 30 mg (n = 12)) orally once daily for 15 days. In protocol 2, volunteers (n = 6) received placebo at day 0 and 75 mg prednisolone at day 1. We collected 24 h urine and serum samples at baseline (day 0), after a single dose (day 1) and after prolonged treatment (day 15) and obtained mass-spectrometry-based urine and serum metabolic profiles. At day 1, high-dose prednisolone treatment increased levels of 13 and 10 proteinogenic amino acids in urine and serum respectively, as well as levels of 3-methylhistidine, providing evidence for an early manifestation of glucocorticoid-induced muscle wasting. Prednisolone treatment also strongly increased urinary carnitine derivatives at day 1 but not at day 15, which might reflect adaptive mechanisms under prolonged treatment. Finally, urinary levels of proteinogenic amino acids at day 1 and of N-methylnicotinamide at day 15 significantly correlated with the homeostatic model assessment of insulin resistance and might represent biomarkers for prednisolone-induced insulin resistance. This study provides evidence that urinary metabolomics represents a noninvasive way of monitoring the effect of glucocorticoids on muscle protein catabolism after a single dose and can derive new biomarkers of glucocorticoid-induced insulin resistance. It might, therefore, help the development of improved synthetic glucocorticoids. ClinicalTrials.gov NCT00971724.


A systematic review of minimally invasive sacroiliac joint fusion utilizing a lateral transarticular technique.
A number of studies have been published regarding minimally invasive surgical (MIS) fusion of the sacroiliac (SI) joint using a lateral transarticular approach. Herein we report a systematic review and meta-analysis to summarize operative measures and clinical outcomes reported in published studies of MIS SI joint fusion. The systematic review was done according to PRISMA standards. PubMed and EMBASE were searched using the terms sacroiliac joint AND fusion. Original peer-reviewed articles in the English language that reported clinical outcomes on at least 5 cases of MIS SI joint fusion using a lateral transarticular approach were included. Random effects meta-analysis (RMA) was performed on selected variables using the DerSimonian and Laird method, including operative measures, VAS SI joint pain ratings (0-10 scale) and Oswestry Disability Index (ODI). Mean and 95% confidence intervals (CI) were calculated and heterogeneity was assessed. Other findings were summarized qualitatively. A total of 18 articles met the inclusion criteria. After accounting for overlapping cohorts, 12 unique cohorts from 4 countries were extracted for a total of 432 subjects. The RMA mean (range) was 59 minutes (27-78) for procedure time, 36.9cc (10-70) for estimated blood loss and 1.7 days (range 0-7) for length of stay (LOS). The RMA mean [95% CI] pain score dropped by 5.2 points at 6 months and 5.3 points at 12 months (baseline score of 8.1 [7.8-8.4], 12-month score of 2.7 [2.1-3.3]), and a 24-month score of 2.0(1.4-2.5). ODI decreased by 31 points at 12 months (baseline score of 56.2 [51.0-61.5], 6-month score of 30.7 [21.8-39.6], and 12-month score of 25.1 [12.3-37.9]). Some estimates showed significant variation across studies and between the types of implants used. Other reported outcomes were supportive of the positive effects of SI joint fusion. Published studies of MIS SI joint fusion using a lateral transarticular approach confirm its minimally invasive characteristics with minimal blood loss and short operating room times, and show consistent, rapid, sustained and clinically important improvements in patient reported SI joint pain, disability and quality of life scores.


Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials.
Two phase 3 placebo-controlled trials of the CYD-TDV vaccine, evaluated in children aged 2-14 y (CYD14) and 9-16 y (CYD15), demonstrated vaccine efficacy (VE) of 56.5% and 60.8%, respectively, against symptomatic virologically confirmed dengue (VCD). Sieve analyses were conducted to evaluate whether and how VE varied with amino acid sequence features of dengue viruses (DENVs). DENV premembrane/envelope amino acid sequences from VCD endpoint cases were aligned with the vaccine insert sequences, and extensions of the proportional hazards model were applied to assess variation in VE with amino acid mismatch proportion distances from vaccine strains, individual amino acid residues, and phylogenetic genotypes. In CYD14, VE against VCD of any serotype (DENV-Any) decreased significantly with increasing amino acid distance from the vaccine, whereas in CYD15, VE against DENV-Any was distance-invariant. Restricting to the common age range and amino acid distance range between the trials and accounting for differential VE by serotype, however, showed no evidence of VE variation with distance in either trial. In serotype-specific analyses, VE against DENV4 decreased significantly with increasing amino acid distance from the DENV4 vaccine insert and was significantly greater against residue-matched DENV4 at eight signature positions. These effects were restricted to 2- to 8-y-olds, potentially because greater seropositivity of older children at baseline might facilitate a broader protective immune response. The relevance of an antigenic match between vaccine strains and circulating DENVs was also supported by greater estimated VE against serotypes and genotypes for which the circulating DENVs had shorter amino acid sequence distances from the vaccine.


New class of precision antimicrobials redefines role of Clostridium difficile S-layer in virulence and viability.
There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specific Clostridium difficile strains and prevents them from colonizing mice. We have since selected two Av-CD291.2-resistant mutants that have a surface (S)-layer-null phenotype due to distinct point mutations in the slpA gene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverse C. difficile isolates in an S-layer sequence-dependent manner. In addition to bacteriophage receptor recognition, characterization of the mutants also uncovered important roles for S-layer protein A (SlpA) in sporulation, resistance to innate immunity effectors, and toxin production. Surprisingly, S-layer-null mutants were found to persist in the hamster gut despite a complete attenuation of virulence. These findings suggest antimicrobials targeting virulence factors dispensable for fitness in the host force pathogens to trade virulence for viability and would have clear clinical advantages should resistance emerge. Given their exquisite specificity for the pathogen, Avidocin-CDs have substantial therapeutic potential for the treatment and prevention of C. difficile infections.


A 20-year experience with secondary rhytidectomy: a review of technique, longevity, and outcomes.
The increasingly more common secondary rhytidectomy patient presents with recurrent soft-tissue descent and stigmata of primary face lift, which can require techniques unique to secondary rhytidectomy. The senior author's (R.J.R.) experience with secondary rhytidectomy is reviewed, focusing on surgical technique, longevity, and outcomes. Data collected after chart review of a 20-year study period included face-lift technique; duration between primary, secondary, and tertiary face lifts; concurrent procedures; and complications (i.e., hematoma, seroma, nerve injury, skin slough, infection, and need for revision). Surgical technique focuses on the "five Rs" of secondary rhytidectomy: (1) resect skin/scar, (2) release of abnormal superficial musculoaponeurotic system (SMAS) vectors, (3) refill by means of fat grafting, (4) reshape with SMASectomy or SMAS-stacking plication, and (5) redrape skin. The longevity of primary and secondary procedures was compared. A total of 811 face lifts were performed during the study period; 60 were secondary procedures. Ten secondary patients went on to have a tertiary face lift. Average duration between primary and secondary face lift was 9.0 years, and that between secondary and tertiary procedures was 7.5 years, showing no difference in longevity (p = 0.2). Complications included one each of seroma, skin slough, and temporary marginal mandibular nerve injury (2 percent). Necessary revisions included one neck, one earlobe, and one preauricular scar. Secondary rhytidectomy has complications similar to those of a primary procedure, and most patients have a second operation a decade later. Adherence to the five Rs of secondary rhytidectomy will enable the plastic surgeon to safely restore youth and correct stigmata of primary face lift.


Depressive symptoms and occurrence of type 2 diabetes among Japanese men.
To examine the relationship between depressive symptoms and the incidence of type 2 diabetes. In 1984, 2,764 male employees of an electrical company in Japan completed a self-administered questionnaire including the Zung Self-Rating Depression Scale (SDS). They were followed for the next 8 years, and 2,380 (86%) responded to the follow-up survey in 1992. During the follow-up survey, occurrence of type 2 diabetes was diagnosed according to World Health Organization criteria. A total of 41 cases of type 2 diabetes were identified during the 8-year follow-up survey. After controlling for other known risk factors for type 2 diabetes, a proportional hazard analysis indicated that subjects who had moderate or severe levels of depressive symptoms (> or = 48 on the SDS) at baseline had a 2.3 times higher risk of having type 2 diabetes at the follow-up survey than those who were not depressed (< or = 39 on the SDS) (P < 0.05). Depressive symptoms may be associated with the onset of type 2 diabetes.


Heterogeneity and origins of the alpha-thalassemias.
The alpha-globin gene cluster is far from static. It shows remarkable diversity within and among populations, both in gene number and in the pattern of polymorphisms involving the hypervariable regions. The deletions that have given rise to alpha(0)-thalassemia appear to have resulted from rare genetic events, and the affected chromosomes have been distributed among localized populations by selection. On the other hand, the deletions that have given rise to at least one of the alpha(+)-thalassemias seem to have occurred on multiple occasions in different populations. The genesis of this condition, the most common single gene disorder, may reflect the concerted evolution of the alpha-globin genes, and the alpha(+)-thalassemias may have arisen as a by-product of this evolutionary process. The existence of such a polymorphic gene family and the fact that its mutations are the most common single gene disorders in man provide us with a remarkable, natural model for studying population genetics at the molecular level. Further analysis of this cluster may provide valuable information about the timing of racial diversions, population movements, and the molecular events that have helped to maintain such high gene frequencies for some of the mutations of these loci.


Tracing the origin of adenocarcinomas with unknown primary using immunohistochemistry: differential diagnosis between colonic and ovarian carcinomas as primary sites.
To discriminate adenocarcinoma metastases originating from either colon or ovary, a panel of immunohistochemical markers was evaluated. For this purpose, paraffin sections from 157 primary and metastatic colonic and ovarian carcinomas were immunostained. These cases were divided into a learning group of 46 colonic and 54 ovarian carcinomas and a test group of 29 colonic and 28 ovarian carcinomas, including all metastatic tumors, among which were five with unknown primary site at the time of testing. The sections were immunostained with antibodies against carcinoembryonic antigen (CEA), cytokeratin 7 (CK7), cytokeratin 20 (CK20), CA125, vimentin, and CA19.9. Staining results were expressed as the product of staining intensity and percentage of positive tumor cells. Stepwise discriminant analysis was applied on the learning set to obtain a classification function for both tumors. The validity of the classification function was evaluated using the test set. There was considerable overlap in immunostaining for both tumor types, but colonic carcinomas were typically positive for CEA and CK20 and negative for CK7 and CA125. Ovarian carcinomas were typically positive for CK7 and CA125 and negative for CEA and CK20. In discriminant analysis, the best combination of markers appeared to be CK7 and CEA. Only one sample of the test group (2%) was misclassified. Taking learning and test groups together, 136 of the 157 samples (87%) were correctly classified with high posterior probability (PP > .8). However, from the 28 mucinous ovarian carcinomas, only 19 (68%) could correctly be classified with high PP. When excluding the nonmucinous ovarian carcinomas from the analysis, overall 87 of 103 (84.5%) of the samples were correctly classified (PP > .8) with a combination of CEA, CK7, and also vimentin. From the 28 mucinous ovarian carcinomas, only two (7%) were misclassified, and four could not be classified with sufficient certainty. In neither analysis did CK20, CA125, or CA19.9 emerge as discriminatory parameters. Based on the same data, an intuitive flow chart was constructed with which 129 of 157 cases could be classified (only one falsely) without further statistical analysis. The five metastases with an at first unknown primary could, according to the follow-up, all be classified correctly with high PP. Most ovarian carcinomas, including the mucinous ones, can be discriminated with high probability from colonic carcinomas using a panel of three antibodies directed against CEA, cytokeratin 7, and vimentin.


Inheritance pattern and clinical response to splenectomy as a reflection of erythrocyte spectrin deficiency in hereditary spherocytosis.
To determine how various inheritance patterns and responses to splenectomy relate to erythrocyte spectrin deficiencies in hereditary spherocytosis, we measured the spectrin content of erythrocytes by radioimmunoassay in 33 patients with this disease. Patients with the dominant form of hereditary spherocytosis generally had mild anemia, with spectrin at 63 to 81 percent of normal levels. Patients with the nondominant form of the disease had anemia ranging from severe to mild, with corresponding spectrin levels of 30 to 74 percent; their siblings were affected similarly. Distantly related homozygotes had different clinical severities with correspondingly different spectrin levels. The parents and offspring of patients with the nondominant form were clinically normal but consistently had subtle erythrocyte abnormalities. Spectrin levels in all patients were inversely related to osmotic fragility (P less than 0.0001), and they were also correlated with the clinical response to splenectomy: patients with spectrin levels above 70 percent achieved normal blood counts, those with levels of 40 to 70 percent had compensated hemolysis, and those with levels below 40 percent improved but remained anemic (P less than 0.0001). We conclude that the inheritance pattern and response to splenectomy in hereditary spherocytosis reflect erythrocyte spectrin deficiencies as determined by radioimmunoassay.


Linguistic influence on mathematical development is specific rather than pervasive: revisiting the Chinese Number Advantage in Chinese and English children.
The relative linguistic transparency of the Asian counting system has been used to explain Asian students' relative superiority in cross-cultural comparisons of mathematics achievement. To test the validity and extent of linguistic transparency in accounting for mathematical abilities, this study tested Chinese and British primary school children. Children in Hong Kong can learn mathematics using languages with both regular (Chinese) and irregular (English) counting systems, depending on their schools' medium of instruction. This makes it possible to compare groups with varying levels of exposure to the regular and irregular number systems within the same educational system, curriculum, and cultural environment. The study included three groups of first/second graders and third/fourth graders with varying degrees of experience to the Chinese language and counting systems: no experience (UK; n = 49); spoke Chinese at home and learnt to count in English at school (HK-E; n = 43); spoke Chinese at home and learnt to count in Chinese at school (HK-C; n = 47). They were compared on counting, numerical abilities and place value representation. The present study also measured nonverbal reasoning, attitude toward mathematics, involvement of parents, and extra-curricular mathematics lessons to explore alternative explanations of children's numeric ability. Results indicated that students in HK-C were better at counting backward and on the numeric skills test than those in HK-E, who were in turn better than the UK students. However, there was no statistical difference in counting forward, place value understanding, and a measure of arithmetic. Our findings add to existent literature suggesting that linguistic transparency does not have an all-pervasive influence on cross-national differences in arithmetic performance.


Impact of M49, Mrp, Enn, and C5a peptidase proteins on colonization of the mouse oral mucosa by Streptococcus pyogenes.
Resistance to phagocytosis is a hallmark of virulent Streptococcus pyogenes (group A streptococcus). Surface-bound C5a peptidase reduces recruitment of phagocytes to the site of infection, and hyaluronic acid capsules and/or the M protein limit the uptake of streptococci. In this study the relative impact of M and M-like proteins and the C5a peptidase on the virulence of a serotype M49 strain was assessed. The capacities of isogenic strains with an insertion mutation in emm49; with a deletion mutation in scpA49 (C5a peptidase gene); and with a deletion that removes all three M-like genes, mrp49, emm49, and enn49, to colonize mice and resist phagocytosis were compared. Experiments confirmed results obtained in an earlier study, which showed that the M49 protein was not required for in vitro resistance to phagocytosis, and also showed that the M protein was not required for colonization of mice. Failure to produce all three M-like proteins, M49, Mrp, and Enn49, significantly reduced the ability of these streptococci to resist phagocytosis in vitro but did not significantly alter the persistence of streptococci on the oral mucosa. In vitro experiments indicate that M+ streptococci are phagocytized by polymorphonuclear leukocytes that have been activated with phorbol-12-myristate 13-acetate or recombinant human C5a. This observation may explain the finding that expression of M49 protein is not essential for short-term colonization of the mouse oral mucosa.


Isolation and sequence analysis of human cadherin-6 complementary DNA for the full coding sequence and its expression in human carcinoma cells.
The expression pattern of E- and P-cadherin in human carcinomas has been reported by many laboratories. However, little is known about the involvement of other cadherin types in human carcinomas. cDNA clones for a cadherin molecule were isolated from a cDNA library of human hepatocellular carcinoma cells which lacked E- and P-cadherin expression but exhibited cell aggregation activity mediated by an unknown cadherin, and they were subjected to sequence analysis. The overlapped clones covered 4315 nucleotides and were found to encode a typical cadherin molecule consisting of 790 amino acids. Since the deduced amino acid sequence was identical to a partially available human cadherin-6 sequence except for two amino acid residues, the clones were considered to be human cadherin-6 cDNAs encoding the entire open reading frame. The deduced amino acid sequence also showed extremely high homology with recently reported rat K-cadherin, 97% for the putative mature protein, suggesting that cadherin-6 is the human counterpart of rat K-cadherin. Expression of cadherin-6 in various human normal tissues and carcinoma cells was examined by Northern blot analysis using a specific probe corresponding to the signal and precursor sequence. Among normal tissues examined, brain, cerebellum, and kidney showed strong expression of cadherin-6, whereas lung, pancreas, and gastric mucosa showed weak expression. Transcripts of cadherin-6 were not detected in normal liver, whereas four of six hepatocellular carcinoma cell lines examined expressed cadherin-6 abundantly. As reported for rat K-cadherin, three renal carcinoma cell lines also expressed cadherin-6 strongly. The most interesting finding was obtained for small cell lung carcinoma lines. Among 15 of such cell lines examined, all of 11 cadherin-6-positive lines were classified into the classic type, whereas the negative cell lines were all of the variant type. The present results suggest that besides E- and P-cadherin, other cadherin molecules are expressed in human cancers and are responsible for additional biological properties of the carcinoma cells.


An investigation into alleged 'hauntings'.
In cases of alleged hauntings, a large number of seemingly trustworthy witnesses consistently report experiencing unusual phenomena (e.g. apparitions, sudden changes in temperature, a strong sense of presence) in certain locations. The two studies reported here explored the psychological mechanisms that underlie this apparent evidence of 'ghostly' activity. The experiments took place at two locations that have a considerable reputation for being haunted-Hampton Court Palace (Surrey, England) and the South Bridge Vaults (Edinburgh, Scotland). Both studies involved participants walking around these locations and reporting where they experienced unusual phenomena. Results revealed significantly more reports of unusual experiences in areas that had a reputation for being haunted. This effect was not related to participants' prior knowledge about the reputation of these areas. However, the location of participants' experiences correlated significantly with various environmental factors, including, for example, the variance of local magnetic fields and lighting levels. These findings strongly suggest that alleged hauntings may not necessarily represent evidence for 'ghostly' activity, but could be, at least in part, the result of people responding to 'normal' factors in their surroundings.


Metagenomic de novo assembly of an aquatic representative of the verrucomicrobial class Spartobacteria.
The verrucomicrobial subdivision 2 class Spartobacteria is one of the most abundant bacterial lineages in soil and has recently also been found to be ubiquitous in aquatic environments. A 16S rRNA gene study from samples spanning the entire salinity range of the Baltic Sea indicated that, in the pelagic brackish water, a phylotype of the Spartobacteria is one of the dominating bacteria during summer. Phylogenetic analyses of related 16S rRNA genes indicate that a purely aquatic lineage within the Spartobacteria exists. Since no aquatic representative from the Spartobacteria has been cultured or sequenced, the metabolic capacity and ecological role of this lineage are yet unknown. In this study, we reconstructed the genome and metabolic potential of the abundant Baltic Sea Spartobacteria phylotype by metagenomics. Binning of genome fragments by nucleotide composition and a self-organizing map recovered the near-complete genome of the organism, the gene content of which suggests an aerobic heterotrophic metabolism. Notably, we found 23 glycoside hydrolases that likely allow the use of a variety of carbohydrates, like cellulose, mannan, xylan, chitin, and starch, as carbon sources. In addition, a complete pathway for sulfate utilization was found, indicating catabolic processing of sulfated polysaccharides, commonly found in aquatic phytoplankton. The high frequency of glycoside hydrolase genes implies an important role of this organism in the aquatic carbon cycle. Spatiotemporal data of the phylotype's distribution within the Baltic Sea indicate a connection to Cyanobacteria that may be the main source of the polysaccharide substrates.


Influence of UV illumination on the cold temperature operation of a LiNbO(3) Q-switched Nd:YAG laser.
UV illumination of a lithium niobate Q-switch was demonstrated as an effective means to eliminate a loss in hold-off and associated prelasing that occurs under cold temperature operation of Q-switched lasers. This degradation occurs due to the pyroelectric effect, where an accumulation of charge on crystal faces results in a reduction in the Q-switch hold-off and a spatially variable loss of the Q-switch in its high-transmission state, both resulting in lowering of the maximum Q-switched pulse energy. With UV illumination, the resulting creation of photo-generated carriers was shown to be effective in eliminating both of these effects. A Q-switched Nd:YAG laser utilizing UV-illuminated LiNbO(3) was shown to operate under cold temperatures without prelasing or spatially variable loss.


ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia.
Severe community-acquired pneumonia (sCAP) is associated with high morbidity and mortality, and whilst European and non-European guidelines are available for community-acquired pneumonia, there are no specific guidelines for sCAP. The European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Latin American Thoracic Association (ALAT) launched a task force to develop the first international guidelines for sCAP. The panel comprised a total of 18 European and four non-European experts, as well as two methodologists. Eight clinical questions for sCAP diagnosis and treatment were chosen to be addressed. Systematic literature searches were performed in several databases. Meta-analyses were performed for evidence synthesis, whenever possible. The quality of evidence was assessed with GRADE (Grading of Recommendations, Assessment, Development and Evaluation). Evidence to Decision frameworks were used to decide on the direction and strength of recommendations. Recommendations issued were related to diagnosis, antibiotics, organ support, biomarkers and co-adjuvant therapy. After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention and implications to health equity, recommendations were made for or against specific treatment interventions. In these international guidelines, ERS, ESICM, ESCMID, and ALAT provide evidence-based clinical practice recommendations for diagnosis, empirical treatment, and antibiotic therapy for sCAP, following the GRADE approach. Furthermore, current knowledge gaps have been highlighted and recommendations for future research have been made.


Relationship between internalized stigma and treatment efficacy in mixed neurotic spectrum and depressive disorders.
Many psychiatric patients suffer from self-stigma. One consequence of these internalized prejudices is decreased treatment efficacy. Much has been written about the effects of self-stigma in patients with severe mental disorders. However, individuals with minor psychiatric disorders also suffer from self-stigma. It is therefore necessary to explore the effect of self-stigma on treatment efficacy of neurotic patients. Aim of out study was to investigate relationship between self-stigma, severity of symptoms, and presence of comorbidit disorder and treatment outcome in neurotic patients. Patients were treated by combined psycho and pharmacotherapy. Level of self-stigma was measured by Internalized Stigma Of Mental Illness scale. Severity of anxiety and depressive symptoms was assed by Beck Anxiety Inventory, Beck Depressive Inventory and Clinical Global Impression Scale. Level of self-stigma was significantly correlated with the levels of anxiety, depression and global evalutions of a mental state on the beginnig of the therapy. Up to our results patients with higher level of self-stigmatization had lower improvement after combined treatmet in respect to perceived anxiety symptoms. Self-stigma seems to be an important factor influencing efficacy of combined treatment. More researches focused on self-stigmatization should be done to find an optimal therapeutic strategy for patients with higher level of self-stigmatization.


Cardiopulmonary exercise testing with right-heart catheterization in patients with systemic sclerosis.
To examine the role of cardiopulmonary exercise testing with right-heart catheterization (CPET/RHC) in patients with systemic sclerosis (SSc) with potentially multifactorial exertional limitation. This was a single-center retrospective cohort study of patients with SSc referred for CPET/RHC. A total of 19 patients with SSc [subtypes: 10 limited, 5 diffuse, 1 systemic lupus erythematosus (SLE)/SSc overlap, and 3 with no subtype specified in the medical record] underwent CPET/RHC testing from February 2003 to February 2008. Of these patients, the primary limitations to exercise were found to be ventilatory (n = 6), deconditioning/cardiovascular (n = 6), pulmonary vascular (PVL; n = 3), and exercise-induced left ventricular diastolic dysfunction (exercise-LVDD; n = 4). No prior physical examination, pulmonary function test, imaging, or echocardiographic data reliably predicted the etiology of exercise limitation determined by CPET/RHC. Vital capacity and ventilatory equivalent for CO(2) did not differ during CPET testing between PVL and exercise-LVDD, limiting the utility of CPET alone for discriminating these etiologies of dyspnea. Exercise alveolar-arterial oxygen gradient was elevated in subjects shown to have PVL [median 48 mm Hg (interquartile range 45.3, 62.0)] compared to those with exercise-LVDD [26.0 (IQR 10.6, 36.0)] and deconditioning [13.9 (IQR 4.0, 16.4); p = 0.02]. Major therapeutic changes occurred in 11/19 (58%) subjects after CPET/RHC testing. CPET/RHC testing in subjects with SSc and potentially multifactorial dyspnea adds potentially useful diagnostic information unavailable from noninvasive testing.


Enhanced DNA cross-link removal: the apparent mechanism of resistance in a clinically relevant melphalan-resistant human breast cancer cell line.
Resistance to the cytotoxic effects of alkylating agents is a major limitation to their clinical efficacy. Although a number of animal and human tumor cell models have been developed to study this problem, it has proven difficult to achieve very high levels of resistance to alkylating agents in vitro. This is consistent with the recent clinical evidence that alkylator resistance can be overcome by dose escalations of less than 10-fold. A number of mechanisms of alkylator resistance have been described, more than one of which may occur in the same model. This paper describes a human breast cancer cell subline selected for 3-fold resistance to melphalan and cross-resistant to other alkylators in which only one of the previously described mechanisms of resistance, enhanced removal of DNA interstrand cross-linking, is demonstrable. Northern blot analysis using the human incisional repair gene ERCC-1 cDNA demonstrated that this particular gene product is not the altered function in these cells, so the molecular characterization of the observed enhanced repair is pending. Because these cells are also cross-resistant to radiation and to adriamycin and epipodophyllotoxin, they may represent a clinically relevant model in which to examine the role of DNA repair of lesions resulting from alkylators and other cytotoxic agents.


Depressive symptoms after stroke are associated with worse recovery.
More studies are needed on how depressive symptoms in stroke patients can impact outcomes. We evaluated the relationship between depression symptom severity and motor outcomes in a cohort of patients with motor impairment from ischemic stroke. We enrolled consecutive ischemic stroke patients without a clinical diagnosis of depression who presented to a single-center urban academic referral hospital. The Patient Health Questionnaire-9 (PHQ-9) scale was used to measure depression symptom severity at three months. Three assessments of motor function were collected at stroke onset and three months: Fugl-Meyer upper extremity (FM-UE), Motricity Index, and Action Research Arm Test (ARAT). We assessed the association between three-month severity on PHQ-9 scores with the outcome measures using univariable and multivariable linear regression models. Fifty-seven patients (mean age 67.8 ± 17.0 years; 50.9% male; 59.6% Caucasian) were included in the final analysis. Mean (standard deviation) outcome scores at three months were PHQ-9: 6.39 (5), Motricity Index: 86.93 (30.04), FM-UE: 52.67 (17.83), and ARAT: 43.77 (20.03). After adjusting for age, initial National Institute of Health Stroke Scale, and if patient discharged after hospitalization on a selective serotonin reuptake inhibitor, sex, and baseline motor outcome, we found that for every point increase in PHQ-9, the Motricity Index decreased by 0.82 points (p = 0.02) and the FM-UE decreased by 0.77 points (p = 0.049). Depressive symptoms are common in the stroke population. Depressive symptoms after stroke are associated with multiple types of motor impairments. We need better understanding of the biologic and psychologic aspects of depression involved in stroke recovery.


A practical approach to monitoring recovery: development of a perceived recovery status scale.
The aim of this study was to develop and test the practical utility of a perceived recovery status (PRS) scale. Sixteen volunteers (8 men, 8 women) performed 4 bouts of high-intensity intermittent sprint exercise. After completion of the baseline trial, in a repeated-measures design, subjects were given variable counterbalanced recovery periods of 24, 48, and 72 hours whereupon they repeated an identical intermittent exercise protocol. After a warm-up period, but before beginning each subsequent bout of intermittent sprinting, each individual provided their perceived level of recovery with a newly developed PRS scale. Similar to perceived exertion during exercise, PRS was based on subjective feelings. The utility of the PRS scale was assessed by measuring the level of agreement of an individual's perceived recovery relative to their performance during the exercise bout. Perceived recovery status and change (both positive and negative) in sprint performance during multiple bouts of repeated sprint exercise were moderately negative correlated (r = -0.63). Additionally, subjects were able to accurately assess level of recovery using the PRS scale indicated by correspondence with negative and positive changes in total sprint time relative to their previous session. The ability to detect changes in performance using a noninvasive psychobiological tool to identify differences in performance was independent of other psychological and physiological markers measured during testing, because there were no differences (p > 0.05) among ratings of perceived exertion (RPE), heart rate, blood lactate concentration, or session RPE values among any of the performance trials. Although further study is needed, current results indicate a subjective approach may be an effective means for assessing recovery from day to day, at least under similar conditions.


Targeting inflammation and oxidative stress in atrial fibrillation: role of 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibition with statins.
Atrial fibrillation (AF) is a burgeoning health-care problem, and the currently available therapeutic armamentarium is barely efficient. Experimental and clinical evidence implicates inflammation and myocardial oxidative stress in the pathogenesis of AF. Local and systemic inflammation has been found to both precede and follow the new onset of AF, and NOX2-dependent generation of reactive oxygen species in human right atrial samples has been independently associated with the occurrence of AF in the postoperative period in patients undergoing cardiac surgery. Anti-inflammatory and antioxidant agents can prevent atrial electrical remodeling in animal models of atrial tachypacing and the new onset of AF after cardiac surgery, suggesting a causal relationship between inflammation/oxidative stress and the atrial substrate that supports AF. Statin therapy, by redressing the myocardial nitroso-redox balance and reducing inflammation, has emerged as a potentially effective strategy for the prevention of AF. Evidence indicates that statins prevent AF-induced electrical remodeling in animal models of atrial tachypacing and may reduce the new onset of AF after cardiac surgery. However, whether statins have antiarrhythmic properties in humans has yet to be conclusively demonstrated, as data from randomized controlled trials specifically addressing the relevance of statin therapy for the primary and secondary prevention of AF remain scanty. A better understanding of the mechanisms underpinning the putative antiarrhythmic effects of statins may afford tailoring AF treatment to specific clinical settings and patient's subgroups. Large-scale randomized clinical trials are needed to support the indication of statin therapy solely on the basis of AF prevention.


Idiopathic pulmonary fibrosis: current concepts.
Idiopathic pulmonary fibrosis (IPF) is generally defined as a progressive, fibrosing inflammatory disease of the lung parenchyma of unknown cause. It is characterized by slowly increasing dyspnea, diffuse interstitial lung infiltrates, restrictive lung dysfunction, and impaired gas exchange. Ultimately, it is fatal in most patients, and treatment options remain unsatisfactory. The advent of high-resolution computed tomography of the chest and modifications in the histopathologic classification of interstitial pneumonias have reshaped the concept of IPF. Although initially thought to be a relatively specific clinicopathologic entity, it seems likely that IPF as previously defined is a heterogeneous disorder consisting of several clinicopathologic entities with differing histopathologic patterns, clinical course, response to therapy, and prognosis. The most common histologic pattern in cases previously defined as IPF is usual interstitial pneumonia, which is associated with a median survival of less than 3 years. For accurate prognosis and optimal management of patients, the clinician should attempt to be as precise as possible in distinguishing various clinicopathologic entities that have been included under the clinical heading of IPF. In the future, we recommend that the use of the term "idiopathic pulmonary fibrosis" be restricted to patients with usual interstitial pneumonia and that clinicians recognize the fact that other idiopathic interstitial pneumonias do not have the same prognostic effect traditionally ascribed to IPF.


Vancomycin-releasing cross-linked collagen sponges as wound dressings.
The study presents a novel vancomycin-releasing collagen wound dressing derived from Cyprinus carpio collagen type I cross-linked with carbodiimide which retarded the degradation rate and increased the stability of the sponge. Following lyophilization, the dressings were subjected to gamma sterilization. The structure was evaluated via scanning electron microscopy images, micro-computed tomography, and infrared spectrometry. The structural stability and vancomycin release properties were evaluated in phosphate buffered saline. Microbiological testing and a rat model of a wound infected with methicillin-resistant Staphylococcus aureus (MRSA) were then employed to test the efficacy of the treatment of the infected wound. Following an initial mass loss due to the release of vancomycin, the sponges remained stable. After 7 days of exposure in phosphate buffered saline (37°C), 60% of the material remained with a preserved collagen secondary structure together with a high degree of open porosity (over 80%). The analysis of the release of vancomycin revealed homogeneous distribution of the antibiotic both across and between the sponges. The release of vancomycin was retarded as proved by in vitro testing and further confirmed by the animal model from which measurable concentrations were observed in blood samples 24 hours after the subcutaneous implantation of the sponge, which was more than observed following intraperitoneal administration. The sponge was also highly effective in terms of reducing the number of colony-forming units in biopsies extracted from the infected wounds 4 days following the inoculation of the wounds with the MRSA solution. The presented sponges have ideal properties to serve as wound dressing for prevention of surgical site infection or treatment of already infected wounds.


High numerical aperture microendoscope objective for a fiber confocal reflectance microscope.
A disposable high numerical aperture microendoscope objective has been designed, fabricated, and tested for use with a fiber confocal reflectance microscope. The objective uses high precision LIGA fabricated components to integrate imaging components and hydraulic suction lines into a housing that measures only 3.85 mm in outer diameter and 14.65 mm in length. The hydraulics are used to translate tissue through the focal plane for three dimensional imaging. This device is diffraction limited for lambda = 850 nm, has a numerical aperture of 1.0, a field of view of 250 microm, and a working distance of 450 microm. The objective is intended for in vivo imaging of precancerous cells.


Synthesis, design and sensing applications of nanostructured ceria-based materials.
Cerium-based materials possess redox properties due to the presence of dual valence states of Ce3+ and Ce4+. In the last few years, the scientific community has paid much attention to designing and synthesizing cerium-based materials through advantageous routes for widespread catalytic and sensing applications in many fields. Cerium materials have been synthesized in many different forms, shapes and sizes. The catalytic and sensing capabilities of cerium nanostructures are highly dependent on their morphologies and can be improved significantly by modifying the sizes and shapes of the nanostructures to develop sensing scaffolds with improved sensing performance. These nanostructures provide a basis for applications in many fields. From a literature survey (2010 to 2015), it can be concluded that the fundamental morphologies, ratios, and capping of cerium nanostructures (CeNSs) constructively affect their properties and applications. Designed sensors utilizing CeNSs exhibit outstanding stability, high selectivity and eminent reproducibility in relation to time and temperature. This review will provide a perspective insight on the future trends in the design of different morphologies of CeNSs and their promising applications.


Reversal of neuropathic pain in diabetes by targeting glycosylation of Ca(V)3.2 T-type calcium channels.
It has been established that Ca(V)3.2 T-type voltage-gated calcium channels (T-channels) play a key role in the sensitized (hyperexcitable) state of nociceptive sensory neurons (nociceptors) in response to hyperglycemia associated with diabetes, which in turn can be a basis for painful symptoms of peripheral diabetic neuropathy (PDN). Unfortunately, current treatment for painful PDN has been limited by nonspecific systemic drugs with significant side effects or potential for abuse. We studied in vitro and in vivo mechanisms of plasticity of Ca(V)3.2 T-channel in a leptin-deficient (ob/ob) mouse model of PDN. We demonstrate that posttranslational glycosylation of specific extracellular asparagine residues in Ca(V)3.2 channels accelerates current kinetics, increases current density, and augments channel membrane expression. Importantly, deglycosylation treatment with neuraminidase inhibits native T-currents in nociceptors and in so doing completely and selectively reverses hyperalgesia in diabetic ob/ob mice without altering baseline pain responses in healthy mice. Our study describes a new mechanism for the regulation of Ca(V)3.2 activity and suggests that modulating the glycosylation state of T-channels in nociceptors may provide a way to suppress peripheral sensitization. Understanding the details of this regulatory pathway could facilitate the development of novel specific therapies for the treatment of painful PDN.


Autoimmune liver serology: current diagnostic and clinical challenges.
Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases (AiLD), namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis variants in adults and children. AIH-1 is specified by anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). AIH-2 is specified by antibody to liver kidney microsomal antigen type-1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1). SMA, ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation. PBC is specified by antimitochondrial antibodies (AMA) reacting with enzymes of the 2-oxo-acid dehydrogenase complexes (chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly reacting with nuclear pore gp210 and nuclear body sp100. Sclerosing cholangitis presents as at least two variants, first the classical primary sclerosing cholangitis (PSC) mostly affecting adult men wherein the only (and non-specific) reactivity is an atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA), also termed perinuclear anti-neutrophil nuclear antibodies (p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis (ASC) with serological features resembling those of type 1 AIH. Liver diagnostic serology is a fast-expanding area of investigation as new purified and recombinant autoantigens, and automated technologies such as ELISAs and bead assays, become available to complement (or even compete with) traditional immunofluorescence procedures. We survey for the first time global trends in quality assurance impacting as it does on (1) manufacturers/purveyors of kits and reagents, (2) diagnostic service laboratories that fulfill clinicians' requirements, and (3) the end-user, the physician providing patient care, who must properly interpret test results in the overall clinical context.


Virtual reality in the treatment of generalized anxiety disorders.
Generalized anxiety disorder (GAD) is a common anxiety disorder characterized by 6 months of "excessive anxiety and worry" about a variety of events and situations. Anxiety and worry are often accompanied by additional symptoms like restlessness, being easily fatigued, difficulty concentrating, irritability, muscle tension and disturbed sleep. GAD is usually treated with medications and/or psychotherapy. In particular, the two most promising treatments seem to be cognitive therapy and applied relaxation. In this study we integrated these approaches through the use of a biofeedback enhanced virtual reality (VR) system used both for relaxation and controlled exposure. Moreover, this experience is strengthened by the use of a mobile phone that allows patients to perform the virtual experience even in an outpatient setting. This paper describe the results of a controlled trial (NCT00602212) involving 20 GAD patients randomly assigned to the following groups: (1) the VR and Mobile group (VRMB) including biofeedback; (2) the VR and Mobile group (VRM) without biofeedback; (3) the waiting list (WL) group. The clinical data underlined that (a) VR can be used also in the treatment of GAD; (b) in a VR treatment, patients take advantage of a mobile device that delivers in an outpatient setting guided experiences, similar to the one experienced in VR.


Exploring the repertoire of IgE-binding self-antigens associated with atopic eczema.
Atopic eczema (AE) is the most common chronic inflammatory skin disease. Recent data demonstrate the presence of autoreactive serum IgE antibodies correlating with the severity of the disease. Although several IgE-binding self-antigens have been reported, the whole repertoire of IgE-binding self-antigens is unknown. We aimed to estimate the repertoire size of autoreactive proteins related to AE and clone, produce, and characterize humoral and T-cell responses against novel self-antigens. Phage surface-displayed human cDNA libraries were enriched for clones binding to serum IgE from patients with AE and screened by using high-throughput technology. Selected clones were used to produce the encoded proteins, to test their IgE-binding ability in Western blots and ELISAs, and their ability to induce mediator release from basophils of sensitized individuals. One hundred forty sequences encoding potential IgE-binding self-antigens associated with AE were identified. Sixteen sequences encoded already described self-antigens. Three new sequences showed homology with environmental allergens, 86 encoded known human proteins, 7 predicted proteins, and 28 showed sequence identity with genomic contigs. Immunoblotting and ELISA experiments demonstrated the presence of IgE antibodies in sera from patients with AE to 5 selected recombinant self-antigens and their ability to induce mediator release from basophils of patients with AE who have self-antigen-specific IgE antibodies. These data demonstrate a broad spectrum of at least 140 IgE-binding self-antigens associated with AE. By binding IgE antibodies or activating specific T cells, they might promote, perpetuate, or both existing skin inflammation.


Association of bone dimensions with a parathyroid hormone gene polymorphism in women.
We have recently shown that bone radiogrammetric dimensions are associated with vitamin D receptor gene polymorphism. Since parathyroid hormone (PTH) plays a central role in maintaining calcium homeostasis and in bone remodeling, we investigated whether bone radiogrammetric dimensions are associated with a PTH gene polymorphism in 91 healthy Caucasian women, who were premenopausal at entry into the study. These women had assessments of bone by radiogrammetry every five years for a median period of 20 years (range 4-27). DNA was extracted from white blood cells. A segment of the PTH gene with a polymorphism at a BstBI restriction site was amplified by polymerase chain reaction. Diameter, cortical thickness and cross-sectional area at standard sites of the metacarpals, radius and femur were measured with radiogrammetry. Higher metacarpal diameter and cross-sectional cortical area, and a slower decrease in radial cortical area with age, were associated with the absence of the BstBI restriction site of the PTH gene. PTH gene polymorphism accounts for about 7-9% of the total variances of bone dimensional variables. These findings suggest that the dimensions of long bones are influenced by allelic variations in the PTH gene or in genes nearby.


Gender effects on components of burden and depression among dementia caregivers.
Previous literature has examined burden and depression predominately as unitary constructs in relation to dementia caregiving. No studies thus far have examined gender differences in the specific components of burden and depression in dementia caregivers. The current study examined whether empirically validated dimensions of caregiver burden differed by gender for dementia caregivers. The sample consisted of 211 dementia caregivers enrolled in a longitudinal intervention study. Only baseline functioning was evaluated in this study. Levels of burden were assessed using the Zarit Burden Interview (ZBI), and levels of depression were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). Factor analysis revealed three facets of burden: impact of caregiving on the caregivers' lives, guilt, and frustration/embarrassment, and four facets of depression: depressed affect, somatic activity, positive affect, and interpersonal feelings. Overall burden (p < .001) and impact of caregiving on the caregivers' life (p < .001) were significantly higher in females. Overall levels of depression (p = .018), somatic and retarded activity (p = .018), depressed affect (p = .005), and positive affect (p = .012) were significantly higher in females. Findings suggest that distressed male and female dementia caregivers experience caregiving differently. Results from this study could be used to identify gender-specific interventions related to subtypes of burden and depression to optimize quality of life for caregivers.


Anthropometrical and physiological determinants of performance in French West Indian monofin swimmers: a first approach.
To characterise the anthropometrical and physiological parameters of French West Indian monofin swimmers, seven French West Indian male competitors underwent anthropometrical measurements and physiological testing. The results were analysed in relation with their performances during national and international events (from 50- to 1500-m). We found that both anthropometrical and physiological (aerobic and anaerobic components) factors contributed to the performances of these swimmers. The results demonstrated that certain parameters consistently contributed to the global performance: aerobic parameters (maximal oxygen uptake and the second ventilatory threshold, R (2) = 0.72 and 0.69, respectively), anaerobic parameters (power obtained with the counter-movement jump [R (2) = 0.58] and the force-velocity test [R (2) = 0.54]), leg volume (V1, R (2) = 0.54) and perimeter (P1, R (2) = 0.64), and fat and lean body mass (R (2) = 0.76 and 0.62, respectively). Further studies are needed to compare these determinants of performance in French West Indian and European swimmers and to investigate how they contribute to swimming technique.


Neurological outcomes and surgical complications in 221 spinal nerve sheath tumors.
OBJECTIVE Among all primary spinal neoplasms, approximately two-thirds are intradural extramedullary lesions; nerve sheath tumors, mainly neurofibromas and schwannomas, comprise approximately half of them. Given the rarity of these lesions, reports of surgical complications are limited. The aim of this study was to identify the rates of new or worsening neurological deficits and surgical complications associated with the resection of spinal nerve sheath tumors and the potential factors related to these outcomes. METHODS Patients were identified through a search of an institutional neuropathology database and a separate review of current procedural terminology (CPT) codes. Age, sex, clinical presentation, presence of neurofibromatosis (NF), tumor type, tumor location, extent of resection characterized as gross total or subtotal, use of intraoperative neuromonitoring, surgical complications, presence of neurological deficit, and clinical follow-up were recorded. RESULTS Two hundred twenty-one tumors in 199 patients with a mean age of 45 years were identified. Fifty-three tumors were neurofibromas; 163, schwannomas; and 5, malignant peripheral nerve sheath tumors (MPNSTs). There were 70 complications in 221 cases, a rate of 32%, which included 34 new or worsening sensory symptoms (15%), 12 new or worsening motor deficits (5%), 10 CSF leaks or pseudomeningoceles (4%), 11 wound infections (5%), 5 cases of spinal deformity (2%), and 6 others (2 spinal epidural hematomas, 1 nonoperative cranial subdural hematoma, 1 deep venous thrombosis, 1 case of urinary retention, and 1 recurrent laryngeal nerve injury). Complications were more common in cervical (36%) and lumbosacral (38%) tumors than in thoracic (18%) lesions (p = 0.021). Intradural and dumbbell lesions were associated with higher rates of CSF leakage, pseudomeningocele, and wound infection. Complications were present in 18 neurofibromas (34%), 50 schwannomas (31%), and 2 MPNSTs (40%); the differences in frequency were not significant (p = 0.834). Higher complication rates were observed in patients with NF than in patients without (38% vs 30%, p = 0.189), although rates were higher in NF Type 2 than in Type 1 (64% vs 31%). There was no difference in the use of intraoperative neuromonitoring when comparing cases with surgical complications and those without (67% vs 69%, p = 0.797). However, the use of neuromonitoring was associated with a significantly higher rate of gross-total resection (79% vs 66%, p = 0.022). CONCLUSIONS Resection is a safe and effective treatment for spinal nerve sheath tumors. Approximately 30% of patients developed a postoperative complication, most commonly new or worsening sensory deficits. This rate probably represents an inevitable complication of nerve sheath tumor surgery given the intimacy of these lesions with functional neural elements.


STRait Razor Online: An enhanced user interface to facilitate interpretation of MPS data.
Since 2013, STRait Razor has enabled analysis of massively parallel sequencing (MPS) data from various marker systems such as short tandem repeats, single nucleotide polymorphisms, insertion/deletions, and mitochondrial DNA. In this paper, STRait Razor Online (SRO), available at https://www.unthsc.edu/straitrazor, is introduced as an interactive, Shiny-based user interface for primary analysis of MPS data and secondary analysis of STRait Razor haplotype pileups. This software can be accessed from any common browser via desktop, tablet, or smartphone device. SRO is available also as a standalone application and open-source R script available at https://github.com/ExpectationsManaged/STRaitRazorOnline. The local application is capable of batch processing of both fastq files and primary analysis output. Processed batches generate individual report folders and summary reports at the locus- and haplotype-level in a matter of minutes. For example, the processing of data from ∼700 samples generated with the ForenSeq Signature Preparation Kit from allsequences.txt to a final table can be performed in ∼40 min whereas the Excel-based workbooks can take 35-60 h to compile a subset of the tables generated by SRO. To facilitate analysis of single-source, reference samples, a preliminary triaging system was implemented that calls potential alleles and flags loci suspected of severe heterozygote imbalance. When compared to published, manually curated data sets, 98.72 % of software-assigned allele calls without manual interpretation were consistent with curated data sets, 0.99 % loci were presented to the user for interpretation due to heterozygote imbalance, and the remaining 0.29 % of loci were inconsistent due to the analytical thresholds used across the studies.


The spectroscopic detection of drugs of abuse on textile fibres after recovery with adhesive lifters.
Fibres are one of the most common forms of evidence associated with forensic investigations. The use of adhesive lifters to recover fibres from crime scene samples has long been established as an effective method to recover such items of evidence. Once fibres have been lifted they are transferred to evidence bags for storage, safe transport and to preserve the chain of evidence. This study shows that when fibres are tape lifted particles of substances present trapped within those fibres are also lifted. Cotton, linen and wool fibres were examined in colours ranging from white to black. Samples of seized ecstasy, cocaine, ketamine and amphetamine were supplied by East Sussex Police and by the TICTAC unit at St Georges Hospital Tooting. The Raman spectra obtained showed that it is possible to identify drugs of abuse from particles trapped within fibres without interference from the fibre itself. It was also possible to obtain spectra after fibres were lifted with adhesive tapes without the detection process being compromised. Raman spectra from particles of drugs of abuse within fibres following tape lifting were also recorded through evidence bags. Again the detection process was not compromised. This initial study has shown that fibres have the potential to provide even more evidence than they do currently. Individuals that have had drugs of abuse about their person may have trace amounts of these substances trapped within the fibres of their clothing. This may be of particular importance if drugs have been carried in pockets of a garment. This technique has the advantage of being non-destructive, allows for re-testing, requires no sample preparation and also can be performed on samples without removal from the evidence bag thus removing any potential risk of contamination. It is important however to remember that when dealing with trace amounts of drugs of abuse the presence of such particles may be due to innocent transfer of such particles. Detection of particles of drugs of abuse on clothing does not necessarily indicate criminal activity in the absence of other evidence.


Cerebrospinal fluid flow dynamics in multiple sclerosis patients through phase contrast magnetic resonance imaging.
We studied cerebrospinal fluid (CSF) flow dynamics at the cervical level in association with internal jugular veins (IJV) flow for 92 patients with multiple sclerosis (MS). Phase contrast magnetic resonance imaging was used to quantify flow of the CSF and major vessels (including the IJV and the carotid arteries) at the C2-C3 level in the neck. Contrast enhanced MR angiography and time-of-flight MR venography were used to subdivide MS patients into stenotic (ST) and non-stenotic (NST) populations. We evaluated: IJV flow normalized by arterial flow; CSF peaks; CSF outflow duration and its onset from systole. We tested if these variables were statistically different among different MS phenotypes and between ST and NST MS patients. The delay between the beginning of beginning of systole and the CSF outflow was higher in ST compared to NST MS. Less IJV flow was observed in ST vs NST MS. None of the measures was different between the different MS phenotypes. These results suggest that alterations of IJV morphology affect both IJV flow and CSF flow timing but not CSF flow amplitude.


Three prevalent mutations in a patient with phenylalanine hydroxylase deficiency: implications for diagnosis and genetic counselling.
Mutation analysis in a patient with mild hyperphenylalaninaemia showed three distinct base substitutions in exon 12 of the phenylalanine hydroxylase (PAH) gene. All three mutations, R413P, Y414C, and D415N, have previously been described as being independently associated with PAH deficiency. Family studies and independent analysis of the PAH alleles of the patient showed cosegregation of the R413P and Y414C mutations. Data on the ethnic background of the family provide evidence that the R413P mutation has occurred on a PAH allele carrying the Y414C mutation. Using current methods for mutation identification, the presence of two known mutations on a single PAH allele implies the risk of misdiagnosis of PAH deficiency and complicates genetic counselling. Our results stress the need for comprehensive mutation scanning of the PAH gene in diagnostic settings.


Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model.
The development of the Artemis programme with the goal of returning to the moon is spurring technology advances that will eventually take humans to Mars and herald a new era of interplanetary space travel. However, long-term space travel poses unique challenges including exposure to ionising radiation from galactic cosmic rays and potential solar particle events, exposure to microgravity and specific nutritional challenges arising from earth independent exploration. Ionising radiation is one of the major obstacles facing future space travel as it can generate oxidative stress and directly damage cellular structures such as DNA, in turn causing genomic instability, telomere shortening, extracellular-matrix remodelling and persistent inflammation. In the gastrointestinal tract (GIT) this can lead to leaky gut syndrome, perforations and motility issues, which impact GIT functionality and affect nutritional status. While current countermeasures such as shielding from the spacecraft can attenuate harmful biological effects, they produce harmful secondary particles that contribute to radiation exposure. We hypothesised that induction of a torpor-like state would confer a radioprotective effect given the evidence that hibernation extends survival times in irradiated squirrels compared to active controls. To test this hypothesis, a torpor-like state was induced in zebrafish using melatonin treatment and reduced temperature, and radiation exposure was administered twice over the course of 10 days. The protective effects of induced-torpor were assessed via RNA sequencing and qPCR of mRNA extracted from the GIT. Pathway and network analysis were performed on the transcriptomic data to characterise the genomic signatures in radiation, torpor and torpor + radiation groups. Phenotypic analyses revealed that melatonin and reduced temperature successfully induced a torpor-like state in zebrafish as shown by decreased metabolism and activity levels. Genomic analyses indicated that low dose radiation caused DNA damage and oxidative stress triggering a stress response, including steroidal signalling and changes to metabolism, and cell cycle arrest. Torpor attenuated the stress response through an increase in pro-survival signals, reduced oxidative stress via the oxygen effect and detection and removal of misfolded proteins. This proof-of-concept model provides compelling initial evidence for utilizing an induced torpor-like state as a potential countermeasure for radiation exposure.


Dental caries experience of British children in an international context.
To document data on current and past levels of dental decay in British children and compare trends with those in other countries, in Europe in particular. Data were abstracted from multiple sources and collated and tabulated. The dental health of the majority of British children has improved dramatically since the early 1970s. Twelve-year-old children now have on average less than one decayed, missing (extracted) or filled tooth. Levels of dental decay in UK children at 5 and 12 years are among the lowest in the world. There are still marked inequalities in the dental decay experience of children between the territorial regions of the UK, high and low socio-economic groups, and regular and symptomatic dental attenders. Many children in areas of deprivation are either not motivated to seek dental treatment or experience barriers in obtaining it. In parallel with improvements in the dental health of the majority of children, the proportion of UK adults who have no natural teeth has fallen from 37% to 12% over the past four decades. Total tooth loss is now confined almost entirely to individuals over 45 years of age. Most of the improvements in children's dental health are attributable to environmental factors, in particular the widespread availability of fluoride containing toothpastes since the 1970s. There are clear benefits from fluoridation of public water supplies over and above those attributable to other factors. The findings suggest initiatives should be directed to bringing children from deprived backgrounds under the umbrella of dental care. To help alleviate the inequalities in dental health, water fluoridation should be implemented, in urban industrial areas in particular, where levels of dental decay are still unacceptably high.


A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.
Most proton pump inhibitors inhibit the bioactivation of clopidogrel to its active metabolite. The clinical significance of this drug interaction is unknown. We conducted a population-based nested case-control study among patients aged 66 years or older who commenced clopidogrel between Apr. 1, 2002, and Dec. 31, 2007, following hospital discharge after treatment of acute myocardial infarction. The cases in our study were those readmitted with acute myocardial infarction within 90 days after discharge. We performed a secondary analysis considering events within 1 year. Event-free controls (at a ratio of 3:1) were matched to cases on age, percutaneous coronary intervention and a validated risk score. We categorized exposure to proton pump inhibitors before the index date as current (within 30 days), previous (31-90 days) or remote (91-180 days). Among 13 636 patients prescribed clopidogrel following acute myocardial infarction, we identified 734 cases readmitted with myocardial infarction and 2057 controls. After extensive multivariable adjustment, current use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03-1.57). We found no association with more distant exposure to proton pump inhibitors or in multiple sensitivity analyses. In a stratified analysis, pantoprazole, which does not inhibit cytochrome P450 2C19, had no association with readmission for myocardial infarction (adjusted OR 1.02, 95% CI 0.70-1.47). Among patients receiving clopidogrel following acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a loss of the beneficial effects of clopidogrel and an increased risk of reinfarction.


Grey matter deficit in long-term recovered anorexia nervosa patients.
Cerebral grey matter (GM) reduction has repeatedly been shown in anorexia nervosa (AN). Evidence concerning completeness of GM restitution in recovered patients is contradictory. Five long-term recovered patients with AN were compared to symptomatic subjects and healthy controls using voxel-based morphometry. Whole brain GM, white matter and cerebrospinal fluid fractions were studied. Additionally, voxels that had shown significant GM reductions in symptomatic patients were investigated. Recovered subjects had been severely affected when symptomatic (mean body mass index: 12.1 kg/m²) and were in remission for a very long time period (>5 years). Whole brain tissue fractions did not differ from controls. Regional analysis showed persistent GM volume reduction, in particular of the precuneus. This study further supports the assumption that GM volume restitution is incomplete in subjects, who had previously been severely affected by anorexia nervosa. The meaning of GM reduction in long-term recovered AN patients, that is, its pathophysiological relevance, however, remains unclear. Furthermore, the precise aetiology of GM reduction remains an open question.


Physicochemical predictors of Multi-Walled Carbon Nanotube-induced pulmonary histopathology and toxicity one year after pulmonary deposition of 11 different Multi-Walled Carbon Nanotubes in mice.
Multi-walled carbon nanotubes (MWCNT) are widely used nanomaterials that cause pulmonary toxicity upon inhalation. The physicochemical properties of MWCNT vary greatly, which makes general safety evaluation challenging to conduct. Identification of the toxicity-inducing physicochemical properties of MWCNT is therefore of great importance. We have evaluated histological changes in lung tissue 1 year after a single intratracheal instillation of 11 well-characterized MWCNT in female C57BL/6N BomTac mice. Genotoxicity in liver and spleen was evaluated by the comet assay. The dose of 54 μg MWCNT corresponds to three times the estimated dose accumulated during a work life at a NIOSH recommended exposure limit (0.001 mg/m3 ). Short and thin MWCNT were observed as agglomerates in lung tissue 1 year after exposure, whereas thicker and longer MWCNT were detected as single fibres, suggesting biopersistence of both types of MWCNT. The thin and entangled MWCNT induced varying degree of pulmonary inflammation, in terms of lymphocytic aggregates, granulomas and macrophage infiltration, whereas two thick and straight MWCNT did not. By multiple regression analysis, larger diameter and higher content of iron predicted less histopathological changes, whereas higher cobalt content significantly predicted more histopathological changes. No MWCNT-related fibrosis or tumours in the lungs or pleura was found. One thin and entangled MWCNT induced increased levels of DNA strand breaks in liver; however, no physicochemical properties could be related to genotoxicity. This study reveals physicochemical-dependent difference in MWCNT-induced long-term, pulmonary histopathological changes. Identification of diameter size and cobalt content as important for MWCNT toxicity provides clues for designing MWCNT, which cause reduced human health effects following pulmonary exposure.


Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics.
While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax) would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA), significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720) and BCL2 (navitoclax) inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175.


AngioVac Suction Thrombectomy Complicated by Thrombus Fragmentation and Distal Embolization Leading to Hemodynamic Collapse: A Case Report.
A 35-year-old morbidly obese woman with a history of deep vein thrombosis and pulmonary embolism presented for right atrial thrombectomy via AngioVac suction system. A portion of the thrombus could not be suctioned into the AngioVac cannula, leading to fragmentation and distal embolization with hemodynamic collapse. This sequence, observed in real time under transesophageal echocardiography, also demonstrated that the clot had echocardiographic features of chronicity. A well-organized chronic clot may be more difficult to extract via this method, leading to the complication described. With increasing popularity of this less invasive method, further investigation to understand the indications and contraindications is warranted.


Generation of a new congenic mouse strain to test the relationships among serum insulin-like growth factor I, bone mineral density, and skeletal morphology in vivo.
Insulin-like growth factor (IGF) I is a critical peptide for skeletal growth and consolidation. However, its regulation is complex and, in part, heritable. We previously indicated that changes in both serum and skeletal IGF-I were related to strain-specific differences in total femoral bone mineral density (BMD) in mice. In addition, we defined four quantitative trait loci (QTLs) that contribute to the heritable determinants of the serum IGF-I phenotype in F2 mice derived from progenitor crosses between C3H/HeJ (C3H; high total femoral BMD and high IGF-I) and C57BL/6J (B6; low total femoral BMD and low IGF-I) strains. The strongest QTL, IGF-I serum level 1 (Igflsl-1; log10 of the odds ratio [LOD] score, approximately 9.0), is located on the middle portion of chromosome (Chr) 6. For this locus, C3H alleles are associated with a significant reduction in serum IGF-I. To test the effect of this QTL in vivo, we generated a new congenic strain (B6.C3H-6T [6T]) by placing the Chr 6 QTL region (D6Mit93 to D6Mit150) from C3H onto the B6 background. We then compared serum and skeletal IGF-I levels, body weight, and several skeletal phenotypes from the N9 generation of 6T congenic mice against B6 control mice. Female 6T congenic mice had 11-21% lower serum IGF-I levels at 6, 8, and 16 weeks of age compared with B6 (p < 0.05 for all). In males, serum IGF-I levels were similar in 6T congenics and B6 controls at 6 weeks and 8 weeks but were lower in 6T congenic mice at 16 weeks (p < 0.02). In vitro, there was a 40% reduction in secreted IGF-I in the conditioned media (CMs) from 6T calvaria osteoblasts compared with B6 cells (p < 0.01). Total femoral BMD as measured by peripheral quantitative computed tomography (pQCT) was lower in both 6T male (-4.8%, p < 0.01) and 6T female (-2.3%, p = 0.06) congenic mice. Geometric features of middiaphyseal cortical bone were reduced in 6T congenic mice compared with control mice. Femoral cancellous bone volume (BV) density and trabecular number (Tb.N) were 50% lower, whereas trabecular separation (Tb.Sp) was 90% higher in 8-week-old female 6T congenic mice compared with B6 control mice (p < 0.01 for all). Similarly, vertebral cancellous BV density and Tb.N were lower (-29% and -19%, respectively), whereas Tb.Sp was higher (+29%) in 16-week-old female 6T congenic mice compared with B6 control mice (p < 0.001 for all). Histomorphometric evaluation of the proximal tibia indicated that 6T congenics had reduced BV fraction, labeled surface, and bone formation rates compared with B6 congenic mice. In summary, we have developed a new congenic mouse strain that confirms the Chr 6 QTL as a major genetic regulatory determinant for serum IGF-I. This locus also influences bone density and morphology, with more dramatic effects in cancellous bone than in cortical bone.


Biological evidence for the acute health effects of secondhand smoke exposure.
A vast number of studies on the unfavorable effects of secondhand smoke (SHS) exist within the international literature, the majority of which evaluate longitudinal epidemiological data. Although limited, the experimental studies that assess the acute and short-term effects of exposure to SHS are also increasing in number. They include cellular, animal, and human studies that indicate a number of pathophysiological mechanisms through which the deleterious effects of SHS may arise. This current review evaluates the existing biological evidence regarding the acute health effects of SHS exposure. Analyses on the inhaled toxicants and the carcinogenicity of SHS are included as well as in-depth discussions on the evidence for acute SHS-induced respiratory, cardiovascular, metabolic, endocrine and immune effects, and SHS-induced influences on oxygen delivery and exercise. The influence of the length of exposure and the duration of the observed effects is also described. Moreover, recent findings regarding the underlying pathophysiological mechanisms related to SHS are depicted so as to generate models that describe the SHS-induced effects on different systems within the human body. Based on the presented biological evidence, it is concluded that brief, acute, transient exposures to SHS may cause significant adverse effects on several systems of the human body and represent a significant and acute health hazard. Future research directions in this area include research on the concentrations of tobacco smoke constituents in the alveolar milieu following SHS exposure, individual susceptibility to SHS, as well as the effects of SHS on neurobehavioral activity, brain cell development, synaptic development, and function.


The Stockholm spinal cord injury study: 4. Psychosocial and financial issues of the Swedish annual level-of-living survey in SCI subjects and controls.
In a series of articles from the Stockholm Spinal Cord Injury Study (SSCIS), the health status of a near-total regional SCI population comprising 353 subjects has been investigated. The present study describes the psycho-social and financial consequences of SCI in this group. It is based on a level-of-living survey that has been used annually on 8000-14,000 Swedes since 1974. The health-focused version of this survey was used for data collection in the subset of 326 subjects in the SSCIS that were residents of the Greater Stockholm area. The normative material consisted of 1978 interviews of residents of the same area, provided by the Swedish Bureau of Statistics. The results show that SCI subjects, although provided with basic material commodities up to par with the general population, have less financial reserves and more frequently express worry about their finances. Less than half of the subjects are gainfully employed, when part-time jobs are also included. Social activities are more restricted, and more centered on the core social network. Several items in the survey point to a preoccupation with personal rather than public matters. We feel that these factors, at least to some degree, are consequential to separation from the workplace, with resulting disadvantageous financial and social effects. Intensified vocational rehabilitation efforts might thus be justified from both an economic and a psycho-social point of view.


Early somatosensory processing in individuals at risk for developing psychoses.
Human cortical somatosensory evoked potentials (SEPs) allow an accurate investigation of thalamocortical and early cortical processing. SEPs reveal a burst of superimposed early (N20) high-frequency oscillations around 600 Hz. Previous studies reported alterations of SEPs in patients with schizophrenia. This study addresses the question whether those alterations are also observable in populations at risk for developing schizophrenia or bipolar disorders. To our knowledge to date, this is the first study investigating SEPs in a population at risk for developing psychoses. Median nerve SEPs were investigated using multichannel EEG in individuals at risk for developing bipolar disorders (n = 25), individuals with high-risk status (n = 59) and ultra-high-risk status for schizophrenia (n = 73) and a gender and age-matched control group (n = 45). Strengths and latencies of low- and high-frequency components as estimated by dipole source analysis were compared between groups. Low- and high-frequency source activity was reduced in both groups at risk for schizophrenia, in comparison to the group at risk for bipolar disorders. HFO amplitudes were also significant reduced in subjects with high-risk status for schizophrenia compared to healthy controls. These differences were accentuated among cannabis non-users. Reduced N20 source strengths were related to higher positive symptom load. These results suggest that the risk for schizophrenia, in contrast to bipolar disorders, may involve an impairment of early cerebral somatosensory processing. Neurophysiologic alterations in schizophrenia precede the onset of initial psychotic episode and may serve as indicator of vulnerability for developing schizophrenia.


A chronoamperometric method to estimate changes in the membrane composition of ion-selective membranes.
A new chronoamperometric method is used to estimate changes in the membrane composition of mobile-site, ionophore-based membranes. The characteristic features of the chronoamperometric curves (initial current, slope, break time) of valinomycin-based, potassium-selective membranes loaded with potassium tetrakis(4-chlorophenyl)borate are correlated with the mobile-site and free ionophore concentration in the membrane. limiting cases for strong and negligible ion pair formation are distinguished. Replicate measurements indicate a relative standard deviation in the calculated values less than 10%. The practical applicability of the method was tested with membranes incorporated into conventional ion-selective electrode bodies or cast onto microfabricated planar sensor structures.


Medicinal Cannabis: A Survey Among Health Care Providers in Washington State
Washington State allows marijuana use for medical (since 1998) and recreational (since 2012) purposes. The benefits of medicinal cannabis (MC) can be maximized if clinicians educate patients about dosing, routes of administration, side effects, and plant composition. However, little is known about clinicians' knowledge and practices in Washington State. An anonymous online survey assessed providers' MC knowledge, beliefs, clinical practices, and training needs. The survey was disseminated through health care providers' professional organizations in Washington State. Descriptive analysis compared providers who had and had not authorized MC for patients. Survey results informed the approach and content of an online training on best clinical practices of MC. Four hundred ninety-four health care providers responded to the survey. Approximately two-third were women, aged 30 to 60 years, and working in family or internal medicine. More than half of the respondents were legally allowed to write MC authorizations per Washington State law, and 27% of those had issued written MC authorizations. Overall, respondents reported low knowledge and comfort level related to recommending MC. Respondents rated MC knowledge as important and supported inclusion of MC training in medical/health provider curriculum. Most Washington State providers have not received education on scientific basis of MC or training on best clinical practices of MC. Clinicians who had issued MC authorizations were more likely to have received MC training than those who had not issued MC authorization. The potential of MCs to benefit some patients is hindered by the lack of comfort of clinicians to recommend it. Training opportunities are badly needed to address these issues.


Healthcare-associated pneumonia in acute care hospitals in European Union/European Economic Area countries: an analysis of data from a point prevalence survey, 2011 to 2012.
An aim of the ECDC point prevalence survey (PPS) in European Union/European Economic Area acute care hospitals was to acquire standardised healthcare-associated infections (HAI) data. We analysed one of the most common HAIs in the ECDC PPS, healthcare-associated pneumonia (HAP). Standardised HAI case definitions were provided and countries were advised to recruit nationally representative subsets of hospitals. We calculated 95% confidence intervals (CIs) around prevalence estimates and adjusted for clustering at hospital level. Of 231,459 patients in the survey, 2,902 (1.3%; 95% CI: 1.2-1.3) fulfilled the case definition for a HAP. HAPs were most frequent in intensive care units (8.1%; 95% CI: 7.4-8.9) and among patients intubated on the day of the survey (15%; 95% CI: 14-17; n = 737 with HAP). The most frequently reported microorganism was Pseudomonas aeruginosa (17% of 1,403 isolates), followed by Staphylococcus aureus (12%) and Klebsiella spp. (12%). Antimicrobial resistance was common among isolated microorganisms. The most frequently prescribed antimicrobial group was penicillins, including combinations with beta-lactamase inhibitors. HAPs occur regularly among intubated and non-intubated patients, with marked differences between medical specialities. HAPs remain a priority for preventive interventions, including surveillance. Our data provide a reference for future prevalence of HAPs at various settings.


Transductive multi-view zero-shot learning.
Most existing zero-shot learning approaches exploit transfer learning via an intermediate semantic representation shared between an annotated auxiliary dataset and a target dataset with different classes and no annotation. A projection from a low-level feature space to the semantic representation space is learned from the auxiliary dataset and applied without adaptation to the target dataset. In this paper we identify two inherent limitations with these approaches. First, due to having disjoint and potentially unrelated classes, the projection functions learned from the auxiliary dataset/domain are biased when applied directly to the target dataset/domain. We call this problem the projection domain shift problem and propose a novel framework, transductive multi-view embedding, to solve it. The second limitation is the prototype sparsity problem which refers to the fact that for each target class, only a single prototype is available for zero-shot learning given a semantic representation. To overcome this problem, a novel heterogeneous multi-view hypergraph label propagation method is formulated for zero-shot learning in the transductive embedding space. It effectively exploits the complementary information offered by different semantic representations and takes advantage of the manifold structures of multiple representation spaces in a coherent manner. We demonstrate through extensive experiments that the proposed approach (1) rectifies the projection shift between the auxiliary and target domains, (2) exploits the complementarity of multiple semantic representations, (3) significantly outperforms existing methods for both zero-shot and N-shot recognition on three image and video benchmark datasets, and (4) enables novel cross-view annotation tasks.


Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.


Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells.
The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive. Here, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib. Thus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR.


Force-balance percolation.
We study models of correlated percolation where there are constraints on the occupation of sites that mimic force balance, i.e., for a site to be stable requires occupied neighboring sites in all four compass directions in two dimensions. We prove rigorously that p(c) < 1 for the two-dimensional models studied. Numerical data indicate that the force-balance percolation transition is discontinuous with a growing crossover length, with perhaps the same form as the jamming percolation models, suggesting that all models belong to the same universality class with the same underlying mechanism driving the transition in both cases. We find a lower bound for the correlation length in the connected phase and that the correlation function does not appear to be a power law at the transition. Finally, we study the dynamics of the culling procedure invoked to obtain the force-balance configurations and find a dynamical exponent similar to that found in sandpile models.


Lung microcytoma: a multidisciplinary therapeutic approach.
This report is of 26 patients diagnosed with microcytoma of the lung in stages I, II, and IIIa. All patients received surgical treatment as well as postoperative chemoradiotherapy when indicated by stage. Mean survival rates were 16 months for stage 1, 10 months for stage II and 6 months for stage IIIa disease. For many years surgery was considered contraindicated in the treatment of pulmonary microcytoma. Now a multidisciplinary approach is being used in which surgery has a crucial role. Microcytoma of the lung has a poor prognosis due to its early metastasis and rapid growth. It is crucial to have early diagnosis and accurate, consistent staging as the basis for treatment. A review of literature shows that the use of surgery, chemotherapy and radiotherapy are all important in treatment of microcytoma. Chemotherapy is successfully utilized preoperatively to improve local control, decrease neoplastic mass, induce histological regression and as postoperative adjuvant therapy. Radiotherapy has been shown to be effective preoperatively to reduce local mass and prophylactically for cerebral metastasis. Surgery is crucial to irradicate the neoplastic mass, improve staging accuracy, decrease the possible selection of neoplastic clones resistant to postoperative therapy, decrease local recurrence and allow less aggressive chemoradiotherapy. We feel the most effective protocol for pulmonary microcytoma includes preoperative chemotherapy and radiotherapy when indicated followed by surgical intervention and finally successive adjuvant therapy. The limited number of our cases does not consent a statistically significative conclusion. Our data confirm the importance of the surgical procedure in stages I and II, where according also to other authors, the best results are obtained. Surgical indication in stage IIIa is still discussed due to precocius lymphnode dissemination that significantly affects long-term survival.


Assembly of a spherical plant virus.
The conditions previously reported as necessary for the reassembly of spherical viruses have been distinctly unphysiological and such reassembly cannot be related directly to the in vivo reaction. Mild conditions for the in vitro reassembly of cowpea chlorotic mottle virus (CCMV) from its isolated components have now been described (Adolph & Butler 1975) and the reassembled virus characterized. This reassembly involved the co-aggregation of the RNA and protein around neutrality and at ionic strength 0.2, giving yields of 70% encapsidation at pH 6.0. The reaction was independent of temperature over the range 5-25 degrees C and did not require the presence of Mg2+ ions. The reassembled virus shows a stability similar to that of native CCMV, with the same change in sedimentation coefficient around pH 6.5. The molecular mass and buoyant density in CsCl are also the same as those of native CCMV, while the electron microscope reveals a surface morphology on the reassembled particles like that on native CCMV. Analysis of the number-average, mass-average, and Z-average molecular masses of the purified protein at both pH 6.0 and pH 7.5 suggests that the active unit for reassembly is a dimer of the protein subunit.