A status-enhancement account of overconfidence.
In explaining the prevalence of the overconfident belief that one is better than others, prior work has focused on the motive to maintain high self-esteem, abetted by biases in attention, memory, and cognition. An additional possibility is that overconfidence enhances the person's social status. We tested this status-enhancing account of overconfidence in 6 studies. Studies 1-3 found that overconfidence leads to higher social status in both short- and longer-term groups, using naturalistic and experimental designs. Study 4 applied a Brunswikian lens analysis (Brunswik, 1956) and found that overconfidence leads to a behavioral signature that makes the individual appear competent to others. Studies 5 and 6 measured and experimentally manipulated the desire for status and found that the status motive promotes overconfidence. Together, these studies suggest that people might so often believe they are better than others because it helps them achieve higher social status.


High-dose yttrium-90-ibritumomab tiuxetan with tandem stem-cell reinfusion: an outpatient preparative regimen for autologous hematopoietic cell transplantation.
To develop high-dose myeloablative therapy for CD20(+) non-Hodgkin's lymphoma (NHL) as a safe and widely applicable regimen. Patients with relapsed/refractory (n = 25) or de novo high-risk (n = 5) NHL received one myeloablative dose of yttrium-90 ((90)Y)-ibritumomab tiuxetan after five chemotherapy courses, including three cycles of anthracycline- or platinum-containing regimens, one cycle of cyclophosphamide (4 to 7 g/m(2)), and one cycle of cytarabine (12 to 24 g/m(2)). The only exclusion criteria were CNS lymphoma and Eastern Cooperative Oncology Group performance status of more than 3. Primary end points were overall survival (OS) and event-free survival (EFS). Secondary end points included safety and applicability of high-dose (90)Y-ibritumomab tiuxetan. To minimize hematologic toxicity, stem cells were reinfused at days 7 and 14 after (90)Y-ibritumomab tiuxetan. Thirteen patients received (90)Y-ibritumomab tiuxetan 0.8 mCi/kg, and 17 patients received 1.2 mCi/kg. At 1.2 mCi/kg, the radiation absorbed by critical nonhematologic organs approached the protocol-defined upper safety limit, defining this as the recommended dose for subsequent studies. Hematologic toxicity was mild to moderate and of short duration. Infections occurred in 27% of patients (none had a severity grade greater than 3). After a median observation time of 30 months (range, 22 to 48 months), no myeloid secondary malignancy or chromosomal abnormality was observed, the OS rate was 87%, and the EFS rate was 69%. High-dose (90)Y-ibritumomab tiuxetan seems to be an innovative myeloablative regimen with unprecedented short-term toxicity and wide applicability. Further studies are required to assess its long-term safety and role in the management of CD20(+) NHL.


Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization.
Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.


Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio-oncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.


HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases.
We established six T cell clones specific for pyruvate dehydrogenase complex (PDC)-E2 peptides from four different patients with primary biliary cirrhosis using 33 different peptides of 17-20 amino acid residues corresponding to human PDC-E2 as stimulating antigens. The minimal T cell epitopes of these six T cell clones were all mapped to the same region of the PDC-E2 peptide 163-176 (GDLLAEIETDKATI), which corresponds to the inner lipoyl domain of PDC-E2. The HLA restriction molecules for this epitope were all identified as HLA DRB4 0101. The common essential amino acids of this epitope for these T cell clones were E, D, and K at positions 170, 172, and 173, respectively; other crucial amino acids for this epitope differed in each T cell clone. In addition, the alanine-substituted peptides at positions 170 and 173, but not 172, inhibited the proliferation of all T cell clones induced by the original peptide of human PDC-E2 163-176, indicating that amino acid D at position 172 is a critical MHC-binding site for all T cell clones tested. Interestingly, all T cell clones reacted to PDC-E2 peptide 36-49 (GDLIAEVETDKATV), which corresponds to the outer lipoyl domain of human PDC-E2. Furthermore, one T cell clone cross-reacted with exogenous antigens such as Escherichia coli PDC-E2 peptide 31-44/134-147/235-248 (EQSLITVEGDKASM), which has an EXDK sequence. This is a definite demonstration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases. It is also considered possible to design peptide-specific immunotherapy based on the findings of T cell autoepitopes in primary biliary cirrhosis.


Occupation and occupational exposure to endocrine disrupting chemicals in male breast cancer: a case-control study in Europe.
Male breast cancer is a rare disease of largely unknown aetiology. In addition to genetic and hormone-related risk factors, a large number of environmental chemicals are suspected of playing a role in breast cancer. The identification of occupations or occupational exposures associated with an increased incidence of breast cancer in men may help to identify mammary carcinogens in the environment. Occupational risk factors for male breast cancer were investigated in a multi-centre case-control study conducted in eight European countries which included 104 cases and 1901 controls. Lifetime work history was obtained during in-person interviews. Occupational exposures to endocrine disrupting chemicals (alkylphenolic compounds, phthalates, polychlorinated biphenyls and dioxins) were assessed on a case-by-case basis using expert judgement. Male breast cancer incidence was particularly increased in motor vehicle mechanics (OR 2.1, 95% CI 1.0 to 4.4) with a dose-effect relationship with duration of employment. It was also increased in paper makers and painters, forestry and logging workers, health and social workers, and furniture manufacture workers. The OR for exposure to alkylphenolic compounds above the median was 3.8 (95% CI 1.5 to 9.5). This association persisted after adjustment for occupational exposures to other environmental oestrogens. These findings suggest that some environmental chemicals are possible mammary carcinogens. Petrol, organic petroleum solvents or polycyclic aromatic hydrocarbons are suspect because of the consistent elevated risk of male breast cancer observed in motor vehicle mechanics. Endocrine disruptors such as alkylphenolic compounds may play a role in breast cancer.


Temporality and collectivity: diversity, history and the rhetorical construction of national entitativity.
Vernacular representations of nationhood collected in England differed from canonical accounts of social categorization in three respects. First, nations were not typically constructed as simple person categories, but rather as hybrid collectivities of human beings, objects and geographical locations. Second, national representation was not confined to the present tense, but was typically conveyed through temporal distinctions and narratives. Third, speakers displayed a reflexive concern over the rationality and morality of national categorization and stereotyping. Speakers could manage the tension between the need to recognize both national diversity and entitativity by forging a distinction between Englishness (identified with homogeneity, ethnic nationalism and the past) and Britishness (identified with pluralism, civic nationalism and historical progress). However, accounts had a dilemmatic quality. The strategies speakers used to promote images of contemporary national in-group diversity often implicitly presupposed a normal moral order of national cultural homogeneity. The association of pluralism with values of progressive social change meant that accounts of 'our' distinctive lack of national character could carry tacit implications of relative superiority. General implications for social identity approaches to social categorization are discussed.


Androgens and cardiac diseases.
Although androgens have been considered deleterious for the cardiovascular system, recent data have demonstrated favourable testosterone effects on cardiac and vascular remodeling and clinical outcome. However, the cardiovascular risk-benefit profile of testosterone therapy remains largely elusive due to lack of well-designed and adequately powered randomized clinical trials. In any case, a large body of clinical evidence underlines that low plasma testosterone levels should be considered a risk factor for cardiovascular disease, and that the evaluation of sex steroids should be included in the routine clinical evaluation of cardiac patients. A better understanding of the mechanism regulating the effects of testosterone on cardiovascular system could lead to novel therapeutic strategies in several cardiac patient populations, such as chronic heart failure patients and those who recently underwent cardiac surgery.


Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for prostate cancer.
We studied the molecular mechanisms of apoptosis in the prostate cancer cell line LNCaP and whether overexpression of caspase activity could force this cell line to undergo apoptosis. The inhibitor of phosphomevalonate decarboxylase, sodium phenylacetate, and the protein kinase inhibitor staurosporine induced (a) release of cytochrome c from the mitochondria to the cytosol; (b) reduction in mitochondrial transmembrane potential; (c) proteolytic processing of caspase-3 and -7 but not -2; (d) cleavage of the DEVD substrate and the death substrates poly(ADP-ribose) polymerase and DNA fragmentation factor; and (e) apoptosis. The panspecific inhibitor of caspase activation N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-FMK) prevented all of these events except release of mitochondrial cytochrome c into the cytosol. None of these apoptotic signaling events were elicited by staurosporine or sodium phenylacetate treatment of LNCaP-Bcl-2 cells that overexpress the oncoprotein Bcl-2. Because caspase-7 is activated in every model of apoptosis that we have characterized thus far, we wished to learn whether overexpression of this protease could directly cause apoptosis of LNCaP cells. By using a replication-defective adenovirus, overexpression of caspase-7 protein in both LNCaP and LNCaP-Bcl-2 cells was accompanied by induction of cleavage of the DEVD substrate and TUNEL. These studies have demonstrated that caspase-7 and -3 are critical mediators of apoptosis in LNCaP cells. Caspase-7 was proteolytically activated in every model of apoptosis that we have developed, and the overexpression of it induced apoptosis of LNCaP and LNCaP-Bcl-2 cells. Thus, adenoviral-mediated transfer of caspase-7 may offer a new effective approach for the treatment of prostate cancer.


Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome.
The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervical spinal cord. Patients were monitored before and after transplantation by clinical, psychological, neuroradiological, and neurophysiological assessment. For up to 60 months after surgery, none of the patients manifested severe adverse effects or increased disease progression because of the treatment. Eleven patients died, and two underwent tracheotomy as a result of the natural history of the disease. We detected a transitory decrease in progression of ALS Functional Rating Scale Revised, starting within the first month after surgery and up to 4 months after transplantation. Our results show that transplantation of hNSC is a safe procedure that causes no major deleterious effects over the short or long term. This study is the first example of medical transplantation of a highly standardized cell drug product, which can be reproducibly and stably expanded ex vivo, comprising hNSC that are not immortalized, and are derived from the forebrain of the same two donors throughout this entire study as well as across future trials. Our experimental design provides benefits in terms of enhancing both intra- and interstudy reproducibility and homogeneity. Given the potential therapeutic effects of the hNSCs, our observations support undertaking future phase II clinical studies in which increased cell dosages are studied in larger cohorts of patients. Stem Cells Translational Medicine 2019;8:887&897.


Disease-modifying effect of strontium ranelate in a subset of patients from the Phase III knee osteoarthritis study SEKOIA using quantitative MRI: reduction in bone marrow lesions protects against cartilage loss.
To explore, using MRI, the disease-modifying effect of strontium ranelate (SrRan) treatment on cartilage volume loss (CVL) and bone marrow lesions (BMLs) in a subset of patients from a Phase III clinical trial in knee osteoarthritis (OA) (SrRan Efficacy in Knee OsteoarthrItis triAl (SEKOIA)). Patients with primary symptomatic knee OA were randomised to receive either SrRan 1 g/day or 2 g/day or placebo (SEKOIA study). A subset of these patients had MRIs at baseline, 12, 24 and 36 months to assess the knee cartilage volume and BMLs. Missing values were imputed and the analyses were adjusted according to Bonferroni. In this MRI subset, the distribution of patients (modified intention-to-treat; n=330) was 113, 105 and 112 for SrRan 1 g/day, 2 g/day and placebo, respectively. The groups were fairly balanced at baseline regarding demographics, clinical symptoms or imaging characteristics. Treatment with SrRan 2 g/day significantly decreased CVL on the plateaus at 12 (p=0.002) and 36 (p=0.003) months compared with placebo. Of note, in the medial femur and plateau, SrRan 1 g/day, but not SrRan 2 g/day, had more CVL than placebo. In patients with BML in the medial compartment at baseline, the BML score at 36 months was decreased in both treatment groups compared with the placebo group (SrRan 1 g/day, p=0.002 and SrRan 2 g/day p=0.001, respectively), and CVL significantly decreased with SrRan 2 g/day (p=0.023) in the plateau compared with placebo. In knee OA patients, treatment with SrRan 2 g/day was found to have beneficial effects on structural changes by significantly reducing CVL in the plateau and BML progression in the medial compartment.


Bone apposition to laminin-1 coated implants: histologic and 3D evaluation.
Laminin-1 has been reported as one of the factors responsible for the nucleation of calcium phosphates and, in vitro, has been reported to selectively recruit osteoprogenitors. This article focused on its in vivo effects, and evaluated the effect of laminin-1 local application on osseointegration. Polished cylindrical hydroxyapatite implants were coated with laminin-1 (test) and the bone responses in the rabbit tibiae after 2 and 4 weeks were evaluated and compared to the non-coated implants (control). Before the samples were processed for histological sectioning, they were three-dimensionally analysed with micro computed tomography (μCT). Both evaluation methods were analysed with regards to bone area around the implant and bone to implant contact. From the histologic observation, new bone formation around the laminin-1 coated implant at 2 weeks seemed to have increased the amount of supporting bone around the implant, however, at 4 weeks, the two groups presented no notable differences. The two-dimensional and three-dimensional morphometric evaluation revealed that both histologic and three-dimensional analysis showed some tendency in favour of the test group implants, however there was no statistical significance between the test and control group results.


Possible sensory receptor of nonadrenergic inhibitory nervous system.
To determine the sensory receptor of the nonadrenergic inhibitory nervous system (NAIS), 22 cats were anesthetized and serotonin was continuously administered (50-250 micrograms.kg-1.min-1 iv) to increase pulmonary resistance (RL) to 377 +/- 57% (SE) of the control value. We then 1) mechanically irritated the trachea, 2) intravenously administered capsaicin (5 micrograms/kg), or 3) induced hypoxia (arterial PO2 30-40 Torr) to stimulate irritant and bronchial C-fiber receptors, pulmonary C-fiber receptors, or the carotid body (chemoreceptors), respectively. After treatment with atropine (3 mg/kg iv) and propranolol (2 mg/kg iv), the serotonin-induced change in RL was reduced by 58.6 +/- 14.3% by mechanical irritation and 63.3 +/- 12.1% by intravenous capsaicin. However, hypoxia produced no dilatation of the airways. In further experiments, we employed capsaicin inhalation to stimulate bronchial C-fiber receptors. Inhaled capsaicin (0.1%, for 5 breaths) also reduced RL by 79.2 +/- 9.2% of the elevated value, after atropine and propranolol. Treatment with a ganglionic blocking agent, hexamethonium (2 mg/kg iv), abolished bronchodilator responses, implying that a reflex pathway through vagal nerves is involved in this phenomenon. These results suggest that pulmonary and bronchial C-fiber receptors may be involved as sensory receptors in NAIS reflex bronchodilatation.


Inclusion of Essential Universal Health Coverage Services in Essential Packages of Health Services: A Review of 45 Low- and Lower- Middle Income Countries.
Expanding service coverage and achieving universal health coverage (UHC) is a priority for many low- and middle-income countries. Though UHC is a long-term goal, its importance and relevance have only increased since the start of the COVID-19 pandemic. The first step on the road to UHC is to define and develop essential packages of health services (EPHSs), a list of clinical and public health services that a government has deemed a priority and is to provide. However, the nature of these lists of services in low- and lower-middle-income countries is largely unknown. This study examines the contents of 45 countries' EPHSs to determine the inclusion of essential UHC (EUHC) services as defined by the Disease Control Priorities, which comprises 21 specific essential packages of interventions. EPHSs were collected from publicly available sources and their contents were analyzed in two stages, firstly, to determine the level of specificity and detail of the content of EPHSs and, secondly, to determine which essential UHC services were included. Findings show that there are large variations in the level of specificity among EPHSs and that though EUHC services are included to a large extent, variations exist regarding which services are included between countries. The results provide an overview of how countries are designing EPHSs as a policy tool and are progressing toward providing a full range of EUHC services. Additionally, the study introduces new tools and methods for UHC policy analysts and researchers to study the contents of EPHSs in future investigations.


Gestational age, infant birth weight, and subsequent risk of type 2 diabetes in mothers: Nurses' Health Study II.
Women with a history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes (T2DM); however, little is known about the association between other common pregnancy complications (eg, preterm birth, macrosomia) and T2DM risk. We examined the associations between first-pregnancy preterm, postterm birth, low birth weight, and macrosomia with subsequent risk of T2DM. We conducted a prospective cohort study of Nurses' Health Study II (NHSII) participants; 51,728 women in the study had a single live birth and complete pregnancy history. NHSII confirmed incident diabetes mellitus through supplemental questionnaires. Participants were followed from year of first birth until 2005. We defined gestational age as very preterm (20 to ≤32 weeks), moderate preterm (33 to ≤37 weeks), term (38 to ≤42 weeks), and postterm (≥43 weeks). We defined low birth weight as an infant born at term weighing less than 5.5 pounds, and we defined macrosomia as an infant born at term weighing 10 pounds or more. We used Cox proportional hazards models, adjusting for potential confounders. Women with a very preterm birth (2%) had an increased T2DM risk (adjusted hazard ratio, 1.34; 95% confidence interval [CI], 1.05-1.71). This increased risk emerged in the decade following pregnancy. Macrosomia (1.5%) was associated with a 1.61 increased T2DM risk, after adjusting for risk factors, including GDM (95% CI, 1.24-2.08). This association was apparent within the first 5 years after pregnancy. Moderate preterm and term low birth weight did not significantly increase the risk of T2DM over the 35-year follow-up time. Women who experienced a very preterm birth or had an infant that weighed 10 pounds or more may benefit from lifestyle intervention to reduce T2DM risk. If replicated, these findings could lead to a reduced risk of T2DM through improved primary care for women experiencing a preterm birth or an infant of nonnormal birth weight.


Decreased ratio of CD8+ T cells to regulatory T cells associated with decreased survival in dogs with osteosarcoma.
Increased numbers of regulatory T cells (Treg) and decreased ratios of CD8+ T cells to Treg have been shown to correlate with decreased survival times (ST) in humans with certain malignancies. A possible connection between Treg and ST in dogs with cancer has not been investigated previously. The purpose of this study was to compare numbers of Treg and T lymphocyte subsets in dogs with osteosarcoma (OSA) to those of healthy dogs and to determine whether pretreatment values were associated with disease-free interval or with ST. We hypothesized that Treg numbers would be increased in dogs with cancer and that dogs with a high percentage of Treg would have a poorer prognosis. Twelve client-owned dogs with appendicular OSA were entered into a prospective clinical trial. Twenty-two healthy dogs were used as controls. The percentages and numbers of Treg and CD4+ and CD8+ T cells in blood, lymph nodes, and tumors were determined with flow cytometry and compared between dogs with OSA and control dogs. Dogs with OSA had significantly fewer circulating CD8+ T cells and significantly more Treg compared with healthy dogs. The CD8/Treg ratio also was significantly lower in dogs with OSA compared with control dogs. In dogs with OSA, a decreased CD8/Treg ratio was associated with significantly shorter STs. These data support a role for Treg in the immune control of canine OSA and suggest that determination of the CD8/Treg ratio may be useful for assessing outcomes.


Relationship of proteinases and proteinase inhibitors with microbial presence in chronic lung disease of prematurity.
A proteolytic imbalance has been implicated in the development of "classical" chronic lung disease of prematurity (CLD). However, in "new" CLD this pattern has changed. This study examines the longitudinal relationship between neutrophil proteinases and their inhibitors in ventilated preterm infants and their relationship to microbial colonisation. Serial bronchoalveolar lavage fluid was obtained from ventilated newborn preterm infants. Neutrophil elastase (NE) activity, cell counts, metalloproteinase (MMP)-9, MMP-9/TIMP-1 complex, SerpinB1 concentration and percentage of SerpinB1 and alpha(1)-antitrypsin (AAT) in complex with elastase were measured. The presence of microbial genes was examined using PCR for 16S rRNA genes. Statistically more infants who developed CLD had NE activity in at least one sample (10/20) compared with infants with resolved respiratory distress syndrome (RDS) (2/17). However, NE activity was present in a minority of samples, occurring as episodic peaks. Peak levels of MMP-9, MMP-9/TIMP-1 complex, percentage of AAT and SerpinB1 in complex and cell counts were all statistically greater in infants developing CLD than in infants with resolved RDS. Peak values frequently occurred as episodic spikes and strong temporal relationships were noted between all markers. The peak values for all variables were significantly correlated to each other. The presence of bacterial 16S rRNA genes was associated with the development of CLD and with elevated elastase and MMP-9. NE activity and MMP-9 appear to be important in the development of "new" CLD with both proteinase and inhibitor concentrations increasing episodically, possibly in response to postnatal infection.


Unveiling Cancer.
This article narrates a multifaceted educational journey undertaken by a medical student through a weekly SCRAPS (surgery, clinical disciplines, radiology, anatomy, psychiatry and laboratory sciences) clinico-pathological meeting held in the College of Medicine & Health Sciences at Sultan Qaboos University in Muscat, Oman. Through a presentation titled 'Unveiling Cancer', the multidisciplinary and interprofessional audience witnessed a simulated interaction between a medical student, a technologist peer and tutors in medicine, pathology and radiology. The presentation was based on the complexities of presentation, diagnosis and management of a patient with anaplastic large cell lymphoma, a rare type of non-Hodgkin lymphoma, in the aftermath of a bone marrow transplantation. After describing the case, the student shared with the audience a spectrum of learning objectives, which included integration in the complex world of contemporary medicine, insight into the triumphs and travails of technology (immunohistochemistry) and peer collaboration, communication and mentorship.


From Singing to Speaking: Why Singing May Lead to Recovery of Expressive Language Function in Patients with Broca's Aphasia.
It has been reported that patients with severely nonfluent aphasia are better at singing lyrics than speaking the same words. This observation inspired the development of Melodic Intonation Therapy (MIT), a treatment whose effects have been shown, but whose efficacy is unproven and neural correlates remain unidentified. Because of its potential to engage/unmask language-capable regions in the unaffected right hemisphere, MIT is particularly well suited for patients with large left-hemisphere lesions. Using two patients with similar impairments and stroke size/location, we show the effects of MIT and a control intervention. Both interventions' post-treatment outcomes revealed significant improvement in propositional speech that generalized to unpracticed words and phrases; however, the MIT-treated patient's gains surpassed those of the control-treated patient. Treatment-associated imaging changes indicate that MIT's unique engagement of the right hemisphere, both through singing and tapping with the left hand to prime the sensorimotor and premotor cortices for articulation, accounts for its effect over nonintoned speech therapy.


Ligand-Binding-Site Structure Shapes Allosteric Signal Transduction and the Evolution of Allostery in Protein Complexes.
The structure of ligand-binding sites has been shown to profoundly influence the evolution of function in homomeric protein complexes. Complexes with multichain binding sites (MBSs) have more conserved quaternary structure, more similar binding sites and ligands between homologs, and evolve new functions slower than homomers with single-chain binding sites (SBSs). Here, using in silico analyses of protein dynamics, we investigate whether ligand-binding-site structure shapes allosteric signal transduction pathways, and whether the structural similarity of binding sites influences the evolution of allostery. Our analyses show that: 1) allostery is more frequent among MBS complexes than in SBS complexes, particularly in homomers; 2) in MBS homomers, semirigid communities and critical residues frequently connect interfaces and thus they are characterized by signal transduction pathways that cross protein-protein interfaces, whereas SBS homomers usually not; 3) ligand binding alters community structure differently in MBS and SBS homomers; and 4) except MBS homomers, allosteric proteins are more likely to have homologs with similar binding site than nonallosteric proteins, suggesting that binding site similarity is an important factor driving the evolution of allostery.


Substrate adhesion affects contraction and mechanical properties of fibroblast populated collagen lattices.
Fibroblasts can condense a hydrated collagen lattice to a tissue-like structure. The purpose of this study was to evaluate the effect of substrate adhesion on the contraction and mechanical properties of fibroblast populated collagen lattices. Bacteriological grade polystyrene (BGPS) plates and tissue culture polystyrene (TCPS) plates were used as substrates for incubation of fibroblast populated collagen lattices. Hydrophobicity of the polystyrene surfaces was measured by the static sessile contact angle method. Collagen lattice contraction was recorded for 2 weeks, after which the lattices were mechanically tested. The BGPS culture plate had a significantly larger contact angle and was more hydrophobic than the TCPS culture plate. Both hydrophobicity and peripheral detachment of the collagen gel significantly decreased the time lag before initiation of gel contraction and increased the strength of the fibroblast populated collagen lattices. Substrate adhesion affects the contractility and strength of cell seeded collagen gels. This information may be useful in developing tissue engineered tendons and ligaments.


Prone or supine body position and sleep characteristics in infants.
To evaluate the potential relation between body position and sleep characteristics in normal infants. Two groups of 3-month-old healthy infants were evaluated: 40 infants who usually slept supine, and 40 who usually slept prone. The two groups were matched for gender, gestational age, postnatal age, birth weight, and total recording time. RECORDING TECHNIQUES: The 80 infants were studied polygraphically during one night in the pediatric sleep laboratory. They were allowed to fall asleep in their usual sleep position, and every 3 hours were gently turned from prone to supine, or from supine to prone. In each group, 6 infants were excluded from the analysis, because they woke up after having been turned over. In both groups, no significant difference was seen between the prone and the supine body positions for the following variables: number of sleep state changes; number of gross body movements; percent of rapid eye movement sleep; saturation with oxygen, arterial blood levels; number and duration of acid esophageal reflux; rectal temperature; mean respiratory rates; water evaporation rates from the forehead skin; and number or duration of central or of obstructive apneas. In both groups of infants, prone body position was associated with a significant increase in sleep duration (+16%) and in non-rapid eye movement sleep (+25%) and a significant decrease in number of arousals (-40%) and in their duration (-43%). No explanation has been found for the sleep-promoting effect of prone body positioning. The finding could be of interest to the study of infants' sleep quality, as well as to the potential relation between body positions and sudden death during sleep.


Figure-8 tachycardia confined to the anterior wall of the left atrium.
Incisional atrial tachycardias have been described most frequently in patients with previous corrective surgery for congenital heart defects and mitral valve disease. Less information is available on atrial tachycardias appearing late after isolated aortic valve surgery. We report the case of a patient who developed a left figure-8 tachycardia after undergoing aortic valve replacement. During electrophysiologic study the entire cycle length of the tachycardia was mapped within a low voltage area confined to the left anterior atrial wall. However, during ablation a transmural lesion could not be attained. The mapping and ablation strategy along with the mechanism of the tachycardia are discussed.


Tissue distribution of Diablo/Smac revealed by monoclonal antibodies.
Diablo/Smac is a mammalian pro-apoptotic protein that can antagonize the inhibitor of apoptosis proteins (IAPs). We have produced monoclonal antibodies specific for Diablo and have used these to examine its tissue distribution and subcellular localization in healthy and apoptotic cells. Diablo could be detected in a wide range of mouse tissues including liver, kidney, lung, intestine, pancreas and testes by Western blot analysis. Immunohistochemical analysis found Diablo to be most abundant in the germinal cells of the testes, the parenchymal cells of the liver and the tubule cells of the kidney. In support of previous subcellular localization analysis, Diablo was present within the mitochondria of healthy cells, but released into the cytosol following the induction of apoptosis by UV.


Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane.
X-linked Emery-Dreifuss muscular dystrophy is caused by loss of emerin, a LEM-domain protein of the nuclear inner membrane. To better understand emerin function, we used affinity chromatography to purify emerin-binding proteins from nuclear extracts of HeLa cells. Complexes that included actin, alphaII-spectrin and additional proteins, bound specifically to emerin. Actin polymerization assays in the presence or absence of gelsolin or capping protein showed that emerin binds and stabilizes the pointed end of actin filaments, increasing the actin polymerization rate 4- to 12-fold. We propose that emerin contributes to the formation of an actin-based cortical network at the nuclear inner membrane, conceptually analogous to the actin cortical network at the plasma membrane. Thus, in addition to disrupting transcription factors that bind emerin, loss of emerin may destabilize nuclear envelope architecture by weakening a nuclear actin network.


Tracking the elusive monophyly of nototheniid fishes (Teleostei) with multiple mitochondrial and nuclear markers.
Since the first molecular study of the suborder Notothenioidei in 1994, many phylogenetic studies have been published. Among these, those with a sufficient number of taxa have all suggested that the Nototheniidae, as currently defined, is monophyletic only with the inclusion of the Channichthyidae, Artedidraconidae, Bathydraconidae and Harpagiferidae. This is corroborated by more recent studies including more taxa, but in these studies either the number of nuclear markers or the number of taxa included remained low. We obtained sequences for a large sampling covering most nototheniid genera for five markers described previously for other samplings (COI, Rhodopsin retrogene, Pkd1, HECW2, and SSRP1) and one nuclear marker never used before in phylogenetic inference (PPM1d). The topology for the combined analysis of the nuclear coding genes, as well as the topology for SSRP1 (non-coding) and the combined analysis for all markers all support the paraphyly of Nototheniidae, the genus Notothenia (including Paranotothenia) is the sister group of the clade Channichthyidae, Artedidraconidae, Bathydraconidae and Harpagiferidae, and genus Gobionotothen is a sister group to both. As in previous studies, Trematomus, Lepidonotothen and Patagonotothen form a clade that also includes Indonotothenia cyanobrancha. The position of Pleuragramma antarctica, Dissostichus species and Aethotaxis mitopteryx remains unstable and dependant on markers and analyses. We therefore propose the inclusion of the four families of the High Antarctic clade in the Nototheniidae, and their transformation into subfamilies. We transfer Paranotothenia magellanica to the genus Notothenia, as Notothenia magellanica.


A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B.
Clevudine is a nucleoside analog with an unnatural beta-L configuration. In a phase I/II clinical trial, once daily doses ranging from 10 to 200 mg for 28 days were well tolerated, and produced significant antiviral activity. The present study was conducted to assess the degree and durability of the antiviral response to 12 weeks of clevudine treatment, and to investigate its safety and tolerability. A total of 98 patients with HBeAg-positive chronic hepatitis B were randomized to placebo (n=32), 30-mg clevudine (n=32), and 50-mg clevudine (n=34) groups. Patients were followed up after 12 weeks of treatment for a further 24 weeks off-therapy. Median serum hepatitis B virus DNA reductions from baseline at week 12 were 0.20, 4.49, and 4.45 log10 copies/mL in the placebo, 30-mg clevudine, and 50-mg clevudine groups, respectively (P < .0001). Posttreatment antiviral activities were sustained, with 3.32 and 2.99 log10 reductions at week 12 off-therapy and 2.28 and 1.40 log10 reductions at week 24 off-therapies in the 30- and 50-mg clevudine groups, respectively. Median serum alanine aminotransferase (ALT) levels decreased markedly from baseline during clevudine treatment and were maintained below the upper limit of normal throughout the 24 weeks off-therapy in the two clevudine-treated groups. The incidences of adverse events and treatment-emergent grade 3 or 4 laboratory abnormalities were similar for the three groups. In conclusion, clevudine showed potent antiviral activity during therapy and induced a sustained posttreatment antiviral effect for 6 months after a 12-week treatment period, and this was associated with a sustained normalization of ALT levels.


A comparative study of RNA-seq analysis strategies.
Three principal approaches have been proposed for inferring the set of transcripts expressed in RNA samples using RNA-seq. The simplest approach uses curated annotations, which assumes the transcripts in a sample are a subset of the transcripts listed in a curated database. A more ambitious method involves aligning reads to a reference genome and using the alignments to infer the transcript structures, possibly with the aid of a curated transcript database. The most challenging approach is to assemble reads into putative transcripts de novo without the aid of reference data. We have systematically assessed the properties of these three approaches through a simulation study. We have found that the sensitivity of computational transcript set estimation is severely limited. Computational approaches (both genome-guided and de novo assembly) produce a large number of artefacts, which are assigned large expression estimates and absorb a substantial proportion of the signal when performing expression analysis. The approach using curated annotations shows good expression correlation even when the annotations are incomplete. Furthermore, any incorrect transcripts present in a curated set do not absorb much signal, so it is preferable to have a curation set with high sensitivity than high precision. Software to simulate transcript sets, expression values and sequence reads under a wider range of parameter values and to compare sensitivity, precision and signal-to-noise ratios of different methods is freely available online (https://github.com/boboppie/RSSS) and can be expanded by interested parties to include methods other than the exemplars presented in this article.


Reliability and Reproducibility of the OTA/AO Classification for Humeral Shaft Fractures.
This study aimed to determine interobserver reliability and intraobserver reproducibility of the OTA/AO classification for humeral shaft fractures, and to evaluate differences between fracture types, fracture groups, and surgical specializations. Thirty observers (25 orthopaedic trauma surgeons and 5 general orthopaedic surgeons) independently classified 90 humeral shaft fractures according to the OTA/AO classification. Patients of 16 years and older were included. Periprosthetic, recurrent, and pathological fractures were excluded. Radiographs were provided in random order, and observers were blinded to clinical information. To determine intraobserver agreement, radiographs were reviewed again after 2 months in a different random order. Agreement was assessed using kappa statistics. Interobserver agreement for the 3 fracture types was moderate (κ = 0.60; 0.59-0.61). It was substantial for type A (κ = 0.77; 0.70-0.84) and moderate for type B (κ = 0.52; 0.46-0.58) and type C fractures (κ = 0.46; 0.42-0.50). Interobserver agreement for the 9 fracture groups was moderate (κ = 0.48; 95% CI, 0.48-0.48). Orthopaedic trauma surgeons had better overall agreement for fracture types, and general orthopaedic surgeons had better overall agreement for fracture groups. Observers classified 64% of fractures identically in both rounds. Intraobserver agreement was substantial for the 3 types (κ = 0.80; 0.77-0.81) and 9 groups (κ = 0.80; 0.77-0.82). Intraobserver agreement showed no differences between surgical disciplines. The OTA/AO classification for humeral shaft fractures has a moderate interobserver and substantial intraobserver agreement for fracture types and groups.


Problem gambling and associated mental health concerns in elite athletes: a narrative review.
Opportunities to participate in gambling have dramatically changed during the past 20 years. Casinos have proliferated as have electronic gambling machines, lotteries, sports betting, and most recently online gambling. Gambling among the general population has moved from being perceived negatively to a socially acceptable pastime. As over 80% of individuals have reported gambling for money during their lifetime, governments recognise that regulating gambling-a multibillion dollar industry-is a significant source of revenue. While the vast majority of individuals engaged in some form of gambling have no or few gambling-related problems, an identifiable proportion of both adolescents and adults experience significant gambling-related problems. Elite athletes have not been immune to the lure of gambling nor its concomitant problems. Prevalence studies suggest higher rates of gambling problems among athletes than the general population. In this narrative review, we examine several risk factors associated with gambling problems among elite athletes and new forms of gambling that may be problematic for this population. Given the potential serious mental health and performance consequences associated with a gambling disorder for athletes, we aim to increase coaches', athletic directors' and health professionals' knowledge concerning the importance of screening and treatment referrals.


The MyHealthRecord System Impacts on Patient Workflow in General Practices.
Digital health is widely believed to have vast potential in improving patient care. MyHealthRecord (MyHR) is a digital health information system which enables Australian citizens to access their health information centrally, making it available anywhere, at anytime. The aim of this study is to explore the adoption of MyHR in general practices in Victoria and understand its impacts. A qualitative case study research method was used to underpin this investigation. Ten general practices were engaged where MyHR was implemented/used. Detailed interviews with MyHR implementers were held and GPs were engaged in short interviews. Twenty observations were made during GP/patient consultations for health summary uploads. Findings indicate that the practice incentive payment (PIP) funding policy change encouraged the use of MyHR, but the adoption was limited to satisfy funding criteria. Change management was often extemporised. Health summary upload was a quick and easy process but was influenced by clinical system data quality and GP familiarity with the system. Community awareness and GP interest in MyHR was lacking. The conclusion is that MyHR was not well integrated in general practices nor the community. As a result, an improved engagement approach between healthcare organisations, the MyHR system operator and Australians is required.


Effectiveness of speech therapy in treating vocal blocking tics in children with Tourette syndrome: Two case reports.
Tourette syndrome is characterized by at least two motor tics and one vocal tic, which persist for over a year. Infrequently, tics can manifest as blocking tics in speech when they prevent a person from starting to speak or interrupt their speech flow. Vocal blocking tics (VBTs) resemble stuttering, and they can be difficult to differentiate from each other. A previous report described two patients with severe VBTs who did not benefit from stuttering-therapy-based speech therapy and were treated effectively with cannabis-based medicine. Here, we present the cases of two patients, seven- and nine-year-old boys, who benefited from speech therapy in which stuttering therapy techniques were used. Detailed descriptions of the interventions are included. Further research is needed to test the effectiveness of speech therapy in treating VBTs in a larger group of children with Tourette syndrome.


The kinematics and mechanism of prey capture in the African pig-nosed frog (Hemisus marmoratum): description of a radically divergent anuran tongue.
High-speed videography and muscle denervation experiments were used to quantify the feeding kinematics of Hemisus marmoratum and to test hypotheses of muscle function. The feeding behavior of H. marmoratum, which feeds on ants and termites, differs radically from that of other frogs that have been studied. During feeding in H. marmoratum, the tongue 'telescopes' straight out of the mouth, as opposed to the 'flipping' tongue trajectory observed in most other frogs. At the time of prey contact, two lateral lobes of tissue at the tongue tip envelop the prey. These lateral lobes are capable of applying significant pulling forces to the prey and the tongue is, therefore, described as prehensile. The trajectory of the tongue can be adjusted throughout protraction so that the frog can 'aim' its tongue in all three dimensions; distance, azimuth and elevation. Bilateral denervation of the genioglossus muscles results in a complete lack of tongue protraction, indicating that the genioglossus muscle is the main tongue protractor in H. marmoratum, as in other frogs. Thus, H. marmoratum provides strong evidence of functional conservatism of the genioglossus muscle within anurans. Bilateral denervation of the hyoglossus muscle indicates that although the hyoglossus is involved in several aspects of normal tongue retraction, including the prehensile capability of the tongue tip, it is not necessary for tongue retraction. Unilateral denervation of the genioglossus muscle causes significant deviation of the tongue towards the denervated side, providing evidence for a mechanism of lateral tongue aiming. On the basis of the kinematics of prey capture, the anatomy of the tongue and the results of the denervation experiments, we propose that H. marmoratum uses a hydraulic mechanism to protract its tongue.


PolyQ-dependent RNA-protein assemblies control symmetry breaking.
Dendritic growth in fungi and neurons requires that multiple axes of polarity are established and maintained within the same cytoplasm. We have discovered that transcripts encoding key polarity factors including a formin, Bni1, and a polarisome scaffold, Spa2, are nonrandomly clustered in the cytosol to initiate and maintain sites of polarized growth in the fungus Ashbya gossypii. This asymmetric distribution requires the mRNAs to interact with a polyQ-containing protein, Whi3, and a Pumilio protein with a low-complexity sequence, Puf2. Cells lacking Whi3 or Puf2 had severe defects in establishing new sites of polarity and failed to localize Bni1 protein. Interaction of mRNAs with Whi3 and Puf2 promotes enrichment of transcripts at established sites of polarized growth and clustering of polarity transcripts throughout the cell body. Thus, aggregation-prone proteins make functional assemblies to position polarity transcripts, and nonrandom positioning of transcripts is required for symmetry-breaking events. This reveals a physiological function for polyQ-driven assemblies in regulating cell polarity.


An Equation to Predict the Accuracy of Genomic Values by Combining Data from Multiple Traits, Populations, or Environments.
Predicting the accuracy of estimated genomic values using genome-wide marker information is an important step in designing training populations. Currently, different deterministic equations are available to predict accuracy within populations, but not for multipopulation scenarios where data from multiple breeds, lines or environments are combined. Therefore, our objective was to develop and validate a deterministic equation to predict the accuracy of genomic values when different populations are combined in one training population. The input parameters of the derived prediction equation are the number of individuals and the heritability from each of the populations in the training population; the genetic correlations between the populations, i.e., the correlation between allele substitution effects of quantitative trait loci; the effective number of chromosome segments across predicted and training populations; and the proportion of the genetic variance in the predicted population captured by the markers in each of the training populations. Validation was performed based on real genotype information of 1033 Holstein-Friesian cows that were divided into three different populations by combining half-sib families in the same population. Phenotypes were simulated for multiple scenarios, differing in heritability within populations and in genetic correlations between the populations. Results showed that the derived equation can accurately predict the accuracy of estimating genomic values for different scenarios of multipopulation genomic prediction. Therefore, the derived equation can be used to investigate the potential accuracy of different multipopulation genomic prediction scenarios and to decide on the most optimal design of training populations.


Biotechnological procedures to select white rot fungi for the degradation of PAHs.
White rot fungi are essential in forest ecology and are deeply involved in wood decomposition and the biodegradation of various xenobiotics. The fungal ligninolytic enzymes involved in these processes have recently become the focus of much attention for their possible biotechnological applications. Successful bioremediation requires the selection of species with desirable characteristics. In this study, 150 taxonomically and physiologically diverse white rot fungi, including 55 species, were investigated for their performance in a variety of biotechnological procedures, such as dye decolorization, gallic acid reaction, ligninolytic enzymes, and tolerance to four PAHs, phenanthrene, anthracene, fluoranthene, and pyrene. Among these fungi, six isolates showed the highest (>90%) tolerance to both individual PAH and mixed PAHs. And six isolates oxidized gallic acid with dark brown color and they rapidly decolorized RBBR within ten days. These fungi revealed various profiles when evaluated for their biotechnological performance to compare the capability of degradation of PAHs between two groups selected. As the results demonstrated the six best species selected from gallic acid more greatly degraded four PAHs than the other isolates selected via tolerance test. It provided that gallic acid reaction test can be performed to rank the fungi by their ability to degrade the PAHs. Most of all, Peniophora incarnata KUC8836 and Phlebia brevispora KUC9033 significantly degraded the four PAHs and can be considered prime candidates for the degradation of xenobiotic compounds in environmental settings.


Continuous glucose monitoring in pregnant women with Type 1 diabetes: benefits for mothers, using pumps or pens, and their babies.
To review the current literature on the use of continuous glucose monitoring during pregnancy in women with Type 1 diabetes. We searched the literature for randomized controlled trials using continuous glucose monitoring during pregnancy in women with Type 1 diabetes. Three randomized trials were found and discussed in this review. One UK study found a reduction in large-for-gestational-age infants; however, only masked continuous glucose monitoring was used in that study. A Danish study used intermittent real-time continuous glucose monitoring and found no differences. The present authors conducted the CONCEPTT trial, in which pregnant women and women planning pregnancy were randomized to receive continuous glucose monitoring or standard care. We found a greater drop in HbA1c , more time spent in the target range, and a reduction in some adverse neonatal outcomes in women using continuous glucose monitoring. Numbers-needed-to-treat to prevent a large-for-gestational-age infant, a neonatal intensive care unit admission for >24 h, and a neonatal hypoglycaemia event were low. These findings were seen in both injection and pump users and across all countries. Possible reasons for differences in study findings are discussed. In addition, several issues need further study. Glycaemic variability and differences in dietary intake may also have played a role. Despite excellent glycaemic control, babies continue to be large. More research is needed to understand the role of glucose targets and the dynamic placental processes involved in fetal growth. The use of continuous glucose monitoring in women with Type 1 diabetes in pregnancy is associated with improved glycaemic control and neonatal outcomes. Further research examining the glycaemic and non-glycaemic variables involved in fetal growth and the cost-benefit of using continuous glucose monitoring in pregnancy is warranted.


Tetrathiafulvalene mono- and bis-1,2,3-triazole precursors by click chemistry: structural diversity and reactivity.
The donor ortho-dimethyl-TTF-(N-n-Bu-1,2,3-triazole) 1,5-isomer has been synthesized by click chemistry following a ruthenium-catalyzed azide-alkyne cycloaddition procedure. The single crystal X-ray analysis showed a planar conformation between the TTF and triazole units and a set of intermolecular interactions at the supramolecular level in the solid state. The same procedure allowed the preparation of the corresponding ortho-dimethyl-TTF-bis(triazole) which was also structurally characterized. Because of the steric hindrance, the triazole units are no longer planar with the TTF backbone. The reactivity of the triazole ring has been investigated in protonation and alkylation reactions, monitored by UV-visible spectroscopy, which clearly showed the red shift of the intramolecular charge transfer band. A TTF-methyl-triazolium salt has been isolated and analyzed by single crystal X-ray analysis. All of the TTF-triazoles and triazolium salts are valuable precursors for radical cation salts due to their oxidation potentials and variety of possible intermolecular interactions.


Regulation of synaptic vesicle recycling by calcineurin in different vesicle pools.
The synaptic vesicles keep recycling by the processes of endocytosis and exocytosis to maintain the normal synaptic transmission. The synaptic vesicles are classified as the readily releasable pool (RRP) and the reserve pool (RP). In the endocytosis process, calcineurin (CaN), a Ca2+/calmodulin-dependent protein phosphatase, has been shown to play important roles. However, it is unclear about its roles in different vesicle pools. Here, we investigated the role of CaN in the regulation of vesicle recycling in the RRP and RP. Vesicle recycling was monitored by using fluorescent dyes FM1-43 and FM4-64 in the primary cultures of hippocampal neurons. Inhibition of CaN by FK506 and cyclosporin A suppressed the endocytosis in the RP, but not in the RRP. Inhibition of CaN also restrained the exocytic process triggered by 10 Hz stimulation, but had no effect on 3-5 Hz stimulation-induced exocytosis. FK506 also reduced the total vesicle pool size in the synaptic terminals. A synthesized CaN inhibitory peptide showed the similar effects as FK506 and cyclosporin A. These results revealed a novel mechanism that CaN plays critical roles in the distinct vesicle recycling processes.


Clinic-based biopsy with a small curette: is it a reliable and safe option in extremity tumours?
To establish the diagnostic accuracy and safety of clinic-based biopsy done with a small curette. The retrospective study was conducted at Aga Khan University Hospital Karachi and comprised data of patients who underwent biopsy procedure of extremity tumours in clinic under local anaesthesia from July 2009 to June 2012. Patients who underwent the procedure in operating room under general anaesthesia were excluded and so were those with insufficient or missing information, or those who had the final procedure done elsewhere. Clinical parameters were evaluated and histo-pathology was compared with the final resected specimen. The mean age of the 51 patients in the study was 32±19.6 years. Lower extremity was involved in 37(73%) cases, and the most common tumour was osteosarcoma in 9(17%).Biopsy was inconclusive in 2(4%) patients, leaving the clinical accuracy to be 94%. The cost of clinic-based biopsy was at least seven times less than those done in the operating room under general anaesthesia. Biopsy done in a clinic with a small curette is accurate, safe and cost-effective method.


Presence of Ribeiroia ondatrae in the developing anuran limb disrupts retinoic acid levels.
The widespread reports of malformed frogs have sparked interest worldwide to try and determine the causes of such malformations. Ribeiroia ondatrae is a digenetic trematode, which has been implicated as one such cause, as this parasite encysts within the developing tadpole hind limb bud and inguinal region causing dramatic limb malformations. Currently, the mechanisms involved in parasite-induced limb deformities remain unclear. We sought to investigate whether the level of retinoic acid (RA), a morphogenetic factor known to play a critical role in limb bud formation, is altered by the presence of R. ondatrae within the infected tadpole. Alteration of RA levels within the limb bud caused by the presence of the parasite may be achieved in three ways. First, metacercariae are actively secreting RA; second, cercariae, upon entering the limb/inguinal region, may release a large amount of RA; finally, the metacercariae may induce either an increase in the synthesis or a decrease in the degradation of the host's endogenous retinoic acid levels. Here, we show through high performance liquid chromatography and mass spectrometry that limb bud tissue of Lithobates sylvaticus, which has been parasitised, contains 70% more RA compared to the unparasitised control. Furthermore, parasites that have encysted within the limb buds appear to contain substantially less RA (56%) than the free swimming cercariae (defined as the infectious stage of the parasite). Taken together, these data illustrate for the first time that encystment of R. ondatrae leads to an increase in RA levels in the tadpole limb bud and may offer insight into the mechanisms involved in parasite-induced limb deformities.


A human-specific de novo protein-coding gene associated with human brain functions.
To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203). Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706's mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimer's brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions.


Reduced left ventricular diastolic function in women with posttraumatic stress disorder.
Women are two to three times more likely to develop posttraumatic stress disorder (PTSD) compared with men after exposure to a major trauma, and PTSD is associated with increased risk for cardiovascular disease in later life. The underlying mechanisms are unclear, but alterations in cardiac function may be involved. We hypothesized that women with PTSD have reduced left ventricular (LV) diastolic function. We studied 14 women with PTSD (PTSD group) and 14 women without PTSD (controls) using echocardiography Doppler to evaluate LV diastolic function, including peak velocities (E and A waves) in transmitral flow; diastolic, atrial kick, and systolic waveform velocities (e', a', and s') in tissue Doppler; the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'); and velocity of propagation (Vp) . Baseline characteristics including age, body size, blood pressure, and heart rate were not significantly different between the two groups. Compared with the control group, women with PTSD showed greater E/e' (controls vs. PTSD group: 7.0 ± 1.3 vs. 9.1 ± 1.3, P = 0.002) and smaller Vp (controls vs. PTSD group: 63.7 ± 11.3 vs. 47.5 ± 6.9 cm/s, P = 0.003). These results suggest that women with PTSD have reduced LV diastolic function, which may contribute, at least in part, to the increased risk of cardiovascular disease later in life.


Distinguishing Ménétrier's disease from its mimics.
Ménétrier's disease (MD) is a rare hypertrophic gastropathy characterised by giant rugal folds, hypochlorhydria, protein loss and a classic constellation of symptoms (nausea, vomiting, abdominal pain and peripheral oedema). It is considered a clinical diagnosis that may at times be difficult to establish. Firm diagnostic criteria for MD are proposed by delineating the clinicopathological features that best differentiate MD from its mimics. 48 patients referred to Vanderbilt University Medical Center for consideration of enrolment in a clinical trial of treatment of patients with MD with cetuximab were evaluated for a definitive diagnosis by assessing the clinical presentation, pertinent laboratory values and histopathological features. MD was confirmed in 25 of the 48 patients (52%). The remaining 23 patients were considered to be mimics of MD, the most common diagnoses being gastric polyps or polyposis syndromes (13/23, 57%). Gastric slides were available from 40 of the 48 patients for detailed histological analysis (22/25 MD and 18/23 non-MD). Foveolar hyperplasia, glandular tortuosity and dilation, and a marked reduction in parietal cell number were present in all 22 cases of MD. Lamina propria smooth muscle hyperplasia and oedema characterised most cases (18/22 and 19/22, respectively). More than half had prominent eosinophils (11/22) and/or plasma cells (12/22) in the lamina propria. The clinical presentation of patients with MD was characterised by significantly younger age of onset, male predominance and increased vomiting compared with non-MD patients, and a lower prevalence of anaemia compared with MD patients with polyps. There was a trend towards increased frequency of peripheral oedema in patients with MD compared with non-MD patients. MD is most accurately diagnosed by clinicohistopathological analysis including oesophagogastroduodenoscopy with gastric pH, appropriate laboratory tests (complete blood count, serum albumin, serum gastrin, Helicobacter pylori and cytomegalovirus serology) and full-thickness mucosal biopsy of the involved gastric mucosa.


Basic numerical processes in very preterm children: a critical transition from preschool to school age.
Serious difficulties in formal mathematical skills have been identified in preterm children. By contrast, basic-level numerical skills like magnitude judgments have not yet been tested in these children. The aim of the present research was to investigate whether preterm birth also affects these basic numerical abilities, with particular attention to the transition from preschool to formal education. One hundred-forty very preterm children and 60 age-matched controls were recruited in a cross-sectional study at 6 and 8years of age. Magnitude comparison tasks with non-symbolic dot displays or symbolic Arabic-number stimuli, measuring accuracy and reaction time, were administered to participants. We also investigated explicit number knowledge, as well as general cognitive developmental levels, to gain a broader picture of preterm abilities. Despite no general cognitive delay, the more simple approximate non-symbolic representation of numerical magnitude was affected by preterm birth, with slower reaction times at both ages compared to controls. Additionally, clear difficulties in the construction of the symbolic representation of numerical magnitude and in explicit number knowledge emerged in the 6-year-old preterm children, with a recovery from this serious delay finally by 8years. The serious delays identified here in basic numerical abilities in preterm children, despite normal IQ, point to the need for further studies in order to elucidate the relationship between basic numerical abilities and subsequent difficulties in formal mathematic achievement at school.


The role of endothelin in the pathogenesis of Chagas' disease.
Infection with Trypanosoma cruzi causes a generalised vasculitis of several vascular beds. This vasculopathy is manifested by vasospasm, reduced blood flow, focal ischaemia, platelet thrombi, increased platelet aggregation and elevated plasma levels of thromboxane A(2) and endothelin-1. In the myocardium of infected mice, myonecrosis and a vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium are observed. Immunohistochemistry studies employing anti-endothelin-1 antibody revealed increased expression of endothelin-1, most intense in the endocardial and vascular endothelium. Elevated levels of mRNA for prepro endothelin-1, endothelin converting enzyme and endothelin-1 were observed in the infected myocardium. When T. cruzi-infected mice were treated with phosphoramidon, an inhibitor of endothelin converting enzyme, there was a decrease in heart size and severity of pathology. Mitogen-activated protein kinases and the transcription factor activator-protein-1 regulate the expression of endothelin-1. Therefore, we examined the activation of mitogen-activated protein kinases in the myocardium by T. cruzi. Western blot demonstrated an extracellular signal regulated kinase. In addition, the activator-protein-1 DNA binding activity, as determined by electrophoretic mobility shift assay, was increased. Increased expression of cyclins A and cyclin D1 was observed in the myocardium, and immunohistochemistry studies revealed that interstitial cells and vascular and endocardial endothelial cells stained intensely with antibodies to these cyclins. These data demonstrate that T. cruzi infection of the myocardium activates extracellular signal regulated kinase, activator-protein-1, endothelin-1, and cyclins. The activation of these pathways is likely to contribute to the pathogenesis of chagasic heart disease. These experimental observations suggest that the vasculature plays a role in the pathogenesis of chagasic cardiomyopathy. Additionally, the identification of these pathways provides possible targets for therapeutic interventions to ameliorate or prevent the development of cardiomyopathy during T. cruzi infection.


Consumption of alcoholic beverages among pregnant urban Ugandan women.
The World Health Organization estimated alcohol consumption in Uganda to be one of the highest in the world. We examined alcohol consumption among Ugandan women prior to and after learning of pregnancy. We developed a screening algorithm using factors that predicted alcohol consumption in this study. In 2006, we surveyed 610 women attending antenatal care at the national referral hospital in Kampala, Uganda about consumption of traditional and commercial alcoholic beverages before and after learning of pregnancy. Predictors of alcohol consumption during pregnancy were examined and a practical screening algorithm was developed for use in antenatal clinics. One hundred eighty women (30%) drank alcohol at least monthly before learning of their pregnancy. Among these women, almost one-third reported usual consumption of at least one beverage type at quantities that equal binging levels for women. Overall, 151 women (25%) consumed alcohol after learning of pregnancy. Commercial beverages, particularly beer, were consumed more often than traditional drinks. A two-stage screening algorithm asking women about their religion, male partner or friends' drinking, and any lifetime drinking predicted self-reported consumption of alcohol during pregnancy with 97% sensitivity and 89% specificity. Alcohol consumption among pregnant Ugandan women attending antenatal care is high. A feasible screening algorithm can help providers target education and counseling to women who are likely drinking during pregnancy. Given the preference for commercial alcoholic beverages, it is recommended that labels be placed prominently on bottled alcoholic beverages warning of the adverse effects of consuming alcohol during pregnancy.


The safety of newer antidepressants in pregnancy and breastfeeding.
The pregnancy and postpartum periods are considered to be relatively high risk times for depressive episodes in women, particularly for those with pre-existing psychiatric illnesses. Therefore, it may be necessary to start or continue the pharmacological treatment of depression during these two timeframes. Hence, the aim of this review is to examine the effects on the fetus and infant of exposure, through the placenta and maternal milk, to the following drugs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, mirtazapine, venlafaxine, reboxetine and bupropion. The teratogenic risks, perinatal toxicity and effects on the neurobehavioural development of newborns associated with exposure through the placenta or maternal milk to these medications need to be carefully assessed before starting psychopharmacological treatment in pregnant or lactating women. In spite of the limitations of some of the studies reviewed, the older selective serotonin-reuptake inhibitors (SSRIs) [as we await further data regarding escitalopram] and venlafaxine seem to be devoid of teratogenic risks. By contrast, the data concerning possible consequences related to exposure to SSRIs via the placenta and breastmilk on neonatal adaptation and long-term neurocognitive infant's development are still controversial. Nevertheless, a number of reports have shown that an association between placental exposure to SSRIs and adverse but self-limiting effects on neonatal adaptation may exist. In addition, the information on both teratogenic and functional teratogenic risks associated with exposure to bupropion, mirtazapine and reboxetine is incomplete or absent; at present, these compounds should not be used as first-line agents in the pharmacological treatment of depression in pregnancy and breastfeeding. Untreated depression is not without its own risks since mothers affected by depression have a negative impact on the emotional development of their children and major depression, especially when complicated by a delusional component, may lead to the mother attempting suicide and infanticide. Consequently, clinicians need to help mothers weigh the risks of prenatal exposure to drugs for their babies against the potential risks of untreated depression and abrupt discontinuation of pharmacological treatment. Given these situations, we suggest that choosing to administer psychopharmacological treatment in pregnant or breastfeeding women with depression will result primarily from a careful evaluation of their psychopathological condition; currently, the degree of severity of maternal disease appears to represent the most relevant parameter to take this clinical decision.


Knee rating scales.
In the past 2 decades, outcome assessment following knee surgery has focused increasingly on the patient's perspective. While traditional measures of outcome, including physical examination, imaging studies, and measures of knee laxity are complementary, questionnaires have become more important in determining the value of a procedure. Reliability, validity, and responsiveness are all important measurement qualities for health-related quality of life instruments. There are several questionnaires available, both for active patients with disorders of the knee, as well as for older patients with degenerative conditions. Activity level is also an important prognostic variable for patients with disorders of the knee. Clinical researchers should also use a validated activity rating scale to evaluate what patients are doing, in addition to how they are doing.


Deconvolution of Complex 1D NMR Spectra Using Objective Model Selection.
Fluorine (19F) NMR has emerged as a useful tool for characterization of slow dynamics in 19F-labeled proteins. One-dimensional (1D) 19F NMR spectra of proteins can be broad, irregular and complex, due to exchange of probe nuclei between distinct electrostatic environments; and therefore cannot be deconvoluted and analyzed in an objective way using currently available software. We have developed a Python-based deconvolution program, decon1d, which uses Bayesian information criteria (BIC) to objectively determine which model (number of peaks) would most likely produce the experimentally obtained data. The method also allows for fitting of intermediate exchange spectra, which is not supported by current software in the absence of a specific kinetic model. In current methods, determination of the deconvolution model best supported by the data is done manually through comparison of residual error values, which can be time consuming and requires model selection by the user. In contrast, the BIC method used by decond1d provides a quantitative method for model comparison that penalizes for model complexity helping to prevent over-fitting of the data and allows identification of the most parsimonious model. The decon1d program is freely available as a downloadable Python script at the project website (https://github.com/hughests/decon1d/).


Cluster analysis of obesity and asthma phenotypes.
Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype. In a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m(2)) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (F(E)NO) and airway hyperresponsiveness (methacholine PC(20)) but were similar with regard to measures of lung function (FEV(1) (%) and FEV(1)/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasone Obesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics.


Stability comparison of two dermal emulsions containing Hippophae Rhamnoides L. oil.
Two formulations of multiple emulsion (ME-1 & ME-2) containing Hipophae rhamnoides L. oil were prepared. Along with emulsifiers (Abil EM 90, Synperonic F127), Magnesium and Zinc were used as stabilizer in ME-1 and ME-2 respectively. Both formulations were prepared using Two-Step Method and after preparation ME-1 and ME-2 were stored at different storage conditions i.e., 4°C, 25°C, 40°C, 40°C+ 75% RH for four weeks for stability evaluation. At 4°C ME-1 and ME-2 showed phase inversion and were excluded from further stability evaluation. While ME-1 and ME-2 both were stable at 25°C for a period of four weeks as no color change, phase separation and liquefaction occurred. ME-1 and ME-2 at 40°C, 40°C+ 75% RH exhibited change in color, liquefaction and phase separation. The decrease in viscosity and globule size whereas increase in electrical conductivity and pH were observed at 40°C, 40°C+ 75% RH for a period of four weeks. Multiple emulsion from Hippophae rhamnoide L. oil are unstable at refrigeration and high temperature conditions. These formulations must be placed at room temperature to increase their shelf life.


Dietary folate intake and breast cancer risk: European prospective investigation into cancer and nutrition.
There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided. A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P trend = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P trend = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P trend = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (>12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P interaction = .035). Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women.


Infantile refsum disease: case report.
Infantile Refsum disease is a rare inborn error of phytanic acid metabolism. It is inherited in an autosomal recessive manner and frequently causes signs and symptoms in the neonate period. The only source of phytanic acid in humans is exogenous, from diet. We report the MR imaging findings in two cases of infantile Refsum disease and note the MR imaging changes that occurred over time because of further progression of the disease. The initial diagnosis in both patients was made on basis of history, clinical findings, and biochemical studies.


Role of protein kinase Czeta in Ras-mediated transcriptional activation of vascular permeability factor/vascular endothelial growth factor expression.
Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a multifunctional cytokine, is regulated by different factors including degree of cell differentiation, hypoxia, and certain oncogenes namely, ras and src. The up-regulation of VPF/VEGF expression by Ras has been found to be through both transcription and mRNA stability. The present study investigates a novel pathway whereby Ras promotes the transcription of VPF/VEGF by activating protein kinase Czeta (PKCzeta). The Ras-mediated overexpression of VPF/VEGF was also found to be inhibited by using the antisense or the dominant-negative mutant of PKCzeta. In co-transfection assays, by overexpressing oncogenic Ha-Ras (12 V) and PKCzeta, there was an additive effect up to 4-fold in activation of Sp1-mediated VPF/VEGF transcription. It has been shown through electrophoretic mobility shift assay that Ras promoted the PKCzeta-induced binding of Sp1 to the VPF/VEGF promoter. In the presence of PDK-1, a major activating kinase for PKC, the Ras-mediated activation of VPF/VEGF promoter through PKCzeta was further increased, suggesting that PKCzeta can serve as an effector for both Ras and PDK-1. In other experiments, with the use of a dominant-negative mutant of phosphatidylinositol 3-kinase, the activation of VPF/VEGF promoter through Ras, PDK-1, and PKCzeta was completely repressed, indicating phosphatidylinositol 3-kinase as an important component of this pathway. Taken together, these data elucidate the signaling mechanism of Ras-mediated VPF/VEGF transcriptional activation through PKCzeta and also provide insight into PKCzeta and Sp1-dependent transcriptional regulation of VPF/VEGF.


Expression of human tumor mucin-associated carbohydrate epitopes, including sialylated Tn, and localization of murine monoclonal antibodies CC49 and B72.3 in a syngeneic rat colon carcinoma model.
Using immunohistochemical techniques and whole-cell enzyme-linked immunosorbent assay, we have determined that monoclonal antibodies (mAbs) B72.3 and CC49, which are widely used in the diagnosis and treatment of several human epithelial cancers, are expressed in a transplantable rat colon carcinoma cell line, K12-TRb. MAbs B72.3 and CC49 react with tumor-associated glycoprotein-72 (TAG-72) which is a carcinoma mucin molecule expressed in colon, breast, pancreatic, ovarian, lung, and gastric cancers. The carbohydrate epitope for mAb B72.3 is sialylated Tn (sTn), whereas CC49 reacts with an unknown carbohydrate epitope. K12-TRb is a transplantable rat colon carcinoma cell line derived from a dimethylhydrazine tumor which grows as progressive tumors in syngeneic BD IX rats. We found that the carbohydrate epitopes for mAbs B72.3 and CC49, including sTn, were more tumor-restricted in the rat than in humans. The only binding these had mAbs to normal rat tissue was to small-intestinal mucosa. MAbs B72.3 and CC49 were radiolabeled with iodine-125 (125I) and injected intravenously into BD IX rats containing subcutaneously grown syngeneic K12-TRb tumors. Biodistribution experiments were conducted by dissecting groups of three rats on days 2, 4, 7, and 14 after injection of radiolabeled mAbs. These experiments confirmed that maBs B72.3 and CC49 localize to K12-TRb tumors in vivo, and that the higher affinity mAb CC49 localized better than mAb B72.3. Gamma-camera imaging of subcutaneous K12-TRb tumors was successfully performed using 125I-labeled mAb CC49. The importance of this model is that mAbs B72.3 and CC49, immunoconjugates of these mAbs, and vaccines containing their corresponding carbohydrate epitopes, including sTn, can be studied in a relevant immunocompetent syngeneic rat colon carcinoma model.


The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target.
Chordoma, the molecular hallmark of which is T (brachyury), is a rare malignant bone tumour with a high risk of local recurrence and a tumour from which metastatic disease is a common late event. Currently, there is no effective drug therapy for treating chordomas, although there is evidence that some patients respond to the empirical use of epidermal growth factor receptor (EGFR) antagonists. The aim of this study was to determine the role of EGFR in the pathogenesis of chordoma. Paraffin-embedded material from 173 chordomas from 160 patients [sacro-coccygeal (n = 94), skull-based (n = 50), and mobile spine (n = 16)] was analysed by immunohistochemistry and revealed total EGFR expression in 69% of cases analysed. Of 147 informative chordomas analysed by FISH, 38% revealed high-level EGFR polysomy, 4% high-level polysomy with focal amplification, 18% low-level polysomy, and 39% disomy. Phospho-receptor tyrosine kinase array membranes showed EGFR activation in the chordoma cell line U-CH1 and all of the three chordomas analysed. Direct sequencing of EGFR (exons 18-21), KRAS, NRAS, HRAS (exons 2, 3), and BRAF (exons 11, 15) using DNA from 62 chordomas failed to reveal mutations. PTEN expression was absent by immunohistochemistry in 19 of 147 (13%) analysed chordomas, only one of which revealed high-level polysomy of EGFR. The EGFR inhibitor tyrphostin (AG 1478) markedly inhibited proliferation of the chordoma cell line U-CH1 in vitro and diminished EGFR phosphorylation in a dose-dependant manner, a finding supported by inhibition of phosphorylated Erk1/2. p-Akt was suppressed to a much lesser degree in these experiments. There was no reduction of T as assessed by western blotting. These data implicate aberrant EGFR signalling in the pathogenesis of chordoma. This study provides a strategy for patient stratification for treatment with EGFR antagonists.


Noninvasive palatal implant removal.
Orthodontic palatal implants are commonly used and do provide reliable absolute anchorage to assist orthodontic treatment. However, once treatment is completed, removal of these temporary implants is not considered easy or risk free. This short communication presents a clinical case in which a novel noninvasive procedure was applied to remove an osseointegrated palatal implant. A customized explantation tool, tightly fixed to the implant and precisely grasping the implant's head, was used in combination with a ratchet to unscrew the implant instead of the traditional removal by trephine. Only a topical anesthetic was necessary before the implant-bone contact was broken by turning the ratchet counterclockwise. The implant was retrieved without any local anesthesia. The explanted palatal implant had no bone appending to it, except in its apical anti-rotational grooves, and the healing process thereafter was unproblematic. Noninvasive palatal implant removal offers a simple and fast approach for explantation. Moreover, it might reduce the risk of adverse patient reactions, iatrogenic tooth and nerve injuries, and possible oro-antral communications.


Who shares? Who doesn't? Factors associated with openly archiving raw research data.
Many initiatives encourage investigators to share their raw datasets in hopes of increasing research efficiency and quality. Despite these investments of time and money, we do not have a firm grasp of who openly shares raw research data, who doesn't, and which initiatives are correlated with high rates of data sharing. In this analysis I use bibliometric methods to identify patterns in the frequency with which investigators openly archive their raw gene expression microarray datasets after study publication. Automated methods identified 11,603 articles published between 2000 and 2009 that describe the creation of gene expression microarray data. Associated datasets in best-practice repositories were found for 25% of these articles, increasing from less than 5% in 2001 to 30%-35% in 2007-2009. Accounting for sensitivity of the automated methods, approximately 45% of recent gene expression studies made their data publicly available. First-order factor analysis on 124 diverse bibliometric attributes of the data creation articles revealed 15 factors describing authorship, funding, institution, publication, and domain environments. In multivariate regression, authors were most likely to share data if they had prior experience sharing or reusing data, if their study was published in an open access journal or a journal with a relatively strong data sharing policy, or if the study was funded by a large number of NIH grants. Authors of studies on cancer and human subjects were least likely to make their datasets available. These results suggest research data sharing levels are still low and increasing only slowly, and data is least available in areas where it could make the biggest impact. Let's learn from those with high rates of sharing to embrace the full potential of our research output.


Blur and illumination robust face recognition via set-theoretic characterization.
We address the problem of unconstrained face recognition from remotely acquired images. The main factors that make this problem challenging are image degradation due to blur, and appearance variations due to illumination and pose. In this paper, we address the problems of blur and illumination. We show that the set of all images obtained by blurring a given image forms a convex set. Based on this set-theoretic characterization, we propose a blur-robust algorithm whose main step involves solving simple convex optimization problems. We do not assume any parametric form for the blur kernels, however, if this information is available it can be easily incorporated into our algorithm. Furthermore, using the low-dimensional model for illumination variations, we show that the set of all images obtained from a face image by blurring it and by changing the illumination conditions forms a bi-convex set. Based on this characterization, we propose a blur and illumination-robust algorithm. Our experiments on a challenging real dataset obtained in uncontrolled settings illustrate the importance of jointly modeling blur and illumination.


Effects of external inspection on sepsis detection and treatment: a study protocol for a quasiexperimental study with a stepped-wedge design.
Inspections are widely used in health care as a means to improve the health services delivered to patients. Despite their widespread use, there is little evidence of their effect. The mechanisms for how inspections can promote change are poorly understood. In this study, we use a national inspection campaign of sepsis detection and initial treatment in hospitals as case to: (1) Explore how inspections affect the involved organizations. (2) Evaluate what effect external inspections have on the process of delivering care to patients, measured by change in indicators reflecting how sepsis detection and treatment is carried out. (3) Evaluate whether external inspections affect patient outcomes, measured as change in the 30-day mortality rate and length of hospital stay. The intervention that we study is inspections of sepsis detection and treatment in hospitals. The intervention will be rolled out sequentially during 12 months to 24 hospitals. Our effect measures are change on indicators related to the detection and treatment of sepsis, the 30-day mortality rate and length of hospital stay. We collect data from patient records at baseline, before the inspections, and at 8 and 14 months after the inspections. We use logistic regression models and linear regression models to compare the various effect measurements between the intervention and control periods. All the models will include time as a covariate to adjust for potential secular changes in the effect measurements during the study period. We collect qualitative data before and after the inspections, and we will conduct a thematic content analysis to explore how inspections affect the involved organisations. The study has obtained ethical approval by the Regional Ethics Committee of Norway Nord and the Norwegian Data Protection Authority. It is registered at www.clinicaltrials.gov (Identifier: NCT02747121). Results will be reported in international peer-reviewed journals. NCT02747121; Pre-results.


The different nature of band edge absorption and emission in colloidal PbSe/CdSe core/shell quantum dots.
We present a quantitative analysis of the absorption and luminescence of colloidal PbSe/CdSe core/shell quantum dots (QDs). In absorption, both the energy and the oscillator strength of the first exciton transition coincide with that of plain PbSe QDs. In contrast, luminescence lifetime measurements indicate that the oscillator strength of the emitting transition is reduced by at least a factor of 4 compared to PbSe core QDs. Moreover, the addition of an electron scavenger quenches the PbSe/CdSe emission, while a hole scavenger does not. This implies that the electron wave function reaches the QD surface, while the hole is confined to the PbSe core. These observations are consistent with calculations based on the effective mass model, which show that PbSe/CdSe QDs are at the boundary between the type-I and quasi-type-II regime, where the electron spreads over the entire nanoparticle and the hole remains confined in the PbSe core. However, as this only leads to a minor reduction of the oscillator strength, it follows that the drastic reduction of the oscillator strength in emission cannot be explained in terms of electron delocalization. In combination with the increased Stokes shift for PbSe/CdSe QDs, this indicates that the emission results from lower energy states that are fundamentally different from the absorbing states.