Erlotinib in patients with previously irradiated, recurrent brain metastases from non-small cell lung cancer: Two case reports

Background: With the current improvements in primary lung care, the long-term control of brain metastases becomes a clinical challenge. No established therapeutic approaches exist for cranial relapse after response to previous radiotherapy and systemic therapy. Tyrosine kinase inhibitors like erlotinib with its proven activity in non-small cell lung cancer may provide clinical benefits in such patients. Patients and Methods: Two case reports are presented illustrating the efficacy of erlotinib in patients with recurrent brain metastases and parallel thoracic progression. Results: Both patients showed lasting partial remissions in the brain and lung, and clinical symptom improvement. Conclusion: The observed survival times of above 18 and 15 months, respectively, since occurrence of cranial disease manifestation in line with the achieved progression-free survival times of 9 and 6 months by the erlotinib third-line therapy are remarkable. The use of targeted therapies after whole-brain irradiation should be investigated more systematically in prospective clinical trials

Variations in hospital standardised mortality ratios (HSMR) as a result of frequent readmissions

BACKGROUND: We investigated the impact that variations in the frequency of readmissions had upon a hospital's standardised mortality ratio (HSMR). An adapted HSMR model was used in the study. Our calculations were based on the admissions of 70 hospitals in The Netherlands during the years 2005 to 2009. METHODS: Through a retrospective analysis of routinely collected hospital data, we calculated standardised in-hospital mortality ratios both by hospital and by diagnostic group (H/SMRs) using two different models. The first was the Dutch 2010 model while the second was the same model but with an additional adjustment for the readmission frequency. We compared H/SMR outcomes and the corresponding quality metrics in order to test discrimination (c-statistics), calibration (Hosmer-Lemeshow) and explanatory power (pseudo-R2 statistic) for both models. RESULTS: The SMR outcomes for model 2 compared to model 1, varied between -39% and +110%. On the HSMR level these variations ranged from -12% to +11%. There was a substantial disagreement between the models with respect to significant death on the SMR level as well as the HSMR level (~ 20%). All quality metrics comparing both models were in favour of model 2. The susceptibility to adjustment for readmission increased for longer review periods. CONCLUSIONS: The 2010 HSMR model for the Netherlands was sensitive to adjustment for the frequency of readmissions. A model without this adjustment, as opposed to a model with the adjustment, produced substantially different HSMR outcomes. The uncertainty introduced by these differences exceeded the uncertainty indicated by the 95% confidence intervals. Therefore an adjustment for the frequency of readmissions should be considered in The Netherlands, since such a model showed more favourable quality metric characteristics compared to a model without such an adjustment. Other countries could well benefit from a similar adjustment to their models. A review period of the data collected over the last three years, at least, is advisable. (aut.ref.

Recognizing Emotions in a Foreign Language

Expressions of basic emotions (joy, sadness, anger, fear, disgust) can be recognized pan-culturally from the face and it is assumed that these emotions can be recognized from a speaker's voice, regardless of an individual's culture or linguistic ability. Here, we compared how monolingual speakers of Argentine Spanish recognize basic emotions from pseudo-utterances ("nonsense speech") produced in their native language and in three foreign languages (English, German, Arabic). Results indicated that vocal expressions of basic emotions could be decoded in each language condition at accuracy levels exceeding chance, although Spanish listeners performed significantly better overall in their native language ("in-group advantage"). Our findings argue that the ability to understand vocally-expressed emotions in speech is partly independent of linguistic ability and involves universal principles, although this ability is also shaped by linguistic and cultural variables

Acylsucrose-Producing Tomato Plants Forces Bemisia tabaci to Shift Its Preferred Settling and Feeding Site

[Background] The whitefly Bemisia tabaci (Genn.) causes dramatic damage to plants by transmitting yield-limiting virus diseases. Previous studies proved that the tomato breeding line ABL 14-8 was resistant to B. tabaci, the vector of tomato yellow leaf curl disease (TYLCD). This resistance is based on the presence of type IV glandular trichomes and acylsucrose production. These trichomes deter settling and probing of B. tabaci in ABL 14-8, which reduces primary and secondary spread of TYLCD.[Methodology/Principal Findings] Whitefly settlement preference was evaluated on the adaxial and abaxial leaf surfaces of nearly-isogenic tomato lines with and without B. tabaci-resistance traits, 'ABL 14-8 and Moneymaker' respectively, under non-choice and free-choice conditions. In addition, the Electrical Penetration Graph technique was used to study probing and feeding activities of B. tabaci on the adaxial and abaxial leaf surfaces of the same genotypes. B. tabaci preferred to settle on the abaxial than on the adaxial surface of 'Moneymaker' leaves, whereas no such preference was observed on ABL 14-8 tomato plants at the ten-leaf growth stage. Furthermore, B. tabaci preferred to feed on the abaxial than on the adaxial leaf surface of 'Moneymarker' susceptible tomato plants as shown by a higher number of sustained phloem feeding ingestion events and a shorter time to reach the phloem. However, B. tabaci standard probing and feeding behavior patterns were altered in ABL 14-8 plants and whiteflies were unable to feed from the phloem and spent more time in non-probing activities when exposed to the abaxial leaf surface.[Conclusions/Significance] The distorted behavior of B. tabaci on ABL 14-8 protects tomato plants from the transmission of phloem-restricted viruses such as Tomato yellow leaf curl virus (TYLCV), and forces whiteflies to feed on the adaxial side of leaves where they feed less efficiently and become more vulnerable to natural enemies. © 2012 Rodriguez-Lopez et al.Ministerio de Ciencia e Innovación Spain (co-financed by FEDER) projects: AGL2007-66760-C02-02/AGR, AGL2007-66399-CO3-02/AGR, and AGL2010-22287-C02-01/AGR, AGL2010-22287-C02-01/AGR Consejería de Innovación y Ciencia, Junta de Andalucía, Spain (co-financed by FEDER-FSE) projects: AGR-214 and AGR-129Peer Reviewe

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

The association of health literacy with adherence in older 2 adults, and its role in interventions: a systematic meta-review

Background: Low health literacy is a common problem among older adults. It is often suggested to be associated with poor adherence. This suggested association implies a need for effective adherence interventions in low health literate people. However, previous reviews show mixed results on the association between low health literacy and poor adherence. A systematic meta-review of systematic reviews was conducted to study the association between health literacy and adherence in adults above the age of 50. Evidence for the effectiveness of adherence interventions among adults in this older age group with low health literacy was also explored. Methods: Eight electronic databases (MEDLINE, ERIC, EMBASE, PsycINFO, CINAHL, DARE, the Cochrane Library, and Web of Knowledge) were searched using a variety of keywords regarding health literacy and adherence. Additionally, references of identified articles were checked. Systematic reviews were included if they assessed the association between health literacy and adherence or evaluated the effectiveness of interventions to improve adherence in adults with low health literacy. The AMSTAR tool was used to assess the quality of the included reviews. The selection procedure, data-extraction, and quality assessment were performed by two independent reviewers. Seventeen reviews were selected for inclusion. Results: Reviews varied widely in quality. Both reviews of high and low quality found only weak or mixed associations between health literacy and adherence among older adults. Reviews report on seven studies that assess the effectiveness of adherence interventions among low health literate older adults. The results suggest that some adherence interventions are effective for this group. The interventions described in the reviews focused mainly on education and on lowering the health literacy demands of adherence instructions. No conclusions could be drawn about which type of intervention could be most beneficial for this population. Conclusions: Evidence on the association between health literacy and adherence in older adults is relatively weak. Adherence interventions are potentially effective for the vulnerable population of older adults with low levels of health literacy, but the evidence on this topic is limited. Further research is needed on the association between health literacy and general health behavior, and on the effectiveness of interventions

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

Calculating the potential for within-flight transmission of influenza A (H1N1)

Abstract Background Clearly air travel, by transporting infectious individuals from one geographic location to another, significantly affects the rate of spread of influenza A (H1N1). However, the possibility of within-flight transmission of H1N1 has not been evaluated; although it is known that smallpox, measles, tuberculosis, SARS and seasonal influenza can be transmitted during commercial flights. Here we present the first quantitative risk assessment to assess the potential for within-flight transmission of H1N1. Methods We model airborne transmission of infectious viral particles of H1N1 within a Boeing 747 using methodology from the field of quantitative microbial risk assessment. Results The risk of catching H1N1 will essentially be confined to passengers travelling in the same cabin as the source case. Not surprisingly, we find that the longer the flight the greater the number of infections that can be expected. We calculate that H1N1, even during long flights, poses a low to moderate within-flight transmission risk if the source case travels First Class. Specifically, 0-1 infections could occur during a 5 hour flight, 1-3 during an 11 hour flight and 2-5 during a 17 hour flight. However, within-flight transmission could be significant, particularly during long flights, if the source case travels in Economy Class. Specifically, two to five infections could occur during a 5 hour flight, 5-10 during an 11 hour flight and 7-17 during a 17 hour flight. If the aircraft is only partially loaded, under certain conditions more infections could occur in First Class than in Economy Class. During a 17 hour flight, a greater number of infections would occur in First Class than in Economy if the First Class Cabin is fully occupied, but Economy class is less than 30% full. Conclusions Our results provide insights into the potential utility of air travel restrictions on controlling influenza pandemics in the winter of 2009/2010. They show travel by one infectious individual, rather than causing a single outbreak of H1N1, could cause several simultaneous outbreaks. These results imply that, during a pandemic, quarantining passengers who travel in Economy on long-haul flights could potentially be an important control strategy. Notably, our results show that quarantining passengers who travel First Class would be unlikely to be an effective control strategy

Cytogenetical studies in five Atlantic Anguilliformes fishes

The order Anguilliformes comprises 15 families, 141 genera and 791 fish species. Eight families had at least one karyotyped species, with a prevalence of 2n = 38 chromosomes and high fundamental numbers (FN). The only exception to this pattern is the family Muraenidae, in which the eight species analyzed presented 2n = 42 chromosomes. Despite of the large number of Anguilliformes species, karyotypic reports are available for only a few representatives. In the present work, a species of Ophichthidae, Myrichthys ocellatus (2n = 38; 8m+14sm+10st+6a; FN = 70) and four species of Muraenidae, Enchelycore nigricans (2n = 42; 6m+8sm+12st+16a; FN = 68), Gymnothorax miliaris (2n = 42; 14m+18sm+10st; FN = 84), G. vicinus (2n = 42; 8m+6sm+28a; FN = 56) and Muraena pavonina (2n = 42; 6m+4sm+32a; FN = 52), collected along the Northeastern coast of Brazil and around the St Peter and St Paul Archipelago were analyzed. Typical large metacentric chromosomes were observed in all species. Conspicuous polymorphic heterochromatic regions were observed at the centromeres of most chromosomes and at single ribosomal sites. The data obtained for Ophichthidae corroborate the hypothesis of a karyotypic diversification mainly due to pericentric inversions and Robertsonian rearrangements, while the identification of constant chromosome numbers in Muraenidae (2n = 42) suggests a karyotype diversification through pericentric inversions and heterochromatin processes