Clinical experience with the novel histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in patients with relapsed lymphoma

Preclinical studies indicate that vorinostat (suberoylanilide hydroxamic acid or SAHA) inhibits histone deacetylase (HDAC) activity, increases acetylated histones H2a, H2b, H3, and H4, and thereby induces differentiation and apoptosis in a variety of tumour cell lines, including murine erythroleukaemia, human bladder transitional cell carcinoma, and human breast adenocarcinoma. On the basis of these favourable preclinical findings, vorinostat has been selected as a candidate for clinical development with the potential to treat patients with selected malignances, including Hodgkin's disease and non-Hodgkin's lymphomas. Phase I clinical trials in patients with haematological malignances and solid tumours showed that both intravenous (i.v.) and oral formulations of vorinostat are well tolerated, can inhibit HDAC activity in peripheral blood mononuclear cells and tumour tissue biopsies, and produce objective tumour regression and symptomatic improvement with little clinical toxicity. The dose-limiting toxicities (DLT) of i.v. vorinostat were primarily haematologic and were rapidly reversible within 4–5 days of therapy cessation. In contrast, the DLT for oral vorinostat were primarily non-haematologic (including dehydration, anorexia, diarrhoea, fatigue) and were also rapidly reversible, usually within 3 days. Further research is warranted to optimise the dosing schedule for vorinostat, particularly with respect to dose, timing of administration, and duration of therapy, and to fully delineate the mechanism(s) of antitumour effect of vorinostat in various types of malignances. Several phase II studies are currently ongoing in patients with haematological malignances and solid tumours

Intestinal lesions in dogs with acute hemorrhagic diarrhea syndrome associated with netF-positive Clostridium perfringens type A

Acute hemorrhagic diarrhea syndrome (AHDS), formerly named canine hemorrhagic gastroenteritis, is one of the most common causes of acute hemorrhagic diarrhea in dogs, and is characterized by acute onset of diarrhea, vomiting, and hemoconcentration. To date, histologic examinations have been limited to postmortem specimens of only a few dogs with AHDS. Thus, the aim of our study was to describe in detail the distribution, character, and grade of microscopic lesions, and to investigate the etiology of AHDS. Our study comprised 10 dogs with AHDS and 9 control dogs of various breeds, age, and sex. Endoscopic biopsies of the gastrointestinal tract were taken and examined histologically (H&E, Giemsa), immunohistochemically (Clostridium spp., parvovirus), and bacteriologically. The main findings were acute necrotizing and neutrophilic enterocolitis (9 of 10) with histologic detection of clostridia-like, gram-positive bacteria on the necrotic mucosal surface (9 of 10). Clostridium perfringens isolated from the duodenum was identified as type A (5 of 5) by multiplex PCR (5 of 5). In addition, each of the 5 genotyped isolates encoded the pore-forming toxin netF. Clostridium spp. (not C. perfringens) were cultured from duodenal biopsies in 2 of 9 control dogs. These findings suggest that the pore-forming netF toxin is responsible for the necrotizing lesions in the intestines of a significant proportion of dogs with AHDS. Given that the stomach was not involved in the process, the term acute hemorrhagic diarrhea syndrome seems more appropriate than the frequently used term hemorrhagic gastroenteritis

Examination of the cut-off scores determined by the Ages and Stages Questionnaire in a population-based sample of 6 month-old Norwegian infants

<p>Abstract</p> <p>Background</p> <p>Few population-based samples have previously published performance on the Ages and Stages Questionnaire (ASQ), a recommended screening tool to detect infant developmental delay. The aim of the study was to investigate performance on the ASQ in a population-based sample of 6-month-old infants.</p> <p>Methods</p> <p>In this population-based questionnaire study from Oslo, Norway, the 30 item ASQ 6 month Questionnaire (N = 1053) were included, however without the pictograms, and compared to the Norwegian reference sample (N.ref) (N = 169) and to US cut-off values. Exclusion criteria were maternal non-Scandinavian ethnicity, infant age < 5.0 or > 7.0 months (corrected age), twins, and birth weight < 2.5 kg. Cut-off = 2.5 percentile (equivalent to mean minus 2 standard deviations). Pearson's Chi square and Mann-Whitney U were used to compare items and areas, respectively, with N.ref.</p> <p>Results</p> <p>The reported ASQ scores were lower on all but one of the 10 significantly different items, and in all areas except Personal social, compared to the N.ref sample. The estimated cut-off values for suspected developmental delay (Communication 25, Gross motor 15, Fine motor 18, Problem solving 25 and Personal social 20) were lower than the recommended American (US) values in all areas, and lower than the Norwegian values in two areas. Scores indicating need for further assessment were reached by 13.8% or 20.5% of the infants (missing items scored according to the US or the Norwegian manual), and by 33.8% or 30.3% of the infants using the recommended US or the Norwegian cut-off values, in this population-based sample. The Fine motor area demonstrated a large variability depending on the different cut-off and scoring possibilities. Both among the items excluding pictograms and the items that do not have pictograms, approximately every third item differed significantly compared to the N.ref sample.</p> <p>Conclusion</p> <p>The psychomotor developmental scores were lower than in the reference samples in this study of ASQ 6 month Questionnaire; to our knowledge the first study to be both representative and comparatively large. Approximately every third child with birth weight above 2.5 kg, received scores suggesting further assessment using recommended ASQ cut-off scores.</p

The Relation Between Cognitive Development and Anxiety Phenomena in Children

We examined the relation between cognitive development and fear, anxiety, and behavioral inhibition in a non-clinical sample of 226 Dutch children aged 4–9 years. To assess cognitive development, children were tested with Piagetian conservation tasks and a Theory-of-Mind (TOM) test. Fears were measured by means of a self-report scale completed by the children, while anxiety symptoms and behavioral inhibition were indexed by rating scales that were filled out by parents. Significant age trends were observed for some anxiety phenomena. For example, younger children displayed higher fear scores, whereas older children exhibited higher levels of generalized anxiety. Most importantly, results of regression analyses (in which we controlled for age) indicated that cognitive development, and in particular TOM ability, made a unique and significant contribution to various domains of behavioral inhibition. In all cases, higher levels of TOM were associated with lower levels of behavioral inhibition. In general, percentages of explained variance were rather small (i.e., <6%), indicating that the role of cognitive development in various anxiety phenomena is limited

Improving lung health in low-income and middle-income countries: from challenges to solutions

Low-income and middle-income countries (LMICs) bear a disproportionately high burden of the global morbidity and mortality caused by chronic respiratory diseases (CRDs), including asthma, chronic obstructive pulmonary disease, bronchiectasis, and post-tuberculosis lung disease. CRDs are strongly associated with poverty, infectious diseases, and other non-communicable diseases (NCDs), and contribute to complex multi-morbidity, with major consequences for the lives and livelihoods of those affected. The relevance of CRDs to health and socioeconomic wellbeing is expected to increase in the decades ahead, as life expectancies rise and the competing risks of early childhood mortality and infectious diseases plateau. As such, the World Health Organization has identified the prevention and control of NCDs as an urgent development issue and essential to the achievement of the Sustainable Development Goals by 2030. In this Review, we focus on CRDs in LMICs. We discuss the early life origins of CRDs; challenges in their prevention, diagnosis, and management in LMICs; and pathways to solutions to achieve true universal health coverage

Non-destructive detection of cross-sectional strain and defect structure in an individual Ag five-fold twinned nanowire by 3D electron diffraction mapping

Coherent x-ray diffraction investigations on Ag five-fold twinned nanowires (FTNWs) have drawn controversial conclusions concerning whether the intrinsic 7.35° angular gap could be compensated homogeneously through phase transformation or inhomogeneously by forming disclination strain field. In those studies, the x-ray techniques only provided an ensemble average of the structural information from all the Ag nanowires. Here, using three-dimensional (3D) electron diffraction mapping approach, we non-destructively explore the cross-sectional strain and the related strain-relief defect structures of an individual Ag FTNW with diameter about 30 nm. The quantitative analysis of the fine structure of intensity distribution combining with kinematic electron diffraction simulation confirms that for such a Ag FTNW, the intrinsic 7.35° angular deficiency results in an inhomogeneous strain field within each single crystalline segment consistent with the disclination model of stress-relief. Moreover, the five crystalline segments are found to be strained differently. Modeling analysis in combination with system energy calculation further indicates that the elastic strain energy within some crystalline segments, could be partially relieved by the creation of stacking fault layers near the twin boundaries. Our study demonstrates that 3D electron diffraction mapping is a powerful tool for the cross-sectional strain analysis of complex 1D nanostructures

Pesticides in house dust from urban and farmworker households in California: an observational measurement study

<p>Abstract</p> <p>Background</p> <p>Studies report that residential use of pesticides in low-income homes is common because of poor housing conditions and pest infestations; however, exposure data on contemporary-use pesticides in low-income households is limited. We conducted a study in low-income homes from urban and agricultural communities to: characterize and compare house dust levels of agricultural and residential-use pesticides; evaluate the correlation of pesticide concentrations in samples collected several days apart; examine whether concentrations of pesticides phased-out for residential uses, but still used in agriculture (i.e., chlorpyrifos and diazinon) have declined in homes in the agricultural community; and estimate resident children's pesticide exposures via inadvertent dust ingestion.</p> <p>Methods</p> <p>In 2006, we collected up to two dust samples 5-8 days apart from each of 13 urban homes in Oakland, California and 15 farmworker homes in Salinas, California, an agricultural community (54 samples total). We measured 22 insecticides including organophosphates (chlorpyrifos, diazinon, diazinon-oxon, malathion, methidathion, methyl parathion, phorate, and tetrachlorvinphos) and pyrethroids (allethrin-two isomers, bifenthrin, cypermethrin-four isomers, deltamethrin, esfenvalerate, imiprothrin, permethrin-two isomers, prallethrin, and sumithrin), one phthalate herbicide (chlorthal-dimethyl), one dicarboximide fungicide (iprodione), and one pesticide synergist (piperonyl butoxide).</p> <p>Results</p> <p>More than half of the households reported applying pesticides indoors. Analytes frequently detected in both locations included chlorpyrifos, diazinon, permethrin, allethrin, cypermethrin, and piperonyl butoxide; no differences in concentrations or loadings were observed between locations for these analytes. Chlorthal-dimethyl was detected solely in farmworker homes, suggesting contamination due to regional agricultural use. Concentrations in samples collected 5-8 days apart in the same home were strongly correlated for the majority of the frequently detected analytes (Spearman ρ = 0.70-1.00, p < 0.01). Additionally, diazinon and chlorpyrifos concentrations in Salinas farmworker homes were 40-80% lower than concentrations reported in samples from Salinas farmworker homes studied between 2000-2002, suggesting a temporal reduction after their residential phase-out. Finally, estimated non-dietary pesticide intake for resident children did not exceed current U.S. Environmental Protection Agency's (U.S. EPA) recommended chronic reference doses (RfDs).</p> <p>Conclusion</p> <p>Low-income children are potentially exposed to a mixture of pesticides as a result of poorer housing quality. Historical or current pesticide use indoors is likely to contribute to ongoing exposures. Agricultural pesticide use may also contribute to additional exposures to some pesticides in rural areas. Although children's non-dietary intake did not exceed U.S. EPA RfDs for select pesticides, this does not ensure that children are free of any health risks as RfDs have their own limitations, and the children may be exposed indoors via other pathways. The frequent pesticide use reported and high detection of several home-use pesticides in house dust suggests that families would benefit from integrated pest management strategies to control pests and minimize current and future exposures.</p

Regulation of BRCA1 expression and its relationship to sporadic breast cancer

Germ-line mutations in the BRCA1 tumour suppressor gene contribute to familial breast tumour formation, but there is no evidence for direct mutation of the BRCA1 gene in the sporadic form of the disease. In contrast, decreased expression of the BRCA1 gene has been shown to be common in sporadic tumours, and the magnitude of the decrease correlates with disease progression. BRCA1 expression is also tightly regulated during normal breast development. Determining how these developmental regulators of BRCA1 expression are co-opted during breast tumourigenesis could lead to a better understanding of sporadic breast cancer aetiology and the generation of novel therapeutic strategies aimed at preventing sporadic breast tumour progression