An unequal endotoxin distribution in typical house types of Ho Chi Minh city.

BACKGROUND: Endotoxin exposure may cause asthma exacerbations and contribute to non-atopic respiratory diseases. Viet Nam, a country with multiple house types, is lacking data on indoor contamination by endotoxin in regard with house types. OBJECTIVE: The comparison of measured settled dust endotoxin levels among house types in Ho Chi Minh city will allow to classify the house types regarding health risks. METHODS: This study is a cross-sectional study. Five identified house types were selected: apartment (APA), rental (REN), rural (RUR), slum (SLU) and tube house (TUB). One hundred house's endotoxin contamination was evaluated by questionnaire and dust sampling. Endotoxin concentration was measured by kinetic chromogenic Limulus assay. RESULTS: dotoxin concentration (geometric mean 126.0 EU/mg, 95%CI 118.3-133.7) is particularly high in settled house dust compared to western countries and is significantly associated with the house type. The highest level was found in RUR in each room (p = 0.002 for living room; p < 0.0001 for bedrooms and for kitchens). Concerning levels in the different rooms, APA and TUB form a low group while REN and SLU (p < 0.001) form a median group and RUR the highest (p < 0.001). Differences in endotoxin levels were associated to the presence of dog, chicken and farm animals, wood cooking, air-conditioning usage. CONCLUSIONS: Further understanding of the relevant factors to endotoxin levels would contribute to prevent asthma exacerbations and chronic respiratory diseases. Public health interventions to reduce exposure to endotoxin include improving housing conditions, eliminating risk factors and a priority to high-risk house types.

Family Anesthesia Experience: Improving Social Support of Residents Through Education of Their Family and Friends.

Introduction: The prevalence of burnout among anesthesiology residents is 41%-51%. Burnout is associated with medical errors, physician turnover, and substance use disorder. Social support and wellness may reduce burnout, but a barrier is support persons' lack of understanding of an anesthesiologist's work demands. We developed the Family Anesthesia Experience (FAX) to help support persons best support their resident. Methods: FAX consisted of a 4-hour event with hands-on experience, didactics portion, and panel discussion. Participants learned about a typical day in the life of an anesthesiology resident, wellness, burnout, substance use disorder, and available support resources, and had hands-on experience with procedures. The panel discussion offered logistical information about anesthesiology residency and allowed support persons to ask panel members questions. A postevent survey collected feedback on the event. Results: Fifty-one participants (first-year anesthesiology residents and their support persons) attended the event. Eight of 11 residents (73%) and 32 of 40 support persons (80%) completed the survey. All enjoyed the event, would recommend it to other anesthesiology resident support persons, and felt the event would improve communication and support. Most learned a moderate (35%) to large amount (50%) from the event. Qualitative feedback suggested most support persons found the event helpful in improving their understanding of anesthesiology residents' work demands. Discussion: The FAX was well liked by participants. Although we did not assess specific knowledge gained and long-term effects of the 2022 event, evaluations of previous years' events suggest that the event improved participants' understanding of anesthesiology residents' work and stressors.

Antimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors.

The antimalarial activity and pharmacology of a series of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors (HDACIs) was evaluated. In in vitro growth inhibition assays approximately 50 analogs were evaluated against four drug resistant strains of Plasmodium falciparum. The range of 50% inhibitory concentrations (IC(50)s) was 0.0005 to >1 microM. Five analogs exhibited IC(50)s of <3 nM, and three of these exhibited selectivity indices of >600. The most potent compound, WR301801 (YC-2-88) was shown to cause hyperacetylation of P. falciparum histones, which is a marker for HDAC inhibition in eukaryotic cells. The compound also inhibited malarial and mammalian HDAC activity in functional assays at low nanomolar concentrations. WR301801 did not exhibit cures in P. berghei-infected mice at oral doses as high as 640 mg/kg/day for 3 days or in P. falciparum-infected Aotus lemurinus lemurinus monkeys at oral doses of 32 mg/kg/day for 3 days, despite high relative bioavailability. The failure of monotherapy in mice may be due to a short half-life, since the compound was rapidly hydrolyzed to an inactive acid metabolite by loss of its hydroxamate group in vitro (half-life of 11 min in mouse microsomes) and in vivo (half-life in mice of 3.5 h after a single oral dose of 50 mg/kg). However, WR301801 exhibited cures in P. berghei-infected mice when combined at doses of 52 mg/kg/day orally with subcurative doses of chloroquine. Next-generation HDACIs with greater metabolic stability than WR301801 may be useful as antimalarials if combined appropriately with conventional antimalarial drugs.

Convolutional neural networks for vibrational spectroscopic data analysis.

In this work we show that convolutional neural networks (CNNs) can be efficiently used to classify vibrational spectroscopic data and identify important spectral regions. CNNs are the current state-of-the-art in image classification and speech recognition and can learn interpretable representations of the data. These characteristics make CNNs a good candidate for reducing the need for preprocessing and for highlighting important spectral regions, both of which are crucial steps in the analysis of vibrational spectroscopic data. Chemometric analysis of vibrational spectroscopic data often relies on preprocessing methods involving baseline correction, scatter correction and noise removal, which are applied to the spectra prior to model building. Preprocessing is a critical step because even in simple problems using 'reasonable' preprocessing methods may decrease the performance of the final model. We develop a new CNN based method and provide an accompanying publicly available software. It is based on a simple CNN architecture with a single convolutional layer (a so-called shallow CNN). Our method outperforms standard classification algorithms used in chemometrics (e.g. PLS) in terms of accuracy when applied to non-preprocessed test data (86% average accuracy compared to the 62% achieved by PLS), and it achieves better performance even on preprocessed test data (96% average accuracy compared to the 89% achieved by PLS). For interpretability purposes, our method includes a procedure for finding important spectral regions, thereby facilitating qualitative interpretation of results.

Inter-species genetic movement may blur the epidemiology of streptococcal diseases in endemic regions.

Streptococcus dysgalactiae subsp. equisimilis (human group G streptococcus, GGS) is generally regarded as a commensal organism but can cause a spectrum of human diseases very similar to that caused by S. pyogenes (group A streptococcus, GAS). Lateral acquisition of genes between these two phylogenetically closely related species is well documented. However, the extent and mechanisms of lateral acquisitions is not known. We report here genomic subtraction between a pathogenic GGS isolate and a community GGS isolate and analyses of the gene sequences unique to the pathovar. Our results show that cross-species genetic transfers are common between GGS and two closely related human pathogens, GAS and the group B streptococcus. We also demonstrate that mobile genetic elements, such as phages and transposons, play an important role in the ongoing inter-species transfers of genetic traits between extant organisms in the community. Furthermore, lateral gene transfers between GAS and GGS may occur more frequently in geographical regions of high GAS endemicity. These observations may have important implications in understanding the epidemiology of streptococcal diseases in such regions.

Evoked itch perception is associated with changes in functional brain connectivity.

Chronic itch, a highly debilitating condition, has received relatively little attention in the neuroimaging literature. Recent studies suggest that brain regions supporting itch in chronic itch patients encompass sensorimotor and salience networks, and corticostriatal circuits involved in motor preparation for scratching. However, how these different brain areas interact with one another in the context of itch is still unknown. We acquired BOLD fMRI scans in 14 atopic dermatitis patients to investigate resting-state functional connectivity before and after allergen-induced itch exacerbated the clinical itch perception in these patients. A seed-based analysis revealed decreased functional connectivity from baseline resting state to the evoked-itch state between several itch-related brain regions, particularly the insular and cingulate cortices and basal ganglia, where decreased connectivity was significantly correlated with increased levels of perceived itch. In contrast, evoked itch increased connectivity between key nodes of the frontoparietal control network (superior parietal lobule and dorsolateral prefrontal cortex), where higher increase in connectivity was correlated with a lesser increase in perceived itch, suggesting that greater interaction between nodes of this executive attention network serves to limit itch sensation via enhanced top-down regulation. Overall, our results provide the first evidence of itch-dependent changes in functional connectivity across multiple brain regions.

Towards histone deacetylase inhibitors as new antimalarial drugs.

Histone deacetylases (HDACs) are important enzymes that effect post-translational modifications of proteins by altering the acetylation state of lysine residues. HDACs control epigenetic changes that trigger cell transformation and proliferation of transformed cells associated with many diseases. These enzymes are validated drug targets for some types of cancer and are promising therapeutic targets for a range of other diseases, including malaria. Annually, there are ~500 million clinical cases of malaria and ~0.8-1.2 million deaths. There is no licensed vaccine for preventing malaria, and parasites that cause malaria are becoming resistant to current drugs, necessitating the search for new therapies. HDAC inhibitors are emerging as a promising new class of antimalarial drugs with potent and selective action against Plasmodium parasites in vitro. Recent studies on the effects of HDAC inhibitors on the growth and development of P. falciparum have provided important new information on transcriptional regulation in malaria parasites and have validated the potential of this class of inhibitors for malaria therapy. To realise effective HDAC inhibitors for clinical trials, next generation inhibitors must not inhibit other human HDACs or proteins required for normal human physiology, be highly selective in killing parasites in vivo without killing normal host cells, and have improved bioavailability and pharmacokinetic profiles. This review summarizes current knowledge about malaria parasite HDACs and HDAC inhibitors with antimalarial properties, and provides insights for their development into new drugs for treatment of malaria.

Kinetic energy density and agglomerate abrasion rate during blending of agglomerates into powders.

Problems related to the blending of a cohesive powder with a free flowing bulk powder are frequently encountered in the pharmaceutical industry. The cohesive powder often forms lumps or agglomerates which are not dispersed during the mixing process and are therefore detrimental to blend uniformity. Achieving sufficient blend uniformity requires that the blending conditions are able to break up agglomerates, which is often an abrasion process. This study was based on the assumption that the abrasion rate of agglomerates determines the required blending time. It is shown that the kinetic energy density of the moving powder bed is a relevant parameter which correlates with the abrasion rate of agglomerates. However, aspects related to the strength of agglomerates should also be considered. For this reason the Stokes abrasion number (St(Abr)) has been defined. This parameter describes the ratio between the kinetic energy density of the moving powder bed and the work of fracture of the agglomerate. The St(Abr) number is shown to predict the abrasion potential of agglomerates in the dry-mixing process. It appeared possible to include effects of filler particle size and impeller rotational rate into this concept. A clear relationship between abrasion rate of agglomerates and the value of St(Abr) was demonstrated.

A density-based segmentation for 3D images, an application for X-ray micro-tomography.

Density-based spatial clustering of applications with noise (DBSCAN) is an unsupervised classification algorithm which has been widely used in many areas with its simplicity and its ability to deal with hidden clusters of different sizes and shapes and with noise. However, the computational issue of the distance table and the non-stability in detecting the boundaries of adjacent clusters limit the application of the original algorithm to large datasets such as images. In this paper, the DBSCAN algorithm was revised and improved for image clustering and segmentation. The proposed clustering algorithm presents two major advantages over the original one. Firstly, the revised DBSCAN algorithm made it applicable for large 3D image dataset (often with millions of pixels) by using the coordinate system of the image data. Secondly, the revised algorithm solved the non-stability issue of boundary detection in the original DBSCAN. For broader applications, the image dataset can be ordinary 3D images or in general, it can also be a classification result of other type of image data e.g. a multivariate image.

Comparative gene expression profiling of P. falciparum malaria parasites exposed to three different histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors are being intensively pursued as potential new drugs for a range of diseases, including malaria. HDAC inhibitors are also important tools for the study of epigenetic mechanisms, transcriptional control, and other important cellular processes. In this study the effects of three structurally related antimalarial HDAC inhibitors on P. falciparum malaria parasite gene expression were compared. The three hydroxamate-based compounds, trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA; Vorinostat®) and a 2-aminosuberic acid derivative (2-ASA-9), all caused profound transcriptional effects, with ~2-21% of genes having >2-fold altered expression following 2 h exposure to the compounds. Only two genes, alpha tubulin II and a hydrolase, were up-regulated by all three compounds after 2 h exposure in all biological replicates examined. The transcriptional changes observed after 2 h exposure to HDAC inhibitors were found to be largely transitory, with only 1-5% of genes being regulated after removing the compounds and culturing for a further 2 h. Despite some structural similarity, the three inhibitors caused quite diverse transcriptional effects, possibly reflecting subtle differences in mode of action or cellular distribution. This dataset represents an important contribution to our understanding of how HDAC inhibitors act on malaria parasites and identifies alpha tubulin II as a potential transcriptional marker of HDAC inhibition in malaria parasites that may be able to be exploited for future development of HDAC inhibitors as new antimalarial agents.

Targeting histone deacetylase inhibitors for anti-malarial therapy.

It is now clear that histone acetylation plays key roles in regulating gene transcription in both eukaryotes and prokaryotes, the acetylated form inducing gene expression while deacetylation silences genes. Recent studies have identified roles for histone acetyltransferases (HATs) and/or histone deacetylases (HDACs) in a number of parasites including Entamoeba histolytica, Toxoplasma gondii, Schistosoma mansoni, Cryptosporidium sp., Leishmania donovani, Neospora caninum, and Plasmodium falciparum. Here we survey fairly limited efforts to date in profiling antimalarial activities of HDAC inhibitors, showing that such compounds are potent inhibitors of the growth of P. falciparum in vitro and in vivo. Most of the compounds evaluated so far have borne a zinc-binding hydroxamate group that tends to be metabolized in vivo, and thus new zinc-binding groups need to be incorporated into second generation inhibitors in order to mask the catalytic zinc in the active site of HDACs. Also the development of compounds that are selective for parasitic HDACs over mammalian HDACs is still in relative infancy and it will take some time to derive antiparasitic HDAC inhibitor compounds with minimal toxicity for the host and acceptable pharmacokinetic and pharmacodynamic profiles for human treatment. Nevertheless, results to date suggest that HDAC inhibitor development represents a promising new approach to the potential treatment of parasitic infections, including those induced by malaria protozoa, and may offer new therapeutic targets within increasingly drug-resistant malarial parasites.