BRAF Mutations in Patients with Myeloid Neoplasms: A Cancer Center Multigene Next-Generation Sequencing Analysis Experience.

BRAF mutations are rare in myeloid neoplasms and are reported to be associated with poor treatment outcomes. The purpose of our study is to characterize BRAF mutations in myeloid neoplasms using a next-generation sequencing (NGS) panel based on the experiences of a single cancer center. We conducted a retrospective review of patients with myeloid neoplasms who underwent the HopeSeq studies between January 2018 and September 2023. A total of 14 patients with myeloid neoplasms carrying BRAF mutations were included in our cohort. The clinical, pathological, and molecular features of these patients were investigated. Our study indicates that BRAF mutations are rare in myeloid neoplasms, constituting only 0.53% (14/2632) of all myeloid neoplasm cases, with the most common BRAF mutation being BRAF V600E (4/14; 28.6%). Interestingly, we observed that six out of seven patients with acute myeloid leukemia (AML) exhibited AML with monocytic differentiation, and all the patients with AML exhibited an extremely poor prognosis compared to those without BRAF mutations. TET2 (5/14; 35.7%), ASXL1 (4/14; 28.6%), and JAK2 (4/14; 28.6%) were the three most frequently co-mutated genes in these patients. Moreover, we noted concurrent KMT2A gene rearrangement with BRAF mutations in three patients with AML (3/7; 42.9%). Our study suggests that although BRAF mutations are rare in myeloid neoplasms, they play a crucial role in the pathogenesis of specific AML subtypes. Furthermore, RAS pathway alterations, including BRAF mutations, are associated with KMT2A gene rearrangement in AML. However, these findings warrant further validation in larger studies.

Gastrointestinal symptoms in 609 Japanese patients with COVID-19: a single-center retrospective study.

BACKGROUND: GI symptoms are common in acute COVID-19 patients. This study aimed to characterize the GI symptoms occurring in Japanese COVID-19 patients. METHODS: This retrospective single-center cohort study included 751 hospitalized acute COVID-19 patients. The primary outcomes were the frequency and severity of GI symptoms. The secondary outcomes included the association between COVID-19 severity and GI symptoms and the timing of GI symptom onset. RESULTS: After exclusion, the data of 609 patients were analyzed. The median age was 62 years, and 55% were male. The median time from initial symptom onset to admission was five days. On admission, 92% of the patients had fever, 35.1% had fatigue, 75% had respiratory symptoms, and 75% had pneumonia. The sample included patients with mild (19%), moderate (59%), and severe COVID-19 (22%). A total of 218 patients (36%) had GI symptoms, of which 93% were classified as grade 1/2; 170 patients had both respiratory and GI symptoms. Diarrhea was the most frequent GI symptom, occurring in 170 patients, followed by anorexia in 73 patients and nausea/vomiting in 36 patients, and abdominal pain in 8 patients. There was no significant relationship between COVID-19 severity and GI symptoms. Among COVID-19 patients with both GI and respiratory symptoms, 48% had respiratory symptoms preceding GI symptoms, 25% had GI symptoms preceding respiratory symptoms and 27% had a simultaneous onset of respiratory and GI symptoms. CONCLUSION: Thirty-six percent of the Japanese COVID-19 patients had GI symptoms; diarrhea was the most frequent GI symptom but did not predict severe COVID-19.

Stratification Based on Risk Factors at Diagnosis Could Predict Progression in Patients with Pancreatic Cysts.

BACKGROUND: Predicting the risk of malignant transformation in pancreatic cyst patients is challenging. AIM: We retrospectively investigated the risk factors for malignant transformation in pancreatic cyst patients. METHODS: Patients with pancreatic cysts diagnosed using imaging tests were followed from November 2008 to December 2021. A significant change was defined as the additional development of high-risk stigmata (HRS), worrisome features (WFs), or pancreatic cancer during monitoring. RESULTS: In total, 479 patients were analyzed, with a median observation period of 50 months. Forty-four patients (9.2%) showed significant changes, and eight (1.7%) developed pancreatic cancer. The univariate analysis showed that the cyst diameter at diagnosis (≥ 14 mm), main pancreatic duct (MPD) diameter at diagnosis (≥ 3 mm), presence of multilocular cysts, and an inconsistent MPD caliber were significant predictive factors for a significant change. One point was assigned for each significant factor. We grouped the patients into three groups: the low-risk group (total score 0), medium-risk group (score 1-2), and high-risk group (score 3-4). The high-risk group had a higher risk of a significant change than the medium- and low-risk groups (age-adjusted HRs for the medium-risk and high-risk groups were 3.0 and 5.2 compared with the low-risk group). CONCLUSION: Stratification based on risk factors may help predict the development of significant changes in pancreatic cyst patients.

Liposomal Bupivacaine vs Ropivacaine for Adductor Canal Blocks in Total Knee Arthroplasty: A Prospective Randomized Trial.

BACKGROUND: The purpose of this study is to determine the benefit of the analgesic liposomal bupivacaine compared to ropivacaine, by assessing pain and joint stiffness, and total oral opioid consumption by milligram morphine equivalent (MME) after total knee arthroplasty. METHODS: Patients were randomized to receive either the study drug (liposomal bupivacaine admixed with bupivacaine) or the control drug (ropivacaine) in an adductor canal block. Only the anesthesiologist performing the block was aware of which arm of the study the patient was randomized to. MME, pain, Knee injury and Osteoarthritis Outcome Score Joint Replacement, and overall benefit of analgesia scores were recorded 24, 48, and 72 hours post-surgery either face-to-face or via telephone depending on patient discharge status. RESULTS: One hundred patients were enrolled into the study and analyzed: 54 in the control group and 46 in the experimental group. Primary outcomes measured were pain as a numerical rating scale, MME, and length of stay in hours. Secondary outcomes were joint pain and stiffness recorded as Knee injury and Osteoarthritis Outcome Score Joint Replacement outcome and overall benefit of analgesia score. No statistically significant between-group differences were observed for any measured outcome. CONCLUSION: We did not find any supporting evidence that liposomal bupivacaine yields increased pain relief following total knee arthroplasty compared to the control drug, ropivacaine.

Follicular cholangitis mimicking cholangiocarcinoma treated with right hepatectomy: A case report and review of published works.

Follicular cholangitis is a new, rare disease that causes severe biliary stricture. We herein describe the findings from a resected case of follicular cholangitis, suggesting a distinct disease entity that causes benign biliary stricture. A 60-year-old man who was referred to our hospital due to elevated γ-glutamyl transpeptidase levels and dilatation of the B8 bile duct. Although bile juice cytology and bile duct brushing cytology showed no malignancy, the dilatation was progressive. Therefore, right hepatectomy combined with caudate lobectomy was carried out on suspicion of intrahepatic cholangiocarcinoma. The wall of the resected bile duct was markedly thickened due to severe fibrosis under the mucosal layer. Histology of the mucosal epithelium indicated no malignancy. Infiltration of plasma cells characterized by remarkable formation of lymphoid follicles with germinal centers was observed around the bile ducts. The patient was diagnosed with follicular cholangitis based on histological findings. We thus observed a rare case of follicular cholangitis. This case and review of published reports suggest that, despite its rarity, follicular cholangitis should be considered at the differential diagnosis of biliary stricture. This case report could contribute to a better understanding of how to address this disease.

Smoke aerosols dispersion and transport from the 2013 New South Wales (Australia) bushfires.

Environmental monitoring and modelling, especially in the regional context, has seen significant progress with the widely usage of satellite measurement in conjunction with local meteorological and air quality monitoring to understand the atmospheric dispersion and transport of air pollutants. This paper studies the application of these data and modelling tools to understand the environment effects of a major bushfire period in the state of New South Wales (NSW), Australia, in 2013. The bushfires have caused high pollution episodes at many sites in the greater Sydney metropolitan areas. The potential long-range transport of aerosols produced by bushfires to other region and states has been seen by regulators as a major concern. Using data and images collected from satellites, in addition to the results obtained from different simulations carried out using HYSPLIT trajectory model and a regional meteorological model called Conformal Cubic Atmospheric Model (CCAM), we were able to identify at least 2 days on which the smoke aerosols from bush fires in NSW has been transported at high altitude to the northern state of Queensland and the Coral Sea. As a result, widespread high particle concentration in South East Queensland including the Brisbane area, as measured by nearly all the air quality monitoring stations in this region, occurred on the day when the smoke aerosols intruded to lower altitude as indicated by the CALIOP (Cloud-Aerosol Lidar with Orthogonal Polarization) Lidar measurements on the CALIPSO (Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation) satellite. The use of meteorological or air quality modelling to connect the ground-based measurements with satellite observations as shown in this study is useful to understand the pollutant transport due to bushfires and its impact on regional air quality.

Vascular histone deacetylation by pharmacological HDAC inhibition.

HDAC inhibitors can regulate gene expression by post-translational modification of histone as well as nonhistone proteins. Often studied at single loci, increased histone acetylation is the paradigmatic mechanism of action. However, little is known of the extent of genome-wide changes in cells stimulated by the hydroxamic acids, TSA and SAHA. In this article, we map vascular chromatin modifications including histone H3 acetylation of lysine 9 and 14 (H3K9/14ac) using chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq). Since acetylation-mediated gene expression is often associated with modification of other lysine residues, we also examined H3K4me3 and H3K9me3 as well as changes in CpG methylation (CpG-seq). RNA sequencing indicates the differential expression of ∼30% of genes, with almost equal numbers being up- and down-regulated. We observed broad deacetylation and gene expression changes conferred by TSA and SAHA mediated by the loss of EP300/CREBBP binding at multiple gene promoters. This study provides an important framework for HDAC inhibitor function in vascular biology and a comprehensive description of genome-wide deacetylation by pharmacological HDAC inhibition.

Dynamic changes in the cardiac methylome during postnatal development.

Relatively little is known about the epigenetic control mechanisms that guide postnatal organ maturation. The goal of this study was to determine whether DNA methylation plays an important role in guiding transcriptional changes during the first 2 wk of mouse heart development, which is an important period for cardiomyocyte maturation, loss of proliferative capacity and loss of regenerative potential. Gene expression profiling (RNA-seq) and genome-wide sequencing of methylated DNA (MBD-seq) identified dynamic changes in the cardiac methylome during postnatal development [2545 differentially methylated regions (DMRs) from P1 to P14 in the mouse]. The vast majority (~80%) of DMRs were hypermethylated between P1 and P14, and these hypermethylated regions were associated with transcriptional shut down of important developmental signaling pathways, including Hedgehog, bone morphogenetic protein, TGF-ß, fibroblast growth factor, and Wnt/ß-catenin signaling. Postnatal inhibition of DNA methylation with 5-aza-2'-deoxycytidine induced a marked increase (~3-fold) in cardiomyocyte proliferation and ~50% reduction in the percentage of binucleated cardiomyocytes compared with saline-treated controls. This study provides novel evidence for widespread alterations in DNA methylation during postnatal heart maturation and suggests that cardiomyocyte cell cycle arrest during the neonatal period is subject to regulation by DNA methylation.

The primary microRNA-208b interacts with Polycomb-group protein, Ezh2, to regulate gene expression in the heart.

The Polycomb-group protein, Ezh2, is required for epigenetic gene silencing in the adult heart by unknown mechanism. We investigated the role of Ezh2 and non-coding RNAs in a mouse model of pressure overload using transverse aortic constriction (TAC) attenuated by the prototypical histone deacetylase inhibitor, trichostatin A (TSA). Chromatin immunoprecipitation of TAC and TAC+TSA hearts suggests interaction of Ezh2 and primary microRNA-208b (pri-miR-208b) in the regulation of hypertrophic gene expression. RNAi silencing of pri-miR-208b and Ezh2 validate pri-miR-208b-mediated transcriptional silencing of genes implicated in cardiac hypertrophy including the suppression of the bi-directional promoter (bdP) of the cardiac myosin heavy chain genes. In TAC mouse heart, TSA attenuated Ezh2 binding to bdP and restored antisense ß-MHC and α-MHC gene expression. RNA-chromatin immunoprecipitation experiments in TAC hearts also show increased pri-miR-208b dependent-chromatin binding. These results are the first description by which primary miR interactions serve to integrate chromatin modifications and the transcriptional response to distinct signaling cues in the heart. These studies provide a framework for MHC expression and regulation of genes implicated in pathological remodeling of ventricular hypertrophy.

Dietary Elimination of Soybean Components Enhances Allergic Immune Response to Peanuts in BALB/c Mice.

BACKGROUND: Food allergy research is hampered by a lack of animal models that consistently mimic human food allergic responses. Laboratory mice are generally fed grain-based chow made with large amounts of soybeans rich in immunomodulatory isoflavones. We tested the role of dietary soy components in the induction of food allergic responses in the BALB/c mouse strain, which is known to be resistant to anaphylaxis when orally challenged by food allergens. METHODS: Mice were fed a soy-free diet for 2 generations. After weaning, mice were maintained on the same diet or fed a diet containing soy isoflavones, i.e. genistein and daidzein, followed by weekly oral sensitizations with crude peanut extract plus cholera toxin and finally challenged at week 7. The anaphylactic symptoms, body temperature, peanut-specific antibodies and mast cell degranulation were assessed. RESULTS: Soy-free diet mice showed significantly higher anaphylactic symptom scores and mast cell degranulation after challenge and higher peanut-specific antibody levels than mice fed regular chow. Introduction of a regular soy diet or an isoflavone diet to soy-free diet mice significantly suppressed the allergic reactions compared to the soy-free diet. CONCLUSION: Rodent diet is an important variable and needs to be taken into consideration when designing experiments involving animal models. Our results indicate that elimination of soy components from the diet enhances peanut sensitization in BALB/c mice. In addition to serving as a valuable tool to mimic human food allergy, the dietary influence on the immune response could have far-reaching consequences in research involving animal models.

Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression.

Brain serotonergic signaling is coupled to arachidonic acid (AA)-releasing calcium-dependent phospholipase A2. Increased brain serotonin concentrations and disturbed serotonergic neurotransmission have been reported in the Flinders Sensitive Line (FSL) rat model of depression, suggesting that brain AA metabolism may be elevated. To test this hypothesis, (14)C-AA was intravenously infused to steady-state levels into control and FSL rats derived from the same Sprague-Dawley background strain, and labeled and unlabeled brain phospholipid and plasma fatty acid concentrations were measured to determine the rate of brain AA incorporation and turnover. Brain AA incorporation and turnover did not differ significantly between controls and FSL rats. Compared to controls, plasma unesterified docosahexaenoic acid was increased, and brain phosphatidylinositol AA and total lipid linoleic acid and n-3 and n-6 docosapentaenoic acid were significantly decreased in FSL rats. Several plasma esterified fatty acids differed significantly from controls. In summary, brain AA metabolism did not change in FSL rats despite reported increased levels of serotonin concentrations, suggesting possible post-synaptic dampening of serotonergic neurotransmission involving AA.

D2-like receptor activation does not initiate a brain docosahexaenoic acid signal in unanesthetized rats.

BACKGROUND: The polyunsaturated fatty acid, docosahexaenoic acid (DHA), participates in neurotransmission involving activation of calcium-independent phospholipase A2 (iPLA2), which is coupled to muscarinic, cholinergic and serotonergic neuroreceptors. Drug induced activation of iPLA2 can be measured in vivo with quantitative autoradiography using 14C-DHA as a probe. The present study used this approach to address whether a DHA signal is produced following dompaminergic (D)2-like receptor activation with quinpirole in rat brain. Unanesthetized rats were infused intravenously with 14C-DHA one minute after saline or quinpirole infusion, and serial blood samples were collected over a 20-minute period to obtain plasma. The animals were euthanized with sodium pentobarbital and their brains excised, coronally dissected and subjected to quantitative autoradiography to derive the regional incorporation coefficient, k*, a marker of DHA signaling. Plasma labeled and unlabeled unesterified DHA concentrations were measured. RESULTS: The incorporation coefficient (k*) for DHA did not differ significantly between quinpirole-treated and control rats in any of 81 identified brain regions. Plasma labeled DHA concentration over the 20-minute collection period (input function) and unlabeled unesterified DHA concentration did not differ significantly between the two groups. CONCLUSION: These findings demonstrate that D2-like receptor initiated signaling does not involve DHA as a second messenger, and likely does not involve iPLA2 activation.

Feasibility study of rehabilitation for cardiac patients aided by an artificial intelligence web-based programme: a randomised controlled trial (RECAP trial)-a study protocol.

INTRODUCTION: Cardiac rehabilitation (CR) delivered by rehabilitation specialists in a healthcare setting is effective in improving functional capacity and reducing readmission rates after cardiac surgery. It is also associated with a reduction in cardiac mortality and recurrent myocardial infarction. This trial assesses the feasibility of a home-based CR programme delivered using a mobile application (app). METHODS: The Rehabilitation through Exercise prescription for Cardiac patients using an Artificial intelligence web-based Programme (RECAP) randomised controlled feasibility trial is a single-centre prospective study, in which patients will be allocated on a 1:1 ratio to a home-based CR programme delivered using a mobile app with accelerometers or standard hospital-based rehabilitation classes. The home-based CR programme will employ artificial intelligence to prescribe exercise goals to the participants on a weekly basis. The trial will recruit 70 patients in total. The primary objectives are to evaluate participant recruitment and dropout rates, assess the feasibility of randomisation, determine acceptability to participants and staff, assess the rates of potential outcome measures and determine hospital resource allocation to inform the design of a larger randomised controlled trial for clinical efficacy and health economic evaluation. Secondary objectives include evaluation of health-related quality of life and 6 minute walk distance. ETHICS AND DISSEMINATION: RECAP trial received a favourable outcome from the Berkshire research ethics committee in September 2022 (IRAS 315483).Trial results will be made available through publication in peer-reviewed journals and presented at relevant scientific meetings. TRIAL REGISTRATION NUMBER: ISRCTN97352737.

Patch and matrix striatonigral neurons differentially regulate locomotion.

Striatonigral neurons, known to promote locomotion, reside in both the patch and matrix compartments of the dorsal striatum. However, their compartment-specific contributions to locomotion remain largely unexplored. Using molecular identifier Kremen1 and Calb1 , we showed in mouse models that patch and matrix striatonigral neurons exert opposite influences on locomotion. Matrix striatonigral neurons reduced their activity before the cessation of self-paced locomotion, while patch striatonigral neuronal activity increased, suggesting an inhibitory function. Indeed, optogenetic activation of patch striatonigral neurons suppressed ongoing locomotion with reduced striatal dopamine release, contrasting with the locomotion-promoting effect of matrix striatonigral neurons, which showed an initial increase in dopamine release. Furthermore, genetic deletion of the GABA-B receptor in Aldehyde dehydrogenase 1A1-positive (ALDH1A1 + ) nigrostriatal dopaminergic neurons completely abolished the locomotion-suppressing effect of patch striatonigral neurons. Our findings unravel a compartment-specific mechanism governing locomotion in the dorsal striatum, where patch striatonigral neurons suppress locomotion by inhibiting ALDH1A1 + nigrostriatal dopaminergic neurons.

Patch and matrix striatonigral neurons differentially regulate locomotion.

The striatonigral neurons are known to promote locomotion1,2. These neurons reside in both the patch (also known as striosome) and matrix compartments of the dorsal striatum3-5. However, the specific contribution of patch and matrix striatonigral neurons to locomotion remain largely unexplored. Using molecular identifier Kringle-Containing Protein Marking the Eye and the Nose (Kremen1) and Calbidin (Calb1)6, we showed in mouse models that patch and matrix striatonigral neurons exert opposite influence on locomotion. While a reduction in neuronal activity in matrix striatonigral neurons precedes the cessation of locomotion, fiber photometry recording during self-paced movement revealed an unexpected increase of patch striatonigral neuron activity, indicating an inhibitory function. Indeed, optogenetic activation of patch striatonigral neurons suppressed locomotion, contrasting with the locomotion-promoting effect of matrix striatonigral neurons. Consistently, patch striatonigral neuron activation markedly inhibited dopamine release, whereas matrix striatonigral neuron activation initially promoted dopamine release. Moreover, the genetic deletion of inhibitory GABA-B receptor Gabbr1 in Aldehyde dehydrogenase 1A1-positive (ALDH1A1+) nigrostriatal dopaminergic neurons (DANs) completely abolished the locomotion-suppressing effect caused by activating patch striatonigral neurons. Together, our findings unravel a compartment-specific mechanism governing locomotion in the dorsal striatum, where patch striatonigral neurons suppress locomotion by inhibiting the activity of ALDH1A1+ nigrostriatal DANs.

Fifteen weeks of dietary n-3 polyunsaturated fatty acid deprivation increase turnover of n-6 docosapentaenoic acid in rat-brain phospholipids.

Docosapentaenoic acid (DPAn-6, 22:5n-6) is an n-6 polyunsaturated fatty acid (PUFA) whose brain concentration can be increased in rodents by dietary n-3 PUFA deficiency, which may contribute to their behavioral dysfunction. We used our in vivo intravenous infusion method to see if brain DPAn-6 turnover and metabolism also were altered with deprivation. We studied male rats that had been fed for 15 weeks post-weaning an n-3 PUFA adequate diet containing 4.6% alpha-linolenic acid (α-LNA, 18:3n-3) or a deficient diet (0.2% α-LNA), each lacking docosahexaenoic acid (22:6n-3) and arachidonic acid (AA, 20:4n-6). [1-(14)C]DPAn-6 was infused intravenously for 5min in unanesthetized rats, after which the brain underwent high-energy microwaving, and then was analyzed. The n-3 PUFA deficient compared with adequate diet increased DPAn-6 and decreased DHA concentrations in plasma and brain, while minimally changing brain AA concentration. Incorporation rates of unesterified DPAn-6 from plasma into individual brain phospholipids were increased 5.2-7.7 fold, while turnover rates were increased 2.1-4.7 fold. The observations suggest that increased metabolism and brain concentrations of DPAn-6 and its metabolites, together with a reduced brain DHA concentration, contribute to behavioral and functional abnormalities reported with dietary n-3 PUFA deprivation in rodents. (196 words).

Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A(2)-VIA (iPLA(2)ß)-knockout mice.

Calcium-independent phospholipase A(2) group VIA (iPLA(2)ß) releases docosahexaenoic acid (DHA) from phospholipids in vitro. Mutations in the iPLA(2)ß gene, PLA2G6, are associated with dystonia-parkinsonism and infantile neuroaxonal dystrophy. To understand the role of iPLA(2)ß in brain, we applied our in vivo kinetic method using radiolabeled DHA in 4 to 5-month-old wild type (iPLA(2)ß(+/+)) and knockout (iPLA(2)ß(-/-)) mice, and measured brain DHA kinetics, lipid concentrations, and expression of PLA(2), cyclooxygenase (COX), and lipoxygenase (LOX) enzymes. Compared to iPLA(2)ß(+/+) mice, iPLA(2)ß(-/-) mice showed decreased rates of incorporation of unesterified DHA from plasma into brain phospholipids, reduced concentrations of several fatty acids (including DHA) esterified in ethanolamine- and serine-glycerophospholipids, and increased lysophospholipid fatty acid concentrations. DHA turnover in brain phospholipids did not differ between genotypes. In iPLA(2)ß(-/-) mice, brain levels of iPLA(2)ß mRNA, protein, and activity were decreased, as was the iPLA(2)γ (Group VIB PLA(2)) mRNA level, while levels of secretory sPLA(2)-V mRNA, protein, and activity and cytosolic cPLA(2)-IVA mRNA were increased. Levels of COX-1 protein were decreased in brain, while COX-2 protein and mRNA were increased. Levels of 5-, 12-, and 15-LOX proteins did not differ significantly between genotypes. Thus, a genetic iPLA(2)ß deficiency in mice is associated with reduced DHA metabolism, profound changes in lipid-metabolizing enzyme expression (demonstrating lack of redundancy) and of phospholipid fatty acid content of brain (particularly of DHA), which may be relevant to neurologic abnormalities in humans with PLA2G6 mutations.

Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability.

Chronic administration of mood stabilizers to rats down-regulates the brain arachidonic acid (AA) cascade. This down-regulation may explain their efficacy against bipolar disorder (BD), in which brain AA cascade markers are elevated. The atypical antipsychotics, olanzapine (OLZ) and clozapine (CLZ), also act against BD. When given to rats, both reduce brain cyclooxygenase activity and prostaglandin E(2) concentration; OLZ also reduces rat plasma unesterified and esterified AA concentrations, and AA incorporation and turnover in brain phospholipid. To test whether CLZ produces similar changes, we used our in vivo fatty acid method in rats given 10 mg/kg/day i.p. CLZ, or vehicle, for 30 days; or 1 day after CLZ washout. [1-(14) C]AA was infused intravenously for 5 min, arterial plasma was collected and high-energy microwaved brain was analyzed. CLZ increased incorporation coefficients ki * and decreased [corrected] rates J(in,i) of plasma unesterified AA into brain phospholipids. [corrected]. These effects disappeared after washout. Thus, CLZ and OLZ similarly down-regulated kinetics and cyclooxygenase expression of the brain AA cascade, likely by reducing plasma unesterified AA availability. Atypical antipsychotics and mood stabilizers may be therapeutic in BD by down-regulating, indirectly or directly respectively, the elevated brain AA cascade of that disease.

Survey of Klebsiella pneumoniae bacteraemia in two South Australian hospitals and detection of hypermucoviscous phenotype and magA/rmpA genotypes in K . pneumoniae isolates.

PURPOSE: Clinical patterns of Klebsiella pneumoniae bacteraemia vary geographically. An invasive syndrome involving abscess formation has emerged in recent years. Putative virulence factors associated with this syndrome include colony hypermucoviscosity, and magA and rmpA genes. We studied epidemiologic and microbiologic characteristics of K. pneumoniae bacteraemia at two South Australian hospitals and identified cases of K. pneumoniae invasive syndrome. We determined the frequency of the hypermucoviscosity, magA and rmpA genes among bacteraemic and selected non-bacteraemic isolates. METHODS: Thirty-one patients with K. pneumoniae bacteraemia treated between June 2010 and July 2011 were included. Existing records were examined for relevant clinical and microbiological data. Urinary and wound isolates were also examined. Hypermucoviscosity was identified by a positive string test, whilst polymerase chain reaction detected magA and rmpA positive isolates. RESULTS: Of 31 blood culture isolates, 22 were associated with community-acquired infection. Biliary infection was the commonest source, occurring in ten patients. Three patients had K. pneumoniae invasive syndrome, all of Asian extraction (p = 0.0044). Four blood isolates demonstrated one or more of hypermucoviscosity, magA or rmpA; three were from patients with liver abscesses. Liver abscess isolates were all K1 serotype and had similar PFGE profiles. CONCLUSIONS: This study augments understanding of local epidemiology and microbiology of K. pneumoniae bacteraemia. It confirms local emergence of K. pneumoniae invasive syndrome and implicates the role of magA and rmpA genes in its pathogenesis.

Prediction Performance of Feature Selectors and Classifiers on Highly Dimensional Transcriptomic Data for Prediction of Weight Loss in Filipino Americans at Risk for Type 2 Diabetes.

Background: Accurate prediction of risk for chronic diseases like type 2 diabetes (T2D) is challenging due to the complex underlying etiology. Integration of more complex data types from sensors and leveraging technologies for collection of -omics datasets may provide greater insights into the specific risk profile for complex diseases.Methods: We performed a literature review to identify feature selection methods and machine learning models for prediction of weight loss in a previously completed clinical trial (NCT02278939) of a behavioral intervention for weight loss in Filipinos at risk for T2D. Features included demographic and clinical characteristics, dietary factors, physical activity, and transcriptomics.Results: We identified four feature selection methods: Correlation-based Feature Subset Selection (CfsSubsetEval) with BestFirst, Kolmogorov-Smirnov (KS) test with correlation featureselection (CFS), DESeq2, and max-relevance-min-relevance (MRMR) with linear forward search and mutual information (MI) and four machine learning algorithms: support vector machine, decision tree, random forest, and extra trees that are applicable to prediction of weight loss using the specified feature types.Conclusion: More accurate prediction of risk for T2D and other complex conditions may be possible by leveraging complex data types from sensors and -omics datasets. Emerging methods for feature selection and machine learning algorithms make this type of modeling feasible.