A Toolkit for Profiling the Immune Landscape of Pediatric Central Nervous System Malignancies.

The prognosis of pediatric central nervous system (CNS) malignancies remains dismal due to limited treatment options, resulting in high mortality rates and long-term morbidities. Immunotherapies, including checkpoint inhibition, cancer vaccines, engineered T cell therapies, and oncolytic viruses, have promising results in some hematological and solid malignancies, and are being investigated in clinical trials for various high-grade CNS malignancies. However, the role of the tumor immune microenvironment (TIME) in CNS malignancies is mostly unknown for pediatric cases. In order to successfully implement immunotherapies and to eventually predict which patients would benefit from such treatments, in-depth characterization of the TIME at diagnosis and throughout treatment is essential. In this review, we provide an overview of techniques for immune profiling of CNS malignancies, and detail how they can be utilized for different tissue types and studies. These techniques include immunohistochemistry and flow cytometry for quantifying and phenotyping the infiltrating immune cells, bulk and single-cell transcriptomics for describing the implicated immunological pathways, as well as functional assays. Finally, we aim to describe the potential benefits of evaluating other compartments of the immune system implicated by cancer therapies, such as cerebrospinal fluid and blood, and how such liquid biopsies are informative when designing immune monitoring studies. Understanding and uniformly evaluating the TIME and immune landscape of pediatric CNS malignancies will be essential to eventually integrate immunotherapy into clinical practice.

Interventions to Increase Leukocyte Testing during Treatment with Dimethyl Fumarate.

Dimethyl fumarate (DMF), a treatment for multiple sclerosis, may cause leukopenia and infection. Accordingly, periodic white blood cell (WBC) monitoring is recommended. We sought to evaluate the US Department of Veteran Affairs' safety program which provides facilities with a list of patients prescribed DMF therapy without a documented white blood cell count (WBC). We identified 118 sites with patients treated with DMF from 1 January 2016 through 30 September 2016. Each site was asked if any of seven interventions were used to improve WBC monitoring (academic detailing, provider education without academic detailing, electronic clinical reminders, request for provider action plan, draft orders for WBC monitoring, patient mailings, and patient calls). The survey response rate was 78%. For the 92 responding sites (78%) included sites (1115 patients) the mean rate of WBC monitoring was 54%. In multivariate analysis, academic detailing increased the rate by 17% (95% CI 4 to 30%, p = 0.011) and provider education increased the rate by 9% (95% CI 0.6 to 18%, p = 0.037). The WBC monitoring rate increased by 3.8% for each additional intervention used (95% CI 1.2-6.4%, p = 0.005). Interventions focused on the physician, including academic detailing, were associated with improved WBC monitoring for patients at risk for leukopenia from DMF treatment.

Integration of high-density genetic mapping with transcriptome analysis uncovers numerous agronomic QTL and reveals candidate genes for the control of tillering in sorghum.

Phenotypes such as branching, photoperiod sensitivity, and height were modified during plant domestication and crop improvement. Here, we perform quantitative trait locus (QTL) mapping of these and other agronomic traits in a recombinant inbred line (RIL) population derived from an interspecific cross between Sorghum propinquum and Sorghum bicolor inbred Tx7000. Using low-coverage Illumina sequencing and a bin-mapping approach, we generated ∼1920 bin markers spanning ∼875 cM. Phenotyping data were collected and analyzed from two field locations and one greenhouse experiment for six agronomic traits, thereby identifying a total of 30 QTL. Many of these QTL were penetrant across environments and co-mapped with major QTL identified in other studies. Other QTL uncovered new genomic regions associated with these traits, and some of these were environment-specific in their action. To further dissect the genetic underpinnings of tillering, we complemented QTL analysis with transcriptomics, identifying 6189 genes that were differentially expressed during tiller bud elongation. We identified genes such as Dormancy Associated Protein 1 (DRM1) in addition to various transcription factors that are differentially expressed in comparisons of dormant to elongating tiller buds and lie within tillering QTL, suggesting that these genes are key regulators of tiller elongation in sorghum. Our study demonstrates the usefulness of this RIL population in detecting domestication and improvement-associated genes in sorghum, thus providing a valuable resource for genetic investigation and improvement to the sorghum community.

Term Delivery following ruptured tubo-ovarian abscess in early pegnancy / Philippine Journal of Obstetrics and Gynecology

@#Tubo-ovarian abscess in pregnancy is extremely rare. Its occurrence increases the maternal and fetal morbidities and mortalities. The clinical presentation is variable ranging from asymptomatic abscess to diffuse peritonitis. In this report, we present a rare case of tubo-ovarian abscess complicating a pregnancy on its 6 weeks and 5 days age of gestation. The patient presented with frank peritonitis. Internal examination revealed uterine, adnexal and cervical tenderness with no masses palpated. A laparotomy was done and intra-operative findings showed an 8 x 4 cm-sized, right, ruptured tubo-ovarian abscess with purulent contamination of the whole pelvic cavity. Right salpingooophorectomy was performed and parenteral antibiotics were given. The pregnancy was eventually carried to term and the patient delivered by repeat low segment cesarean section without fetal and maternal complications.

The regulatory landscape of a core maize domestication module controlling bud dormancy and growth repression.

Many domesticated crop plants have been bred for increased apical dominance, displaying greatly reduced axillary branching compared to their wild ancestors. In maize, this was achieved through selection for a gain-of-function allele of the TCP transcription factor teosinte branched1 (tb1). The mechanism for how a dominant Tb1 allele increased apical dominance, is unknown. Through ChIP seq, RNA seq, hormone and sugar measurements on 1 mm axillary bud tissue, we identify the genetic pathways putatively regulated by TB1. These include pathways regulating phytohormones such as gibberellins, abscisic acid and jasmonic acid, but surprisingly, not auxin. In addition, metabolites involved in sugar sensing such as trehalose 6-phosphate were increased. This suggests that TB1 induces bud suppression through the production of inhibitory phytohormones and by reducing sugar levels and energy balance. Interestingly, TB1 also putatively targets several other domestication loci, including teosinte glume architecture1, prol1.1/grassy tillers1, as well as itself. This places tb1 on top of the domestication hierarchy, demonstrating its critical importance during the domestication of maize from teosinte.

Detection of potential look-alike/sound-alike medication errors using Veterans Affairs administrative databases.

PURPOSE: Results of a study to estimate the prevalence of look-alike/sound-alike (LASA) medication errors through analysis of Veterans Affairs (VA) administrative data are reported. METHODS: Veterans with at least 2 filled prescriptions for 1 medication in 20 LASA drug pairs during the period April 2014-March 2015 and no history of use of both medications in the preceding 6 months were identified. First occurrences of potential LASA errors were identified by analyzing dispensing patterns and documented diagnoses. For 7 LASA drug pairs, potential errors were evaluated via chart review to determine if an actual error occurred. RESULTS: Among LASA drug pairs with overlapping indications, the pairs associated with the highest potential-error rates, by percentage of treated patients, were tamsulosin and terazosin (3.05%), glipizide and glyburide (2.91%), extended- and sustained-release formulations of bupropion (1.53%), and metoprolol tartrate and metoprolol succinate (1.48%). Among pairs with distinct indications, the pairs associated with the highest potential-error rates were tramadol and trazodone (2.20%) and bupropion and buspirone (1.31%). For LASA drug pairs found to be associated with actual errors, the estimated error rates were as follows: lamivudine and lamotrigine, 0.003% (95% confidence interval [CI], 0-0.01%); carbamazepine and oxcarbazepine, 0.03% (95% CI, 0-0.09%); and morphine and hydromorphone, 0.02% (95% CI, 0-0.05%). CONCLUSION: Through the use of administrative databases, potential LASA errors that could be reviewed for an actual error via chart review were identified. While a high rate of potential LASA errors was detected, the number of actual errors identified was low.

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis.

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii, which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-α) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1ß (IL-1ß) (rs16944, rs1143634, and rs1143627), IL-1α (rs1800587), gamma interferon (IFN-γ) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls (P = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e-07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients (P = 7e-04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-γ was associated with OT (P = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e-04). Haplotype "GAG" of the IL-1ß gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT (P = 0.0494). The IL-10, IFN-γ, and IL-1ß polymorphisms influence the development of OT in the Colombian population.

Human rabies: a descriptive observation of 21 children in Kinshasa, the Democratic Republic of Congo.

OBJECTIVES: Human rabies has recently emerged as a significant public health threat in Kinshasa, Democratic Republic of Congo (DRC). However, there is little epidemiological information on human rabies especially in children. METHODS: We performed at Pediatrics Department of General Reference hospital of Kinshasa between December 2008 and July 2009, a retrospective study to assess the incidence and to describe their clinical aspects and outcome. RESULTS: A total of 21 cases were observed, rather three cases per month. There were 12 boys (57·1%) and 9 girls (42·9%). Biting animal was found to be dog in all cases (100%). The dog was not immunized in all of cases. On admission, all patients (100%) showed furious rabies manifestations. Only two (9·5%) had their wounds treated and received an anti-rabies vaccine (ARV) after the bite incident. Two (9·5%) patients received rabies immunoglobulin (RIG). The case-fatality rate was 100%. CONCLUSIONS: The disease emerges as a new major public health problem because of a lack of knowledge regarding rabies risk, the poor management of dog bites. Preventative vaccination for rabies should be recommended in the population of Kinshasa, area at high risk to contract rabies, particularly in children.

Nocturnal enuresis in children in Kinshasa, Democratic Republic of Congo.

AIM: To determine the prevalence of nocturnal enuresis in children of Kinshasa in Democratic Republic of Congo. METHODS: In all, 506 questionnaires were sent to parents of children aged 6-12 years randomly selected from four primary schools in Kinshasa, Democratic Republic of Congo. The questionnaire was designed to collect information about prevalence and factors associated with nocturnal enuresis. RESULTS: A total of 415 (82.0%) were correctly completed. In this series, 109 children were identified as nocturnal enuresis in which 50 boys and 56 girls (p > 0.05). Factors associated with nocturnal enuresis were deep sleep, young age and familial history of enuresis (p < 0.05). Only 11% of patients have been consulted by doctors. Twelve children (11.0%) were treated by healers traditional. In the other part, 43 children (39.4%) were frequently punished by their parents. The common self-help strategies were 79 children (72.5%) were submitted to fluid restrictions before going to sleep and 68 (62.4%) were waking the child at night to void. CONCLUSION: In Kinshasa, the prevalence of nocturnal enuresis was high to those reported in Asian and Western countries. Nocturnal enuresis remains an important clinical problem in children but only a small percentage of parents seek medical help.

Y chromosome microdeletions, sperm DNA fragmentation and sperm oxidative stress as causes of recurrent spontaneous abortion of unknown etiology.

BACKGROUND: The aim of the present study was to evaluate the implication of male factor, in terms of sperm DNA oxidation and fragmentation, and Y chromosome microdeletions in recurrent spontaneous abortion (RSA) of unknown origin in a strictly selected cohort. METHODS: A prospective cohort study was carried out in a private university-affiliated setting. Three groups, each comprised of 30 males, were compared. The first was formed by healthy and fertile sperm donors (SD) with normal sperm parameters (control group), the second by men presenting severe oligozoospermia (SO) without RSA history, and the third by men from couples who had experienced idiopathic RSA. Frequency of Y chromosome microdeletions and mean sperm DNA fragmentation and oxidation were determined. RESULTS: Y chromosome microdeletions were not detected in any of the males enrolled in the study. Moreover, sperm DNA oxidation measurements were not demonstrated to be relevant to RSA. Interestingly, sperm DNA fragmentation was higher in the SO group than in the RSA and the SD groups, and also higher in the RSA group compared with the SD group, but lacked an adequate predictive power to be employed as a discriminative test of RSA condition. CONCLUSIONS: Sperm DNA features and Y chromosome microdeletions do not seem to be related to RSA of unknown origin. Other molecular features of sperm should be studied to determine their possible influence on RSA. Clinicaltrials.gov reference: NCT00447395.

Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene.

We observed that a naturally occurring mouse strain developed age-related retinal degeneration (arrd2). These mice had normal fundi, electroretinograms (ERGs) and retinal histology at 6 months of age; vessel attenuation, RPE atrophy and pigmentary abnormalities at 14 months, which progressed to complete loss of photoreceptors and extinguished ERG by 22 months. Genetic analysis revealed that the retinal degeneration in arrd2 segregates in an autosomal recessive manner and the disease gene localizes to mouse chromosome 10. A positional candidate cloning approach detected a nonsense mutation in the mouse double minute-1 gene (Mdm1), which results in the truncation of the putative protein from 718 amino acids to 398. We have identified a novel transcript of the Mdm1 gene, which is the predominant transcript in the retina. The Mdm1 transcript is localized to the nuclear layers of neural retina. Expression of Mdm1 in the retina increases steadily from post-natal day 30 to 1 year, and a high level of Mdm1 are subsequently maintained. The Mdm1 transcript was found to be significantly depleted in the retina of arrd2 mice and the transcript was observed to degrade by nonsense-mediated decay. These results indicate that the depletion of the Mdm1 transcript may underlie the mechanism leading to late-onset progressive retinal degeneration in arrd2 mice. Analysis of a cohort of patients with age-related macular degeneration (AMD) wherein the susceptibility locus maps to chromosome 12q, a region bearing the human ortholog to MDM1, did not reveal association between human MDM1 and AMD.

Use of fourier transform infrared spectroscopy to follow the heterocumulene aided thermal dehydration of phthalic and naphthalic acids.

Fourier transform infrared (FT-IR) spectroscopy has been successfully employed to follow the formation of phthalic anhydride and 1,8-naphthalic anhydride on heating their corresponding acids. The effects of three heterocumulenes, cyanamide, dicyandiamide, and sodium cyanate, on the temperature of formation of the anhydrides were also investigated using this method. It was found that the carbodiimides cyanamide and dicyandiamide dramatically lowered the temperature at which thermal dehydration of the acid led to anhydride formation. It was noted that cyanamide had a stronger catalytic effect than dicyandiamide, presumably due to the electron-withdrawing effect of the amidine group. Sodium cyanate was also found to promote the thermal dehydration of the acids to form the corresponding anhydrides. Under more severe conditions, phthalic acid anhydride formed is seen to react further, leading to the formation of phthalimide. The discrepancy between the products obtained with cyanamide and sodium cyanate leads to the conclusion that, unlike earlier claims, imide formation is not due to the reaction of the anhydride with the urea formed but with sodium cyanate itself. However, only the phthalic anhydride five-membered ring system is sufficiently reactive towards the CNO- nucleophile to form the imide; the six-membered 1,8-naphthalic anhydride system does not react in this way.

Potentially inappropriate prescribing in elderly veterans: are we using the wrong drug, wrong dose, or wrong duration?

OBJECTIVES: To identify the extent of inappropriate prescribing using criteria for proper use developed by the Agency for Healthcare Research and Quality (AHRQ) and dose-limitation criteria defined by Beers, as well as to describe duration of use and patient characteristics associated with inappropriate prescribing for older people. DESIGN: Retrospective national Veterans Health Administration (VA) administrative database analysis. SETTING: VA outpatient facilities during fiscal year 2000 (FY00). PARTICIPANTS: Veterans aged 65 and older having at least one VA outpatient visit in FY00 (N=1,265,434). MEASUREMENTS: Operational definitions of appropriate use were developed based on recommendations of an expert panel convened by the AHRQ (Zhan criteria). Inappropriate use was identified based on these criteria and inappropriate use of drugs per Beers criteria for dose-limitations in older people. Furthermore, duration of use and patient characteristics associated with inappropriate use were described. RESULTS: After adjusting for diagnoses, dose, and duration, inappropriate prescribing decreased from 33% to 23%. Exposure to inappropriate drugs was prolonged. Pain relievers, benzodiazepines, antidepressants, and musculoskeletal agents constituted 61% of inappropriate prescribing. Whites, patients with psychiatric comorbidities, and patients receiving more medications were most likely to receive inappropriate drugs. Women were more likely to receive Zhan criteria drugs; men were more likely to receive dose-limited drugs CONCLUSION: For the most part, the Zhan criteria did not explain inappropriate prescribing, which includes problems related to dose and duration of prescriptions. Interventions targeted at prescriptions for pain relievers, benzodiazepines, antidepressants, and musculoskeletal agents may dramatically decrease inappropriate prescribing and improve patient outcomes.

Micellar electrokinetic capillary chromatography analysis of phthalic acid isomers.

A capillary electrophoretic method for the analysis and separation of ortho- and para-phthalic acid isomers was developed. The best separation was achieved using micellar electrokinetic capillary chromatography (MECC) performed in a 110 mM borate buffer pH 8.3 also containing 40 mM sodium dodecyl sulfate (SDS) and 20% methanol. The effect of the addition of methanol, acetonitrile, and beta-cyclodextrin on the separation of the isomers was investigated. The buffer system developed was shown to provide a dependable method of analysis from which the concentration of each analyte could be reliably determined.

Limited transmission of multidrug-resistant tuberculosis despite a high proportion of infectious cases in Los Angeles County, California.

Preventing transmission of multidrug-resistant tuberculosis is critical because of treatment toxicity, cost, and the lack of effective therapy for latent infection. We attempted to determine the extent of transmission in Los Angeles County by comparing relatedness of multidrug-resistant tuberculosis cases using restriction fragment length polymorphism and by cross-matching contact information to the Tuberculosis Registry. Strain typing was done on isolates of 102 pulmonary multidrug-resistant cases identified between August 1993 and 1998. Seventy-one (70%) of the cases had cavitary lesions on chest radiograph, and 94 (92%) had sputa smear-positive for acid fast bacilli. Fifteen (15%) of the cases were known to be infected with human immunodeficiency virus. Four molecular clusters of two cases each and one closely related pair were identified among the 102 cases; contact investigation successfully identified all clusters but one. Among 946 contacts identified and cross-matched with the county's Tuberculosis Registry, one secondary case due to drug-resistant Mycobacterium bovis was found. To summarize, a very high proportion of pulmonary multidrug-resistant tuberculosis cases in Los Angeles County were infectious. Molecular strain typing indicated limited spread of disease, although it underestimated transmission compared with contact investigation. We believe aggressive surveillance and case management were critical to limiting the spread of multidrug- resistant tuberculosis.