Clonal hematopoiesis related TET2 loss-of-function impedes IL1ß-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.

Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1ß is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1ß promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1ß administration, which is resisted by Tet2-deficient HSPCs, and thus IL1ß enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1ß-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.

A multi-species powder dropper for magnetic fusion applications.

We present a device for controlled injection of a variety of materials in powder form. The system implements four independent feeder units, arranged to share a single vertical drop tube. Each unit consists of a 80 ml reservoir, coupled to a horizontal linear trough, where a layer of powder is advanced by piezo-electric agitation at a speed proportional to the applied voltage, until it falls into a drop tube. The dropper has been tested with a number of impurities of low (B, BN, C), intermediate (Si, SiC), and high Z (Sn) and a variety of microscopic structures (flakes, spheres, rocks) and sizes (5-200 µm). For low Z materials, drop rates ∼2-200 mg/s have been obtained showing good repeatability and uniformity. A calibrated light-emitting diode (LED)-based flowmeter allows measuring and monitoring the drop rate during operation. The fast time-response of the four feeders allows combination of steady and pulsed injections, providing a flexible tool for controlled-dose, real-time impurity injection in fusion plasmas.

Evaluating the immediate effects of wearing foot orthotics in children with Joint Hypermobility Syndrome (JHS) by analysis of temperospatial parameters of gait and dynamic balance: A preliminary study.

Joint Hypermobility Syndrome (JHS) in children, presents with increased joint range of motion and can lead to altered gait strategies and reduced dynamic balance. Despite limited evidence foot orthoses are sometimes prescribed to patients with JHS with the aim to improve the stability of their gait pattern and theoretically reduce associated symptoms of fatigue and joint pain. The purpose of this study was therefore to analyse the immediate effects of 'off the shelf' orthoses on temporospatial parameters of gait and dynamic balance in this cohort. METHODS: A total of 21 patients were recruited for the study (13 female) with a median age of 10 years (IRQ = 4.12). Each patient had their gait analysed using the GAITRite walkway in their own footwear and immediately after being prescribed the orthoses. Gait was tested at both the patients' preferred speed and when asked to walk slower to challenge their dynamic balance. RESULTS: Gait appeared more synchronised, with a reduction in step length and width variability, when participants were provided with orthotics. The variation was greatest when participants were asked to walk slower. Double stance was significantly less at slower speeds when orthotics were added (1.61%, 95% CI = 0.34, 2.89, p = 0.015) CONCLUSION: Results of this study indicate that orthotics have a definite immediate influence on gait patterns in patients with JHS. Future studies should investigate the long-term effects of orthotics in this population and include outcome measures for symptoms such as pain.

Mechanism of Anti-rotavirus Synergistic Activity by Epigallocatechin Gallate and a Proanthocyanidin-Containing Nutraceutical.

Epigallocatechin gallate (EGCG) of green tea and the nutraceutical CystiCran®-40 (containing 40% proanthocyanidins) of the cranberry plant have been associated with antiviral activity. The purpose of this work was to determine the mechanism of antiviral synergy between each compound. Coliphage T4II (phage T4) and the rotavirus strain SA-11(RTV) were used as model virus systems. Individual and combined flavonoids structural and molecular weight analyses were performed by NMR and HPCL/MS, respectively. A suboptimal concentration of EGCG or C-40 alone or in combination reduced phage infectivity by ≤10%. Similarly, EGCG (30 µg/ml) and C-40 (25 µg/ml), respectively, reduced RTV titers by 3 and 13%. However, RTV titers were reduced by 32% (p < .05) with both flavonoids used in combination. RTV was not recognized in host cells by electron microscopy 24-h post-inoculation. NMR and HPLC/MS findings revealed significant structural and potential changes in molecular weight of the flavonoids in complex.

AT1 receptor blockade increases cardiac bradykinin via neutral endopeptidase after induction of myocardial infarction in rats.

ACE inhibition protects the heart against ischemic injury by reducing angiotensin II and promoting bradykinin (BK) accumulation. Since neutral endopeptidase (NEP) metabolizes BK, we determined its activity after induction of myocardial infarction (MI) and examined whether it is influenced by treatment with an ACE inhibitor or AT1 receptor blocker. Rats were studied 6 days and 3 wk after coronary occlusion. Starting 48 h after MI induction, additional animals were treated with the ACE inhibitor quinapril (2 mg x kg(-1) x day-1) or the AT1 blocker irbesartan (50 mg x kg(-1) x day-1). Animals were hemodynamically characterized. Finally, NEP-specific activity and BK concentrations were detected in homogenates of heart compartments. Quinapril and irbesartan treatment improved left ventricular function 6 days and 3 wk after MI induction, and NEP activity was elevated only in the infarcted area of untreated compared with sham-operated rats. After 6 days, irbesartan reversed this increase by 80% and quinapril by 35%. Quinapril had no effect after 3 wk, whereas irbesartan almost completely blocked the increased NEP activity in the infarcted area and concomitantly induced a further rise in the BK concentrations. These results indicate mechanisms of NEP regulation influenced by the AT1 receptor. Our data suggest that NEP is more decisive than ACE in mediating BK degradation and may indicate BK involvement in the cardioprotective effects of AT1 antagonists.

Fetal, neonatal cord, and maternal plasma concentrations of angiotensin-converting enzyme (ACE).

OBJECTIVES: Angiotensin converting enzyme (ACE), a component of the renin-angiotensin system (RAS), catalyses the degradation of angiotensin I to angiotensin II. It was the aim of the present study to measure ACE activity in human fetal blood and to determine its changes with advancing gestational age. METHODS: Fetal blood was sampled by cordocentesis from six control fetuses and six fetuses with Rh isoimmunisation. Cord blood was sampled from six preterm neonates, 15 neonates after spontaneous delivery at term and six neonates at term after caesarean section. In addition, maternal ACE values were determined. ACE activity was measured using the miniaturised fluorimetric method. RESULTS: In normal fetuses (13.31+/-1.41 nmol HL/min/ml) and fetuses with Rh isoimmunisation (13.08+/-2.00 nmol HL/min/ml, p<0.05). Neonatal cord blood of preterm newborns (10.43+/-0.69 nmol HL/min/ml) and term newborns (8.99+/-0.49 nmol HL/min/ml) showed a significantly decreased ACE activity compared to the fetal controls. CONCLUSION: We conclude that the high fetal ACE activity and the stringent regulation with advancing gestational age indicate the physiological importance of the enzyme during prenatal development.

Analyzing the influence of tic-related talk on vocal and motor tics in children with Tourette's syndrome.

This study examined the effect of tic-related talk on the vocal and motor tics of 2 boys with Tourette's syndrome. Using ABAB withdrawal designs, the boys were alternately exposed to conditions with and without talk of their tics. For both boys, vocal tics markedly increased when talk pertained to tics and decreased when talk did not pertain to tics, but motor tic covariance was less consistent.

Cost-effectiveness of sulfadoxine-pyrimethamine for the prevention of malaria-associated low birth weight.

Prevention of placental malaria through administration of antimalarial medications to pregnant women in disease-endemic areas decreases the risk of delivery of low birth weight (LBW) infants. In areas of high Plasmodium falciparum transmission, two intermittent presumptive treatment doses of sulfadoxine-pyrimethamine (SP) during the second and third trimesters of pregnancy are effective in decreasing the prevalence of placental malaria in human immunodeficiency virus (HlV)-negative women, while HIV-positive women may require a monthly SP regimen to reduce their prevalence of placental parasitemia. A decision-analysis model was used to compare the cost-effectiveness of three different presumptive SP treatment regimens with febrile case management with SP in terms of incremental cost per case LBW prevented. Factors considered included HIV seroprevalence, placental malaria prevalence, LBW incidence, the cost of SP, medical care for LBW infants, and HIV testing. For a hypothetical cohort of 10,000 pregnant women, the monthly SP regimen would always be the most effective strategy for reducing LBW associated with malaria. The two-dose SP and monthly SP regimens would prevent 172 and 229 cases of LBW, respectively, compared with the case management approach. At HIV seroprevalence rates greater than 10%, the monthly SP regimen is the least expensive strategy. At HIV seroprevalence rates less than 10%, the two-dose SP regimen would be the less expensive option. When only antenatal clinic costs are considered, the two-dose and monthly SP strategies cost US $11 and $14, respectively, well within the range considered cost effective. Presumptive treatment regimens to prevent LBW associated with malaria and the subsequent increased risk of mortality during the first year of life are effective and cost effective strategies in areas with both elevated HIV prevalence and malaria transmission rates.

Detecting differential rater functioning over time (DRIFT) using a Rasch multi-faceted rating scale model.

This paper describes a class of rater effects that depict rater-by-time interactions. We refer to this class of rater effects as DRIFT differential rater functioning over time. This article describes several types of DRIFT (primacy/recency, differential centrality/extremism, and practice/fatigue) and Rasch measurement procedures designed to identify these types of DRIFT in rating data. These procedures are applied to simulated data and are shown to be useful in classifying raters as being aberrant or non-aberrant for primacy, recency, and differential centrality and extremism, particularly for moderate or larger effect sizes. Rates of correct classification for practice and fatigue were lower and statistical power exceeded.50 only with very large effect sizes. Type I error rates (i.e., incorrect nomination) were near expected levels in all cases.

Drug court effectiveness: a review of California evaluation reports, 1995-1999.

Over the past two decades, drug courts have emerged as a viable alternative for addressing drug cases within the criminal justice system. In California, the Drug Court Partnership Program (DCPP) was created in 1998 and has supported and funded the development of drug courts throughout the State. This article reports on a review of California drug court evaluations through January 2000 conducted as part of an evaluation of the California DCPP. A total of 23 evaluations were collected. Seventeen were reviewed in detail, and six were excluded because they were internal reports rather than evaluations. A standardized review process was initiated which led to a scored rating of the evaluation reports. Results of this review support previous findings that drug court participants may experience reduced rearrest rates by 11% to 14% compared to nonparticipants. The largest reduction in rearrest rates appears among graduates. The graduation rates were between 19% and 54%. Costs and savings associated with drug courts were discussed but no conclusions were possible based on the findings from these evaluations. The evaluation of the effectiveness of drug courts presents unique challenges. This review concludes with a discussion of evaluation methods (e.g. standardizing rate calculations, term definitions) that would strengthen drug court research.

Equating and item banking with the Rasch model.

This article describes Rasch measurement procedures for equating multiple test forms or calibrating an item bank. The procedures entail (a) selecting an appropriate data collection design, (b) estimating parameters, (c) transforming the parameters from multiple forms to a common scale, and (d) evaluating the quality of the linkage between these forms. Data collection designs include (a) anchor tests, (b) single group, (c) single data set, and (d) equivalent groups. Estimation procedures may involve (a) separate or (b) simultaneous calibration of data from multiple forms. Transformation is typically accomplished using (a) estimation scaling, but may involve (b) parameter anchoring or (c) computing equating constants. Link quality is evaluated using four fit indices: (a) item-within-link, (b) item-between-link, (c) link-within-bank, and (d) form-within-bank. These procedures are illustrated using an anchor test design.

Development of a scale for measuring invasive plant environmentalism.

The ecological impact of invasive plant species is a serious concern among environmental scientists and conservationists. Educating the public about invasive plant issues is a major hurdle, given that several invaders come into the environment through ornamental gardening. An important first step in planning an educational program concerning invasive plant issues is to assess public knowledge and attitudes concerning these issues. This paper describes the development of an instrument that measures invasive plant environmentalism. Responses from 237 nursery customers from the southeastern U.S. to a 17-item standardized interview were scaled using the partial credit model, a member of the family of Rasch (1960) measurement models. Our results indicate that the instrument adequately measures this construct. Substantive interpretations of the results are also discussed.

Development of a nutrition self-efficacy scale for prospective physicians.

Diet is associated with 5 of the 10 leading causes of death in the U.S., including coronary heart disease, certain types of cancer, atherosclerosis, and type 2 diabetes. Physicians can play a pivotal role in promoting nutritional management of diabetes and other chronic diseases. Therefore, it is important that valid instruments are created so administrators can better assess the educational needs of prospective physicians, their practices, and patient outcomes. Two comparable studies, one year apart, were undertaken to create an instrument that measures nutritional competence and self-efficacy among prospective physicians. This paper: (a) describes the development of a nutrition self-efficacy scale (NSES) and (b) demonstrates reliability and validity of the NSES using Rasch modeling. It concludes with a discussion of potential contributions of this scale for assessing mastery of applied nutrition among prospective physicians.

Measuring change across multiple occasions using the Rasch Rating Scale Model.

When latent trait models are used to measure change across time, it is difficult to disentangle changes in one facet of the measurement context from changes in other facets. Hence, it is difficult to diagnose change. Wright (1999b) proposed an algorithm for disentangling change, and previously the authors applied this algorithm to measuring change across two occasions (Wolfe and Chiu, 1999). In this article we extend Wright's algorithm to disentangle changes in measures across three occasions. We describe a standard Rasch rating scale analysis of a multi-occasion evaluation that produces confusing results when subjected to a series of "separate" calibrations. Then, we apply Wright's correction to the same data to show that the algorithm reveals changes that are more similar to ones that would be expected. Our demonstration shows that Wright's procedure can reduce misfit to the Rasch Rating Scale Model as well as changing the interpretation of change within the measurement context.

Measuring pretest-posttest change with a Rasch Rating Scale Model.

When measures are taken on the same individual over time, it is difficult to determine whether observed differences are the result of changes in the person or changes in other facets of the measurement situation (e.g., interpretation of items or use of rating scale). This paper describes a method for disentangling changes in persons from changes in the interpretation of Likert-type questionnaire items and the use of rating scales (Wright, 1996a). The procedure relies on anchoring strategies to create a common frame of reference for interpreting measures that are taken at different times and provides a detailed illustration of how to implement these procedures using FACETS.

Malaria surveillance--United States, 1995.

PROBLEM/CONDITION: Malaria is caused by four species of Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, or P. malariae), which are transmitted by the bite of an infective female Anopheles sp. mosquito. Most malaria infections in the United States occur among persons who have traveled to areas with ongoing transmission. Occasionally, cases occur in the United States through exposure to infected blood products, by congenital transmission, or by local mosquito-borne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. REPORTING PERIOD: Cases with onset of illness during 1995. DESCRIPTION OF SYSTEM: Malaria cases confirmed by blood smears are reported to local and/or state health departments by health-care providers and/or laboratory staff. Case investigations are conducted by local and/or state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS). Data from NMSS serve as the basis for this report. RESULTS: CDC received reports of 1,167 cases of malaria with onset of symptoms during 1995 among persons in the United States or one of its territories. This number represents an increase of 15% from the 1,014 cases reported for 1994. P. vivax, P. falciparum, P. malariae, and P. ovale were identified in 48.2%, 38.6%, 3.9%, and 2.2% of cases, respectively. More than one species was present in three patients (0.3% of total). The infecting species was not determined in 80 (6.9%) cases. The number of reported malaria cases acquired in Africa (n=519) remained approximately the same as in 1994 (n=517); cases acquired in Asia increased by 32.4% (n=335); and cases acquired in the Americas increased by 37.4 % (n=246). Of 591 U.S. civilians who acquired malaria abroad, 15.6% had followed a chemoprophylactic drug regimen recommended by CDC for the area where they had traveled. Nine patients became infected in the United States. Of these nine cases, five were congenitally acquired; one was acquired by organ transplantation; and one was acquired by a blood transfusion. For two of the nine cases, the source of infection was unknown. Six deaths were attributed to malaria. INTERPRETATION: The 15% increase in malaria cases in 1995 compared with 1994 resulted primarily from increases in cases acquired in Asia and the Americas, most notably a 100% increase in the number of cases reported from South America. This change could have resulted from local changes in disease transmission, travel patterns, reporting errors, or a decreased use of effective antimalarial chemoprophylaxis. In most reported cases, U.S. civilians who acquired infection abroad were not on an appropriate chemoprophylaxis regimen for the country where they acquired malaria. ACTIONS TAKEN: Additional information was obtained concerning the six fatal cases and the nine infections acquired in the United States. Malaria prevention guidelines were updated and distributed to health-care providers. Persons traveling to a malarious area should take the recommended chemoprophylaxis regimen and use personal protection measures to prevent mosquito bites. Any person who has been to a malarious area and who subsequently develops a fever or influenza-like symptoms should seek medical care; investigation should include a blood smear for malaria. Malaria infections can be fatal if not diagnosed and treated promptly. Recommendations concerning prevention and treatment of malaria can be obtained from CDC.

Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B against Cryptococcus neoformans.

The activity of fluconazole and amphotericin B against three isolates of Cryptococcus neoformans was evaluated, with fluconazole and amphotericin B MICs of 2.0-4.0 mg/L and 1.0 mg/L respectively, using time-kill curve methods. Fluconazole was fungistatic against all isolates tested (<99.9% decrease in cfu from initial inoculum). The fungistatic activity of fluconazole was not enhanced by increasing the concentration of antifungal in solution. In contrast, amphotericin B was markedly fungicidal (> or = 99.9% decrease in cfu from initial inoculum). Both the rate and the extent of amphotericin B activity were enhanced when drug concentration was increased.

Assessment of diagnostic performance of quantitative flow measurements in normal subjects and patients with angiographically documented coronary artery disease by means of nitrogen-13 ammonia and positron emission tomography.

OBJECTIVES: Regional myocardial blood flow (MBF) and flow reserve measurements using nitrogen-13 (N-13) ammonia positron emission tomography (PET) were compared with quantitative coronary angiography to determine their utility in the detection of significant coronary artery disease (CAD). BACKGROUND: Dynamic PET protocols using N-13 ammonia allow regional quantification of MBF and flow reserve. To establish the diagnostic performance of this method, the sensitivity and specificity must be known for varying decision thresholds. METHODS: MBF and flow reserve for three coronary territories were determined in 20 normal subjects and 31 patients with angiographically documented CAD by means of dynamic PET and a three-compartment model for N-13 ammonia kinetics. Ten normal subjects defined the normal mean and SD of MBF and flow reserve, and 10 normal subjects were compared with patients. PET flow obtained in the territory with the most severe stenosis in each patient was correlated with the angiographic assessment of the stenosis (severity > or = 50%, > or = 70%, > or = 90%). Receiver operating characteristic (ROC) curve analysis was performed for 1.5, 2.0, 2.5, 3.0 and 4.0 SD of flow abnormalities. RESULTS: MBF and flow reserve values from the normal subjects and from territories with documented stenoses > or = 50% were significantly different (p < 0.05). A significant difference was found between normal subjects and angiographically normal territories of patients with CAD. High diagnostic accuracy and sensitivity, with moderately high specificity, were demonstrated for detection of all stenoses. CONCLUSIONS: Quantification of myocardial perfusion using dynamic PET and N-13 ammonia provides a high performance level for the detection and localization of CAD. The specificity of dynamic PET was excellent in patients with a low likelihood of CAD, whereas an abnormal flow reserve in angiographically normal territories was postulated to represent early functional abnormalities of vascular reactivity.

Relationship between reason for placement and medical findings among children in foster care.

OBJECTIVE: To determine the reasons for placement of children in foster care, the prevalence of medical findings during initial placement, and the relationship between reason for placement and medical findings. The association between placement reasons and parental substance abuse also was explored. METHODS: Population-based analysis of medical records of 749 children examined at the Child Protection Center in San Francisco from October 1, 1991, to December 31, 1992. Health evaluations consisted of a clearance examination of children during entry into foster care and a comprehensive examination 3 weeks later. Reasons for foster placement included abandonment, neglect, no available caretaker, physical abuse, sexual abuse, and failed placement. RESULTS: Nearly 50% of children in our study were < 6 years of age. Neglect (30%), physical abuse (25%), and no available caretaker (24%) were the most frequent placement reasons, followed by abandonment (9%), failed placement (7%), and sexual abuse (5%). Substance abuse was documented in 30% of parents, 51% when the placement reason was neglect. Medical findings were identified in 60% of children. Among 0 to 6-year-olds, 27% had upper respiratory illnesses, 23% had developmental delay, and 21% had skin conditions; for children 7 to 12 years of age, 32% failed vision screening, 12% had dental caries, and 11% had upper respiratory illnesses; and among 13- to 18-year-olds, 31% failed vision screening and 12% had positive tuberculin skin tests. For younger children, skin conditions were associated with neglect, no available care taker, and failed placement, and developmental delay with neglect and abandonment. For adolescents, history of psychiatric illness was associated with neglect and failed placement. Marks of abuse for all age groups were limited to children who had been physically abused. Three or more diagnoses were identified for approximately 20% of children who had been neglected or abandoned or had failed placement, compared with 10% of children who had been either physically or sexually abused. CONCLUSIONS: Specific medical findings associated with reasons for placement provide health professionals with additional information to assess more accurately the health care needs of children entering foster care. As important, screening tests revealed high rates of vision problems and exposures to tuberculosis, warranting earlier and more comprehensive screening. Finally, children who have endured variations of neglect or failed placement may have more health problems than anticipated previously.

Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B tested against Candida albicans.

Time-kill curves were determined for three isolates of Candida albicans tested against fluconazole and amphotericin B at multiples of the MIC. Fluconazole produced fungistatic activity, with concentration-related growth effects observed over a narrow range of concentrations. Amphotericin B exhibited fungicidal activity, with enhancement of activity over a broader range of concentrations.