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On Sunday evening July 14, 1878, attorney Alexander McSween and more than 50 armed partisans rode into the town of Lincoln, New Mexico Territory, and took up positions in preparation [...]

The young man that Miguel Antonio Otero Jr. observed in the plaza in Las Vegas, New Mexico Territory, appeared a cheerful beardless youth, not a desperate outlaw. He wore a [...]

High weight gain in pregnancy is associated with greater postpartum weight retention, yet long-term implications remain unknown. We aimed to assess whether gestational weight change was associated with mortality more than 50 years later.

The Huntington’s Disease Integrated Staging System (HD-ISS) has four stages that characterize disease progression. Classification is based on CAG length as a marker of Huntington’s disease (Stage 0), striatum atrophy as a biomarker of pathogenesis (Stage 1), motor or cognitive deficits as HD signs and symptoms (Stage 2), and functional decline (Stage 3). One issue for implementation is the possibility that not all variables are measured in every study, and another issue is that the stages are broad and may benefit from progression subgrouping. Impute stages of the HD-ISS for observational studies in which missing data precludes direct stage classification, and then define progression subgroups within stages. A machine learning algorithm was used to impute stages. Agreement of the imputed stages with the observed stages was evaluated using graphical methods and propensity score matching. Subgroups were defined based on descriptive statistics and optimal cut-point analysis. There was good overall agreement between the observed stages and the imputed stages, but the algorithm tended to over-assign Stage 0 and under-assign Stage 1 for individuals who were early in progression. There is evidence that the imputed stages can be treated similarly to the observed stages for large-scale analyses. When imaging data are not available, imputation can be avoided by collapsing the first two stages using the categories of Stage≤1, Stage 2, and Stage 3. Progression subgroups defined within a stage can help to identify groups of more homogeneous individuals.

Cushing’s disease (CD) is often explained by a single somatic sequence change. Germline defects, however, often go unrecognized. We aimed to determine the frequency and associated phenotypes of genetic drivers of CD in a large cohort.

A central challenge of antimalarial therapy is the emergence of resistance to the components of artemisinin-based combination therapies (ACTs) and the urgent need for new drugs acting through novel mechanism of action. Over the last decade, compounds identified in phenotypic high throughput screens (HTS) have provided the starting point for six candidate drugs currently in the Medicines for Malaria Venture (MMV) clinical development portfolio. However, the published screening data which provided much of the new chemical matter for malaria drug discovery projects have been extensively mined. Here we present a new screening and selection cascade for generation of hit compounds active against the blood stage of Plasmodium falciparum. In addition, we validate our approach by testing a library of 141,786 compounds not reported earlier as being tested against malaria. The Hit Generation Library 1 (HGL1) was designed to maximise the chemical diversity and novelty of compounds with physicochemical properties associated with potential for further development. A robust HTS cascade containing orthogonal efficacy and cytotoxicity assays, including a newly developed and validated nanoluciferase-based assay was used to profile the compounds. 75 compounds (Screening Active hit rate of 0.05%) were identified meeting our stringent selection criteria of potency in drug sensitive (NF54) and drug resistant (Dd2) parasite strains (IC50≤ 2 µM), rapid speed of action and cell viability in HepG2 cells (IC50≥ 10 µM). Following further profiling, 33 compounds were identified that meet the MMV Confirmed Active profile and are high quality starting points for new antimalarial drug discovery projects.

Background: Unmetabolized serum folic acid (UMFA) has been detected in adults. Previous research indicates that high folic acid intakes may be associated with risk of cancer. Objective: The objective was to examine UMFA concentrations in relation to dietary and supplemental folate and status biomarkers in the US population aged [greater than or equal to] 60 y. Design: Surplus sera were analyzed with the use of data from the National Health and Nutrition Examination Survey (NHANES) 2001-2002, a cross-sectional, nationally representative survey (n = 1121). Results: UMFA was detected in 38% of the population, with a mean concentration of 4.4 [+ or -] 0.6 nmol/L (median: 1.2 [+ or -] 0.2 nmol/L). The group with UMFA (UMFA+) had a significantly higher proportion of folic acid supplement users than did the group without UMFA (60% compared with 41%). UMFA+ men and women also had higher supplemental and total (food + supplements) folic acid intakes than did their counterparts without UMFA. Forty percent of the UMFA+ group was in the highest quartile of total folic acid intake, but total folic acid intake was only moderately related to UMFA concentrations ([r.sup.2] = 0.07). Serum folate concentrations were significantly higher in the UMFA+ group and were predictive of UMFA concentrations ([r.sup.2] = 0.15). Serum 5 - methyltetrahydrofolate and vitamin B-12 concentrations were higher in the UMFA+ group, whereas there was no difference between the 2 UMFA groups in red blood cell folate, serum homocysteine, or methylmalonic acid concentrations. Conclusions: Approximately 40% of older adults in the United States have UMFA that persists after a fast, and the presence of UMFA is not easily explained in NHANES by folic acid intakes alone. Given the possibility that excessive folic acid exposure may relate to cancer risk, monitoring of UMFA may be warranted. doi: 10.3945/ajcn.2010.29499.

Background: Obesity affects almost one-third of pregnant women and causes many complications, including neural tube defects. It is not clear whether the risk of congenital heart defects, the most common malformations, is also increased. Objective: This study was conducted to determine whether obesity is associated with an increased risk of congenital heart defects. Design: A population-based, nested, case-control study was conducted in infants born with congenital heart defects and unaffected controls from the cohort of all births (n = 1,536,828) between 1993 and 2003 in New York State, excluding New York City. The type of congenital heart defect, maternal body mass index (BMI; in kg/[m.sup.2]), and other risk factors were obtained from the Congenital Malformations Registry and vital records. Mothers of 7392 congenital heart defect cases and 56,304 unaffected controls were studied. Results: All obese women (BMI [greater than or equal to] 30) were significantly more likely than normal-weight women (BMI: 19-24.9) to have children with a congenital heart defect [odds ratio (OR): 1.15; 95% CI: 1.07, 1.23; P < 0.0001]. Overweight women were not at increased risk (OR: 1.00; 95% CI: 0.94, 1.06). The risk in morbidly obese women (BMI [greater than or equal to] 40) was higher (OR: 1.33; 95% CI: 1.15, 1.54; P = 0.0001) than that in obese women with a BMI of 30-39.9 (OR: 1.11; 95% CI: 1.04, 1.20; P = 0.004). There was a highly significant trend of increasing OR for congenital heart defects with increasing maternal obesity (P < 0.0001). The offspring of obese women had significantly higher ORs for atrial septal defects, hypoplastic left heart syndrome, aortic stenosis, pulmonic stenosis, and tetralogy of Fallot. Conclusions: Obese, but not overweight, women are at significantly increased risk of bearing children with a range of congenital heart defects, and the risk increases with increasing BMI. Weight reduction as a way to reduce risk should be investigated. doi: 10.3945/ajcn.2009.28865.

1 The Name: Sure, 'Jesse James' rolls off the tongue pretty easily, but it doesn't have the same level of panache or commercial appeal as 'Billy the Kid.' 2 The [...]

Background: Animal studies indicate that maternal prenatal choline supplementation leads to permanent enhancement of attention and spatial memory abilities in offspring, whereas dietary choline restriction during pregnancy impairs cognitive function in offspring. The association between gestational choline concentrations and neurodevelopmental outcome in humans has not been studied. Objective: Our objective was to assess the relation between maternal and cord blood choline concentrations and child intelligence quotient (IQ) scores at 5 y of age. Design: With data and samples from a prospective study (n = 404 maternal-child pairs), serum concentrations of free and total choline were measured in maternal serum at 4 gestational age intervals (16-18 wk, 24-26 wk, 30-32 wk, and 36-38 wk) and in cord blood. Child IQ at 5 y of age was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised. Multiple regression techniques were used to estimate the relation between choline concentrations and Full Scale IQ, Verbal and Performance IQ, and subscales that assess spatial relation and memory ability while adjusting for other factors that affect IQ. Results: There was no effect at gestational ages 16-18 wk, 24-26 wk, 30-32 wk, and 36-38 wk or in cord blood of serum concentrations of free or total choline on Full Scale child IQ or on selected scales related to visuospatial processing and memory. Conclusion: Gestational and newborn choline concentrations in the physiologic range showed no correlation with childhood intelligence.

Background: Little is known about the interactions between choline and folate and homocysteine metabolism during pregnancy despite the facts that pregnancy places considerable stress on maternal folate and choline stores and that choline is a critical nutrient for the fetus. Choline, via betaine, is an important folate-independent source of methyl groups for remethylating homocysteine in liver. Objectives: Our aims were to examine the intermediates of choline oxidation in maternal and umbilical cord plasma and to determine the relations between this pathway and folate-dependent homocysteine remethylation. Design: Blood samples were taken from 201 pregnant women and, at delivery, from the umbilical cord veins of their healthy, full-term infants. The blood samples were analyzed for plasma free choline, betaine, dimethylglycine, folate, vitamin B-12, total homocysteine (tHcy), and creatinine concentrations. Results: Choline concentrations in umbilical cord plasma were [approximately equal to] 3 times those in maternal plasma (geometric [bar.x]: 36.6 and 12.3 [micro]mol/L, respectively; P < 0.0001). Betaine and dimethylglycine concentrations were also significantly higher in umbilical cord than in maternal plasma. Choline was positively associated with tHcy (r = 0.34, P < 0.0001), betaine (r = 0.58, P < 0.0001), and dimethylglycine (r = 0.30, P < 0.0001) in maternal blood. Much weaker relations were seen in the fetal circulation. In a multiple regression model, choline was a positive predictor of maternal tHcy, whereas vitamin B-12 and betaine were negative predictors. Conclusions: The positive association between maternal choline and tHcy during pregnancy suggests that the high fetal demand for choline stimulates de novo synthesis of choline in maternal liver, with a resultant increase in tHcy concentrations. If this is confirmed, it may be appropriate to provide choline supplements during pregnancy to prevent elevated tHcy concentrations. KEY WORDS Choline, betaine, dimethylglycine, homocysteine, umbilical cord, neonate, pregnancy, folate, vitamin B-12

The Knowledge Edge Knowledge is power. The old adage is true in the business world as well as in the military. Intelligence about our adversaries, our battlespace and ourselves is [...]

OBJECTIVE--Early pregnancy losses increase with marked hyperglycemia in diabetic pregnancy. However, mean loss rates do not differ from those of nondiabetic pregnancy. This observation might be explained by increased fetal [...]

Background and Purpose. Suprascapular neuropathy, resulting in shoulder pain and weakness, is frequently misdiagnosed. The consequences of misdiagnosis can include inappropriate physical rehabilitation or surgical procedures. The purpose of this case report is to describe the differential diagnosis of suprascapular neuropathy. Case Descriptions. Five patients were initially diagnosed with subacromial impingement syndrome and referred for physical therapy. Physical therapist examination findings were consistent with subacromial impingement syndrome and suprascapular neuropathy. Subsequent electrophysiologic testing confirmed the diagnosis of suprascapular neuropathy in all 5 patients. Discussion. The differential diagnosis of patients with suprascapular neuropathy includes subacromial impingement syndrome, rotator cuff pathology, C5-6 radiculopathy, and upper trunk brachial plexopathy. The diagnostic process and a table with key findings based on evidence and clinical experience is presented for differential diagnosis. [Walsworth MK, Mills JT III, Michener LA. Diagnosing suprascapular neuropathy in patients with shoulder dysfunction: a report of 5 cases. Key Words: Electrodiagnosis, Electromyography, Nerve, Shoulder, Suprascapular neuropathy., Suprascapular neuropathy (SSN) may be overlooked of mistaken for other conditions such as subacromial impingement syndrome (SAIS), rotator cuff injury, cervical radiculopathy, or brachial plexopathy. (1-6) The signs and symptoms [...]

Background: In some patients with vitamin B-12 deficiency mistakenly treated with folic acid, anemia resolved but neurologic complications became worse (masking). Fortification of enriched cereal grains with folic acid has raised concerns that people who consume large quantities of cereal grains, particularly the elderly, may be at increased risk of masking. It is unclear, however, what proportion of people with low vitamin B-12 concentrations do not have anemia and whether the proportion is increasing. Objective: We investigated whether fortification has increased the proportion of patients with low vitamin B-12 but without anemia. Design: We reviewed the laboratory results of every patient for whom a vitamin B-12 concentration was measured at the Veterans Affairs Medical Center in Washington, DC, between 1992 and 2000. Those with a low vitamin B-12 concentration (< 258 pmol/L) had their hematocrits and mean cell volumes checked. The proportion without anemia was examined by year before, during, and after folic acid fortification began. Results: There were 1573 subjects with a low vitamin B-12 concentration. The proportion without anemia did not increase significantly from the prefortification period (39.2%) to the period of optional fortification (45.5%) and the postfortification period (37.6%). These findings did not change when the analysis was limited to patients aged > 60 y or when a more conservative definition of low vitamin B-12 (< 150 pmol/L) was used. Conclusions: Despite evidence that folic acid exposure has increased dramatically since food fortification began, this population showed no evidence of an increase in low vitamin B-12 concentrations without anemia. If confirmed, these results would indicate that food fortification has not caused a major increase in masking of vitamin B-12 deficiency. KEY WORDS Pernicious anemia, vitamin B-12, cobalamin, folate, folic acid, vitamin B-12 deficiency, masking of pernicious anemia

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of β-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LeD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Oar results provide evidence for further heterogeneity in MODY., Maturity-onset diabetes of the young (MODY) is characterized by β-cell dysfunction, no requirement for insulin in the first years of the disease, an autosomal dominant mode of inheritance, and an [...]

The amount of homocysteine in the blood of a pregnant woman can determine how much homocysteine is in the blood of her baby, according to a study of 201 women. Homocysteine levels that are higher than normal are a risk factor for cardiovascular disease, preeclampsia, miscarriage, and other complications of pregnancy.

Optics are being developed to allow electro-optical/infrared guided missiles to have an ellipsoid shaped nose.

ABSTRACTIncreasing use of non-combusted forms of nicotine such as e-cigarettes poses important public health questions regarding their specific risks relative to combusted tobacco products such as cigarettes. To fully delineate these risks, improved biomarkers that can distinguish between these forms of nicotine use are needed. Prior work has suggested that methylation status at cg05575921 may serve as a specific biomarker of combusted tobacco smoke exposure. We hypothesized combining this epigenetic biomarker with conventional metabolite assays could classify the type of nicotine product consumption. Therefore, we determined DNA methylation and serum cotinine values in samples from 112 smokers, 35 e-cigarette users, 19 smokeless tobacco users, and 269 controls, and performed mass spectroscopy analyses of urine samples from all nicotine users and 22 verified controls to determine urinary levels of putatively nicotine product-specific substances; propylene glycol, 2-cyanoethylmercapturic acid (CEMA), and anabasine. 1) Cigarette smoking was associated with a dose dependent demethylation of cg05575921 and increased urinary CEMA and anabasine levels, 2) e-cigarette use did not demethylate cg05575921, 3) smokeless tobacco use also did not demethylate cg05575921 but was positively associated with anabasine levels 4) CEMA and cg05575921 levels were highly correlated and 5) propylene glycol levels did not reliably distinguish use groups. Cg05575921 assessments distinguish exposure to tobacco smoke from smokeless sources of nicotine including e-cigarettes and smokeless tobacco, neither of which are associated with cg05575921 demethylation. A combination of methylomic and metabolite profiling may allow for accurate classification use status of a variety of nicotine containing products.

Automating the cell surgery processes is a potential solution to eliminate human involvement and promote the development of cell surgery. Here, we propose a real-time 3D visual servocontrol system for single cell surgery with the experimental results of single cell injection of an embryo and analysis of experimental data. Real time 3D image processes are a necessary requirement since during cell surgery, when a micropipette contacts the embryo, the embryo is deformed, repositioning the internal components of the cell to be injected. An innovative 3D edge extraction algorithm is demonstrated for the real time 3D image processes. Visual servocontrol of the cell surgery process acquires the real-time target cell blastomere 3 dimensional position is used to maneuver the micropipette under real-time closed-loop feedback control. The automated embryo microinjection process is conducted using the proposed real-time 3D visual servocontrol system, which is proven to be a potential solution for microinjection automation.

Huntington’s disease (HD) is an autosomal dominant, neurological disease caused by an expanded CAG repeat near the N-terminus of the huntingtin (HTT) gene. A leading theory concerning the etiology of HD is that both onset and progression are driven by cumulative exposure to the effects of mutant (or CAG expanded) huntingtin (mHTT). The CAG-Age-Product (CAP) score (i.e., the product of excess CAG length and age) is a commonly used measure of this cumulative exposure. CAP score has been widely used as a predictor of a variety of disease state variables in HD. The utility of the CAP score has been somewhat diminished, however, by a lack of agreement on its precise definition. The most commonly used forms of the CAP score are highly correlated so that, for purposes of prediction, it makes little difference which is used. However, reported values of CAP scores, based on commonly used definitions, differ substantially in magnitude when applied to the same data. This complicates the process of inter-study comparison. In this paper, we propose a standardized definition for the CAP score which will resolve this difficulty. Our standardization is chosen so that CAP = 100 at the expected age of diagnosis. Statistical methods include novel survival analysis methodology applied to the 13 disease landmarks taken from the Enroll-HD database (PDS 5) and comparisons with the existing, gold standard, onset model. Useful by-products of our work include up-to-date, age-at-onset (AO) results and a refined AO model suitable for use in other contexts, a discussion of several useful properties of the CAP score that have not previously been noted in the literature and the introduction of the concept of a toxicity onset model. We suggest that taking L = 30 and K = 6.49 provides a useful standardization of the CAP score, suitable for use in the routine modeling of clinical data in HD.

Using quantitative PCR diagnostics in a phase 3 clinical trial of Rotasiil in Niger, we identified Shigella, Cryptosporidium, rotavirus, and heat-stabile toxin-producing Escherichia colito be the top 4 leading etiologies of moderate-to-severe diarrhea in children 0-2 years of age.

Background: Health-related behaviors are of particular concern in survivors of childhood cancer as they are at increased risk for second cancers and long-term organ dysfunction. The purpose of this study was to compare the smoking behavior and associated factors in young-adult survivors of childhood acute lymphoblastic leukemia (ALL) with those in sibling controls. Methods: A telephone interview that surveyed smoking behavior was conducted with 592 young-adult survivors, treated before age 20 years on Children's Cancer Group ALL protocols, and 409 sibling controls. Using stratified chi-squared analyses and Cox proportional hazards models, we compared the rates of smoking initiation and smoking cessation between survivors and control subjects. Demographic characteristics (age, sex, race, and education) and psychological factors (mood and self-concept) were examined as predictors interacting with survivorship in logistic regression analyses to try to distinguish a subgroup of survivors who may be at greater risk for smoking. Results: Survivors were significantly less likely to have ever smoked (23.0% versus 35.7%; P [is less than] .0001) and thus were less likely to ever be regular, daily smokers than sibling controls (19.1% versus 31.3%; P [is less than] .0001). Survivors were less likely to quit smoking than sibling controls (26.6% versus 35.2%), although this result was not statistically significant. There were no interactions between survivor status and either demographic or psychological features on smoking behavior. Conclusions: Young-adult survivors of childhood ALL are less likely to experiment with smoking but, once having started, are at similar risk for becoming habitual, persistent smokers as sibling controls. [J Natl Cancer Inst 1998;90:219-25]

While smoking may reduce the risk for preeclampsia in pregnant women it appears to substantially increase the risk for other birth complications. The health records of 317,652 deliveries to first-time mothers aged 15 to 34 years were studied. Mothers who smoked were half as likely to have severe preeclampsia than nonsmokers. However, infants of women who smoked 10 or more cigarettes a day were more likely to die at or around the time of birth or to be born small for their age. Smoking mothers were also at increased risk for having a detached placenta.

Mothers who consume normal amounts of vitamin A during and shortly after their pregnancies do not seem to put their infants at any increased risk for birth defects. Telephone interviews were conducted with 548 mothers of infants with neural tube defects, 387 mothers of infants with other birth defects, and 573 mothers of healthy infants. Mothers were asked about their vitamin A consumption during pregnancy and 45 days after birth. An equal percentage of women in each study group consumed between 8,000 and 25,000 units of vitamin A daily. Birth defect risk was similar if the mother consumed more than 8,000 units or less than 5,000 units.

Byline: Sven Cnattingius, James L. Mills, Jonathan Yuen, Olle Eriksson, Helena Salonen Keywords: Abruptio placentae; perinatal mortality; preeclampsia; small for gestational age; smoking Abstract: OBJECTIVES: Smoking is associated with a reduced risk of preeclampsia, but what is the outcome of pregnancy when preeclampsia develops in women who smoke? STUDY DESIGN: Single births in Sweden from 1987 through 1993 to nulliparous women aged 15 to 34 years (N = 317,652) were included. Poisson regression analyses were used to calculate adjusted relative risks and rates of adverse pregnancy outcomes. RESULTS: Maternal smoking was associated with significantly reduced risks of mild and severe preeclampsia (relative risks = 0.6 and 0.5, respectively). In pregnancies with severe preeclampsia, smoking at least 10 cigarettes per day was associated with increased rates of perinatal mortality (from 24 to 36 per 1000), abruptio placentae (from 31 to 67 per 1000), and being small for gestational age (from 28% to 68%), whereas the corresponding smoking-related increases in rates in nonhypertensive pregnancies were considerably less. CONCLUSIONS: Smokers in whom preeclampsia develops have very high risks of perinatal mortality, abruptio placentae, and small-for-gestational-age infants.(Am J Obstet Gynecol 1997;177:156-61) Author Affiliation: Uppsala, Sweden, and Bethesda, Maryland Article History: Received 5 November 1996; Revised 12 February 1997; Accepted 10 March 1997 Article Note: (footnote) [star] From the Departments of Cancer Epidemiology,a Social Medicine,b and Obstetrics and Gynecology,c Uppsala University, and the Division of Epidemiology, Statistics and Preventive Research, National Institute of Child Health and Human Development, National Institutes of Health.d , [star][star] Reprint requests: Sven Cnattingius, MD, Department of Cancer Epidemiology, University Hospital, S-751 85 Uppsala, Sweden., a 6/1/81734

ABSTRACTMortality assessments are conducted for both civil and commercial purposes. Recent advances in epigenetics have resulted in DNA methylation tools to assess risk and aid in this task. However, widely available array-based algorithms are not readily translatable into clinical tools and do not provide a good foundation for clinical recommendations. Further, recent work shows evidence of heritability and possible racial bias in these indices. Using a publicly available array data set, the Framingham Heart Study (FHS), we develop and test a five-locus mortality-risk algorithm using only previously validated methylation biomarkers that have been shown to be free of racial bias, and that provide specific assessments of smoking, alcohol consumption, diabetes and heart disease. We show that a model using age, sex and methylation measurements at these five loci outperforms the 513 probe Levine index and approximates the predictive power of the 1030 probe GrimAge index. We then show each of the five loci in our algorithm can be assessed using a more powerful, reference-free digital PCR approach, further demonstrating that it is readily clinically translatable. Finally, we show the loci do not reflect ethnically specific variation. We conclude that this algorithm is a simple, yet powerful tool for assessing mortality risk. We further suggest that the output from this or similarly derived algorithms using either array or digital PCR can be used to provide powerful feedback to patients, guide recommendations for additional medical assessments, and help monitor the effect of public health prevention interventions.