Whole-Genome Sequencing in Healthy People

Recent technological advances have radically changed genetic testing from an expensive and burdensome undertaking to a rapid and less costly option for many purposes. The utility of “next-generation” sequencing has been found to establish the diagnosis for hundreds of genetic disorders, to assess pharmacogenomic variants, and to identify treatable targets within malignant neoplasms. The ready availability of genomic information has led to the question of whether there would be clinical benefit of sequencing the genome of individuals who are not seeking a diagnosis, that is, genomic screening in generally healthy people, to provide anticipatory insights for their health care. Little research has been conducted in this area. We examine the considerable unresolved scientific and ethical issues encountered when considering whole-genome sequencing of healthy people.     

Hepatic function in mononucleosis induced by Epstein-Barr virus and cytomegalovirus

We evaluated serial enzyme and bilirubin determinations as aids to diagnosis of Epstein-Barr virus-induced infectious mononucleosis (121 cases) and the heterophil-negative mononucleosis-like illness due to cytomegalovirus (33 cases). Laboratory evidence for either type of mononucleosis includes mild to moderate hepatic dysfunction, with aspartate aminotransferase activity increased, but lower than commonly encountered in active viral hepatitis. Of the enzymes commonly assayed in evaluating liver function, aspartate aminotransferase activity was the most commonly abnormal: in 96.7% of those with Epstein-Barr virus disease and 87.9% with cytomegalovirus disease. Values for alkaline phosphatase were increased in 94.2% of the Epstein-Barr virus cases and 63.6% of the cytomegalovirus cases, and gamma-glutamyltransferase values were increased in 90.9% and 75.8%, respectively. We conclude that, in serially studied patients, normal results for liver-function studies or very high aspartate aminotransferase activities (greater than 1000 U/L) eliminate, for practical purposes, both Epstein-Barr virus and cytomegalovirus as diagnostic considerations.     

Children's ibuprofen suspension for the acute treatment of pediatric migraine

OBJECTIVE: To compare the efficacy of a single over-the-counter dose (7.5 mg/kg, p.o.) of children's ibuprofen suspension vs. placebo for the acute treatment of pediatric migraine. BACKGROUND: Migraine occurs in 4% of young children. There is a paucity of controlled clinical research in the treatment of childhood migraine and there are currently no approved drugs in the USA for treatment of migraine in children < or = 12 years of age. The purpose of this study is to assess the efficacy and tolerability of a single OTC dose of ibuprofen suspension for the acute treatment of childhood migraine. METHODS: Prospective, double-blind, placebo-controlled, parallel group, randomized study of children 6-12 yrs with migraine (I.H.S.-R 1997) treating 1 attack with a 7.5 mg/kg liq. ibuprofen vs matching placebo. Efficacy measures: (1). Headache severity based upon a 4 pt scale (severe, mod., mild, no headache) at 30, 60, 90, 120, 180 and 240 minutes post dose, and (2). nausea, vomiting, and photo/phonophobia at 120 min. The 1 degrees endpoint was cumulative % of responders (severe or mod. headache reduced to mild or none) by 120 minutes. Secondary endpoints were headache recurrence within 4-24 hours and need for rescue medicines within 4 hours. RESULTS: 138 enrolled; 84 treated/completed diary. 45 active agent, 39 placebo. The 2 groups were comparable (active: placebo) - Ages: 9: 9.1, gender boy/girl - 1.25: 1.6, and diagnosis: migraine w/o aura - 86%: 79%. Concomitant use of prophylactic Rx: 24%: 10% (Table 3). Nausea was eliminated in 60% of the ibuprofen treated patients and 39% of the placebo group (p<0.001). Vomiting, photophobia and phonophobia had marginal, but not statistically significant, decreases at 2 hours. A striking gender difference was noted (Table 4): No AE's were reported. CONCLUSION: Children's ibuprofen suspension at an OTC dose of 7.5 mg/kg is an effective and well-tolerated agent for pain relief in the acute treatment of childhood migraine, particularly in boys. There is a striking difference in gender response rates and placebo responder rates between girls and boys. The boys responded at a statistically significant rate, and girls failed to do so because of a very high placebo responder rate. Multi-center trials are recommended.     

MR imaging of female pelvic malignancies

This article reviews the most common gynecologic malignancies and their MR imaging features. The overall goal remains early disease detection and accurate staging to optimize treatment and thereby to reduce morbidity and mortality. MR imaging, when available, may play an important role in the accurate staging and evaluation of female pelvic malignancies and, thus, may become part of their routine investigation. In the authors' experience, MR imaging has proven useful in the preoperative evaluation of these malignancies. With ongoing research into imaging protocols designed to improve image quality and reduce examination time, the importance of MR imaging will continue to grow.     

Compensatory advantages of toe walking

OBJECTIVES: The study's hypothesis is that toe walking requires less peak muscle strength distally about the ankle and knee compared with normal heel-toe walking and thus may have compensatory advantages for patients with upper motor neuron injury and distal muscle weakness. DESIGN: Motion analysis and force platform data were collected in able-bodied subjects during toe walking and normal walking. Sagittal plane joint torques reflecting muscle force requirements and joint powers reflecting nonisometric muscle contraction were compared between the two conditions using paired t tests, applying a Bonferroni correction for multiple comparisons. SETTING: A gait laboratory. SUBJECTS: Seventeen able-bodied adults, 9 of whom were ballet dancers. MAIN OUTCOME MEASURES: Peak hip, knee, and ankle joint torque and power variables during walking. RESULTS: Peak ankle plantarflexor torque and ankle power generation during terminal stance and preswing were reduced (p<.001), as compared with normal heel-toe walking. The normal ankle dorsiflexor torque at initial contact-and the knee extensor torque and knee power generation during loading response were all essentially absent during toe walking. Hip extensor torque and hip power generation during the loading response phase were greater for toe walking (p<.001). CONCLUSION: Toe walking may require less ankle plantarflexor, ankle dorsiflexor, and knee extensor strength than normal heel-toe walking and thus may have compensatory advantages for patients with upper motor neuron injury and distal lower extremity weakness.     

Factors associated with attrition of African Americans during the recruitment phase of a clinical trial examining adherence among individuals with rheumatoid arthritis

OBJECTIVE: To examine factors contributing to the loss of potential minority participants in a study of medication adherence among rheumatoid arthritis patients. METHODS: Chi-square statistics were used to test for differences in refusal/ineligibility by race and site at 4 screening points (initial eligibility review, initial patient contact, adherence screening, and informed consent). Differences in criteria-specific risks for exclusion at initial eligibility review were examined across 4 sites by race. Odds ratios (95% confidence intervals) were estimated if differences were significant. Multivariate logistic regression was used to examine sociodemographic factors associated with the probability for ineligibility at the initial eligibility review. Stated reasons for refusal were qualitatively quantified. RESULTS: A greater percentage of African Americans were lost at every screening point when compared with whites, but only the difference at the initial eligibility review was statistically significant. CONCLUSION: Factors associated with attrition included selection of area medical sites, research design issues, comorbid conditions, alcohol abuse, and being younger, unmarried, African American, and male.     

Effects of alcohol intake on endothelial function in men: a randomized controlled trial

BACKGROUND: Regular light consumption of alcohol appears to reduce the risk of cardiovascular disease, whereas in heavier drinkers the opposite effect is seen. This biphasic relationship could partly be due to contrasting actions of low and high alcohol intake on endothelial function. OBJECTIVE: To determine whether reducing alcohol intake in moderate-to-heavy drinkers (40-110 g/day) would improve conduit artery endothelial function as assessed by post-ischaemic brachial artery flow-mediated dilatation (FMD). METHODS: In a two-way cross-over study, 16 healthy men either substituted their usual alcohol intake with a 0.9% alcohol beer or maintained their usual alcohol intake during sequential 4-week periods. At the end of each period of FMD and glyceryl trinitrate-induced brachial artery dilatation, blood pressure, plasma lipids, homocysteine and biomarkers of alcohol consumption (gamma-glutamyl transpeptidase) and endothelial function (E-selectin, von Willebrand factor, endothelin-1) were assessed. RESULTS: The participants reduced their alcohol intake from 72.4 to 7.9 g/day. This self-reported reduction in alcohol intake was corroborated by significant decreases in gamma-glutamyl transpeptidase (24%). The decrease in alcohol intake resulted in reductions in total cholesterol (5%), high-density lipoprotein cholesterol (17%), homocysteine (9%) and systolic and diastolic blood pressure [5 mmHg (P = 0.01) and 4 mmHg (P = 0.003), respectively]. There was no effect of alcohol on FMD (6.23 +/- 0.75% compared with 6.24 +/- 0.71%, P = NS), glyceryl trinitrate-induced vasodilatation, E-selectin, endothelin-1 and von Willebrand factor. CONCLUSION: Substantial reduction in alcohol intake in healthy moderate-to-heavy drinkers does not improve endothelial function as measured by post-ischaemic flow-mediated dilatation of the brachial artery or biomarkers of endothelial function.     

A candidate vaccine for hepatitis B containing the complete viral surface protein

The entire surface protein of hepatitis B virus serotype ayw containing the preS (preS1+preS2) and S domains has been expressed in the yeast Saccharomyces cerevisiae. Yeast containing a recombinant plasmid utilizing a constitutive promoter did not express this gene successfully due to the toxicity of the protein. A plasmid using a regulatable promoter directed expression which initiated late in the exponential phase of growth and resulted in the accumulation of high intracellular levels of the complete surface protein. The purified polypeptide aggregates into a form which, although not comprised of typical 20 nm particles, displays antigenic determinants encoded by the preS1, preS2 and S domains. Immunization of rabbits elicited the formation of antibodies directed against all three domains. This candidate vaccine will be useful for studying the contributions to viral immunity of the host response to the preS1 and preS2 domains.     

Do gender disparities persist in gastroenterology after 10 years of practice?

BACKGROUND: Cross-sectional studies confirm gender disparity in many aspects of the practice of medicine and surgery. Some data suggest the disparities diminish after 10 yr of practice. This study aims to examine gender discrepancies in income, social, and professional status of gastroenterologists after 10 yr of practice.
METHODS: Prospective, observational, cohort study of gastroenterologists incepted upon graduation from a U.S. GI fellowship program in 1993 and 1995. A 36-item questionnaire was sent to the cohort at 3, 5, and 10 yr after graduation from GI fellowship training. The following are the results of the final, 10th year survey.
RESULTS: A total of 168 men and 25 women (mean age 45.5 yr) responded. Men and women were equally likely to be board certified and married, however, women had fewer children. Men earned a mean annual gross income of $375,000 versus $245,000 for women ( P = 0.001). After adjusting for practice setting, work hours, practice-ownership, free endoscopy center practice, and vacation time, female gastroenterologists earned $82,000 (22%) less per year than their male colleagues (95% CI $34,000–130,000, P = 0.001). Women were more frequently in academic practice (38% vs 17%), but were less likely to hold the most advanced academic positions.
CONCLUSIONS: After 10 yr of practice, significant economic, professional, and social disparities persist between male and female gastroenterologists in this cohort. Women were more likely to practice in a setting with flexible work hours, a family leave provision, and in a practice with other women. Initiatives to equalize pay and ensure opportunities for professional advancement for women may diminish the significant practice disparities incurred by women in gastroenterology.