A genome-wide association study of coping behaviors suggests FBXO45 is associated with emotional expression.

Individuals use coping behaviors to deal with unpleasant daily events. Such behaviors can moderate or mediate the pathway between psychosocial stress and health-related outcomes. However, few studies have examined the associations between coping behaviors and genetic variants. We conducted a genome-wide association study (GWAS) on coping behaviors in 14088 participants aged 35 to 69 years as part of the Japan Multi-Institutional Collaborative Cohort Study. Five coping behaviors (emotional expression, emotional support seeking, positive reappraisal, problem solving and disengagement) were measured and analyzed. A GWAS analysis was performed using a mixed linear model adjusted for study area, age and sex. Variants with suggestive significance in the discovery phase (N = 6403) were further examined in the replication phase (N = 7685). We then combined variant-level association evidence into gene-level evidence using a gene-based analysis. The results showed a significant genetic contribution to emotional expression and disengagement, with an estimation that the 19.5% and 6.6% variance in the liability-scale was explained by common variants. In the discovery phase, 12 variants met suggestive significance (P < 1 × 10-6 ) for association with the coping behaviors and perceived stress. However, none of these associations were confirmed in the replication stage. In gene-based analysis, FBXO45, a gene with regulatory roles in synapse maturation, was significantly associated with emotional expression after multiple corrections (P < 3.1 × 10-6 ). In conclusion, our results showed the existence of up to 20% genetic contribution to coping behaviors. Moreover, our gene-based analysis using GWAS data suggests that genetic variations in FBXO45 are associated with emotional expression.

Relationship between Cnm-positive Streptococcus mutans and cerebral microbleeds in humans.

OBJECTIVE: Cerebral hemorrhage has been shown to occur in animals experimentally infected with Streptococcus mutans carrying the collagen-binding Cnm gene. However, the relationship between cerebral microbleeds and oral hygiene, with a focus on Cnm gene-positive S. mutans infection, remains unclear. MATERIAL AND METHODS: One hundred and thirty-nine subjects participated. The presence or absence of Cnm-positive S. mutans and its collagen-binding activity were investigated using saliva samples, and relationship with cerebral microbleeds detected on MRI investigated, including clinical information and oral parameters. RESULTS: Fifty-one subjects were identified as Cnm-positive S. mutans carriers (36.7%), with cerebral microbleeds being detected in 43 (30.9%). A significantly larger number of subjects carried Cnm-positive S. mutans in the cerebral microbleeds (+) group. S. mutans with Cnm collagen-binding ability was detected in 39 (28.1%) of all subjects, and the adjusted odds ratio for cerebral microbleeds in the Cnm-positive group was 14.4. Regarding the presence of cerebral microbleeds, no significant differences were noted in the number of remaining teeth, dental caries, or in classic arteriosclerosis risk factors. CONCLUSIONS: The occurrence of cerebral microbleeds was higher in subjects carrying Cnm-positive S. mutans, indicating that the presence of Cnm-positive S. mutans increases cerebral microbleeds, and is an independent risk for the development of cerebrovascular disorders.

British and Canadian views on the ethics of paediatric clinical trials.

BACKGROUND: Ethical problems are quoted as a reason not to perform clinical trials in children. Little is known about the views of researchers regarding ethics. OBJECTIVES: A pilot study was conducted to assess the applicability of a questionnaire design containing trial scenarios to examine views regarding the use of children in drug trials and to elicit possible international differences. SETTING: Paediatricians and researchers in the United Kingdom and Canada. METHODS: Responders were presented with a questionnaire containing direct questions and six trial scenarios, each containing an ethical dilemma. Responders were asked regarding their own approval and their perceived opinion of whether an ethical review board (ERB) would approve. RESULTS: One hundred questionnaires (50 each country) were received. Few responders had research ethics training (14% United Kingdom and 8% Canada). Most (80 and 88%) felt children could be harmed by participation in trials and half (47 and 59%) felt children should only participate if they receive direct benefit. Many (58 and 61%) disagreed with payments beyond travel expenses. In the trial scenarios, 34% of responders were willing to enter healthy children in a pharmacokinetics study of an antibiotic for cystic fibrosis and 22% considered their ERBs would approve. Only a third (33%) would enter children in an analgesia trial that was placebo-controlled. CONCLUSION: Using healthy children and placebos in trials caused concern. Similar views were found between the two countries. The majority had no training in research ethics. The study highlights the usefulness of a questionnaire with clinical trial scenarios to try to elicit views on the ethics of conducting research in children.

Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study.

OBJECTIVE: Because there are no studies available on the safety of venlafaxine during pregnancy, the authors' goal in this study was to determine whether venlafaxine increases the risk for major malformations. METHOD: Data on 150 women exposed to venlafaxine during pregnancy in seven pregnancy counseling centers were compared with data from studies of pregnant women who 1) received selective serotonin reuptake inhibitor antidepressants (SSRIs) (N=150) and 2) who received nonteratogenic drugs (N=150). RESULTS: Among the 150 women who were exposed to venlafaxine during pregnancy, 125 had live births, 18 had spontaneous abortions, and seven had therapeutic abortions; two of the babies had major malformations. There were no significant differences between these women and the two comparison groups on any of the measures analyzed. CONCLUSIONS: These results suggest that the use of venlafaxine during pregnancy does not increase the rates of major malformations above the baseline rate of 1%-3%.

Multiple antibiotic sensitivity syndrome in children.

BACKGROUND: Multiple antibiotic sensitivity syndrome with adverse drug reactions to multiple classes of antibiotics has been described in adults but is not well characterized in children. PATIENTS AND METHODS: Charts of children referred to the adverse drug reaction clinic at the Children's Hospital of Western Ontario, London, Ontario, with adverse drug reactions to multiple antibiotics were reviewed to determine the number of patients with adverse drug reactions to multiple classes of antibiotics and the clinical characteristics of the adverse events. RESULTS: The records of 97 children who were selected as possible candidates for multiple antibiotic sensitivity were studied. These records constituted 11% of referrals to a highly specialized adverse drug reaction clinic, suggesting that in usual clinical practice, this entity, if it does indeed constitute a distinct clinical entity, is quite uncommon. Age at time of the first adverse drug reaction was 26.1+/-26.3 (mean +/- SD) months. Among the 97 children, adverse reactions to five classes of antibiotic were noted in 3.1%, to four in 10.3%, to three in 47. 4% and to two in 39.2%. Most children (85.6%) experienced an adverse reaction to a penicillin, while 71.1% reacted to a cephalosporin, 80. 4% to a sulphonamide and 35.1% to a macrolide. Clinical presentations of the adverse reactions included urticaria or pruritus, other rash, serum sickness-like reaction, angioedema or anaphylaxis, erythema multiforme or Stevens-Johnson syndrome. CONCLUSIONS: There are children who have what appears to be immunologically mediated adverse drug reactions to antibiotics of multiple classes. These reactions, which most commonly manifest as urticaria or other rashes, follow drug use patterns. It remains to be defined whether this is a distinct clinical syndrome or a manifestation of a more fundamental problem in dealing with xenobiotics in the setting of infection. Further work on the immunological and/or biochemical determinants of the multiple antibiotic sensitivity syndrome (MASS) is needed to understand the pathophysiology and determinants of MASS and whether MASS constitutes a distinct clinical entity.

Palatability of oral antibiotics among children in an urban primary care center.

OBJECTIVE: To evaluate the palatability of antimicrobial agents effective against beta-lactamase-producing bacteria in American children. DESIGN: In a taste test of 4 antimicrobial agents, azithromycin (cherry flavored), cefprozil (bubble gum flavored), cefixime (strawberry flavored), and amoxicillin-clavulanic acid (banana flavored) were compared. SETTING: An urban inner-city primary care clinic. SUBJECTS: A volunteer sample of 30 healthy children (aged 5-8 years). INTERVENTION: Palatability was determined using a single-blind taste test of 4 flavored antimicrobial agents. The 4 antimicrobial agents used were azithromycin, cefprozil, cefixime, and amoxicillin-clavulanic acid. MAIN OUTCOME MEASURES: After each antimicrobial test dose, subjects rated the taste on a 10-cm visual analog scale incorporating a facial hedonic scale. Preference assessments for the best-tasting and worst-tasting agent were also conducted. RESULTS: Of the 20 children who expressed a preference, significantly more children (9 [45%], P<.05) selected the cefixime preparation as the best-tasting formulation compared with the other preparations. The cefixime preparation was also significantly the least likely to be selected as the worst-tasting preparation (2 [10%], P<.05). There were no significant differences between the other 3 preparations with respect to being selected as either the best or worst tasting. The mean (+/- SD) visual analog scale score for cefixime was highest (8.53 [2.49]) compared with the scores for azithromycin (6.78 [3.45]), cefprozil (6.26 [4.04]), and amoxicillin-clavulanic acid (6.24 [4.01]). CONCLUSION: The cefixime preparation was most commonly rated as best tasting by children.

Compliance with prescription filling in the pediatric emergency department.

OBJECTIVES: To determine the rate of compliance with filling of prescriptions written in a pediatric emergency department and to examine the reasons for not filling the prescriptions. DESIGN: Compliance with filling prescriptions was determined using a follow-up standardized telephone questionnaire, designed so that it was not obvious that assessing prescription filling was the major reason for the study. Compliance herein was defined as having the prescription filled on the same or next day of the pediatric emergency department visit. SETTING: Pediatric emergency department of a tertiary care hospital. SUBJECTS: Pediatric patients discharged home with a drug prescription. MAIN OUTCOME MEASURE: The proportion of prescriptions written in the pediatric emergency department that were filled on either the same or next day as determined by telephone follow-up. This outcome is expressed as a proportion with 95% confidence interval. RESULTS: Follow-up was completed in 1014 (83%) of the 1222 children, aged 4.5 +/- 4.2 (mean +/- SD) years. Compliance with prescription filling was 92.7% (940/1014). Parental reasons for not filling the prescription included medication unnecessary (27%), financial (6.8%), and not enough time (6.8%). Dissatisfaction with the explanation of the medical problem, instructions for treatment, and instructions for follow-up treatment were significantly associated with noncompliance by univariable logistic regression (P<.05). CONCLUSION: The rate of prescription nonfilling in children seen in a pediatric emergency department is at least 7%, although lower than that in adults in a similar setting.

Selection of treatment of cefaclor-associated urticarial, serum sickness-like reactions and erythema multiforme by emergency pediatricians: lack of a uniform standard of care.

BACKGROUND: Serum sickness-like reactions (SSLR) and erythema multiforme are common adverse effects of cefaclor therapy and can be associated with significant morbidity. No standardized evidence-based protocol for the optimal treatment of drug-induced SSLR exists. OBJECTIVES: To define the standard of care used by physicians treating adverse reactions associated with cefaclor. METHODS: A retrospective review of the medical records of children discharged from a pediatric emergency room with a diagnosis of adverse events to cefaclor was conducted. Charts of patients were reviewed to determine which therapy was prescribed. RESULTS: During the study period, 74 cases of adverse events attributed to cefaclor presented to the emergency department. SSLR were the most common pattern of adverse events seen (31 cases, 42%), followed by urticarial reactions (26 cases, 35%) and erythema multiforme (17 cases, 23%). An antihistamine was the treatment most often prescribed (88%) for erythema multiforme. Significantly more children with SSLR than with erythema multiforme or urticaria were treated with prednisone, either alone or in combination (P<0.05). CONCLUSIONS: The treatment most often prescribed for serious cefaclor-associated erythema multiforme was an antihistamine. In the case of SSLR, an antihistamine and prednisone were most commonly used. Prospective randomized, controlled trials are needed to define the role of various therapeutic agents and to determine the optimal therapy for SSLR and other serious adverse drug reactions.

Fgf10 is essential for limb and lung formation.

The interactions between fibroblast growth factors (FGF) and their receptors have important roles in mediating mesenchymal-epithelial cell interactions during embryogenesis. In particular, Fgf10 is predicted to function as a regulator of brain, lung and limb development on the basis of its spatiotemporal expression pattern in the developing embryo. To define the role of Fgf10, we generated Fgf10-deficient mice. Fgf10-/- mice died at birth due to the lack of lung development. Trachea was formed, but subsequent pulmonary branching morphogenesis was disrupted. In addition, mutant mice had complete truncation of the fore- and hindlimbs. In Fgf10-/- embryos, limb bud formation was initiated but outgrowth of the limb buds did not occur; however, formation of the clavicles was not affected. Analysis of the expression of marker genes in the mutant limb buds indicated that the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) did not form. Thus, we show here that Fgf10 serves as an essential regulator of lung and limb formation.

Pregnancy outcome following first trimester exposure to sumatriptan.

We prospectively compared pregnancy outcome after exposure to sumatriptan with that of disease-matched controls and nonteratogen controls. There were no differences in the rates of live births, spontaneous abortions, therapeutic abortions, or major birth defects among the three groups. This first prospective report suggests that the use of sumatriptan during organogenesis is not associated with an apparent increased risk of major birth defects.

A review of common dental treatments during pregnancy: implications for patients and dental personnel.

In general, pregnant females tend to over estimate the risk of teratogenicity in the foetus resulting from medical and dental procedures and/or drugs. This may cause them to avoid necessary treatment, leading to detrimental health effects for both the foetus and themselves. In this review, the concerns of pregnant dental patients and personnel will be discussed, including the perceived risks associated with amalgam restorations, radiation, local anesthetics, nitrous oxide gas, antibiotics and analgesics administered in a dental setting. Pregnant dental personnel have special concerns related to their daily occupational exposure to mercury and nitrous oxide. After assessing the potential risks of undergoing dental treatment during pregnancy, it can be stated that necessary treatment should not be with-held. In addition, dental treatments are best performed in the second trimester for the benefit of the foetus, and optimal comfort for the pregnant woman.

Physicians' attire as perceived by young children and their parents: the myth of the white coat syndrome.

OBJECTIVE: To determine if young children have a preference regarding whether physicians do or do not wear a white coat. METHODS: One hundred one children, ages four to eight years, and their parents were recruited from the outpatient setting of a pediatric referral center. Two pairs of photographs, the same man with and without a white coat and the same woman with and without a white coat, were shown to the children and their parents, and both were asked which of each pair they would like to have as their or their child's doctor, respectively. Parents filled out a questionnaire rating the appropriateness of various aspects of a physician's attire and appearance. RESULTS: The children selected the person in the white coat 69% of the time. The parents also selected the white coat more often (66%). On the questionnaire parents identified a name tag as the most appropriate item of dress followed by a white coat. A groomed mustache and groomed beard were also rated favorably. Open-toed sandals, clogs, and shorts were rated negatively, while parents were neutral with respect to hospital greens, blouse and skirt or dress, and shirt and tie. CONCLUSIONS: Physicians may wear a white coat without fear that they are negatively affecting their relationship with their pediatric patients four to eight years of age. The appropriateness of wearing a name tag is confirmed.

Valoración en niños de la aceptabilidad de antibióticos resistentes a beta-lactamasas / Assessment of the palatability of beta-lactamase-resistant antibiotics in children

Se evaluó la aceptabilidad de tres antibióticos conocidos por su resistencia a beta-lactamasas en una muestra integrada por niños. Los resultados fueron comparados con los obtenidos en adultos. La aceptabilidad al sabor de los antibióticos en suspensión fue calificada con base en una escala analógica de 10 cm. Tanto en niños como en adultos, se asignó la calificación más alta a la azitromicina. Las significativas diferencias entre los sabores sugieren que este factor debe ser tomado en cuenta en todo estudio de aceptabilidad

Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study.

CONTEXT: Although a large number of women of reproductive age use new selective serotonin reuptake inhibitors (SSRIs) and half of all pregnancies are unplanned, no data exist on the safety of these agents for the human fetus. OBJECTIVE: To assess fetal safety and risk of fluvoxamine, paroxetine, and sertraline. DESIGN: A prospective, multicenter, controlled cohort study. SETTING: Nine Teratology Information Service centers in the United States and Canada. PATIENTS: All women who were counseled during pregnancy following exposure to a new SSRI and followed up by the participating centers. Controls were randomly selected from women counseled after exposure to nonteratogenic agents. MAIN OUTCOME MEASURES: Rates of major congenital malformations. RESULTS: A total of 267 women exposed to an SSRI and 267 controls were studied. Exposure to SSRIs was not associated with either increased risk for major malformations (9/222 live births [4.1%] vs 9/235 live births [3.8%] in the controls, relative risk, 1.06, 95% confidence interval, 0.43-2.62) or higher rates of miscarriage, stillbirth, or prematurity. Mean (SD) birth weights among SSRI users (3439 [505] g) were similar to the controls (3445 [610] g) as were the gestational ages (39.4 [1.7] weeks vs 39.4 [1.9] weeks). CONCLUSION: The new SSRIs, fluvoxamine, paroxetine, and sertraline, do not appear to increase the teratogenic risk when used in their recommended doses.

Electronic measurement of compliance with mercaptopurine in pediatric patients with acute lymphoblastic leukemia.

UNLABELLED: Twenty-four pediatric patients with acute lymphoblastic leukemia (ALL) on maintenance therapy were evaluated for their compliance with taking their prescribed doses of oral mercaptopurine (6-MP). PROCEDURE AND RESULTS: We utilized the Medication Event Monitoring System (MEMS; Aprex Corporation, Fremont, CA) for the study. Compliance was defined as the number of days doses were taken as a percentage of the total number of days doses were prescribed during the study period. The mean age of the patients was 7.3 years (range 2.6-17.2 (years). Patients were evaluated for a mean of 44 days (range 15-94 days). Thirty-three percent of patients (8) took less than 90% and 17% (4) took less than 80% of their prescribed pills. Eight patients were also evaluated for a difference in compliance between morning and evening administration. For the comparison of compliance between a morning vs. an evening schedule a tren toward improved compliance in the evening was found. Five patients had an increase and one patient a decrease in compliance with an evening schedule (differences ranged from 0.2% to 51.3%), with two patients having 100% compliance on both schedules. CONCLUSIONS: Our data raise concern that a significant proportion of pediatric patients are non-compliant with pill taking and demonstrate that the timing of administration of 6-MP in children with ALL may be crucial in some patients and supports the hypothesis that evening administration of 6-MP is associated with a lower risk of relapse.

A prospective controlled multicentre study of clarithromycin in pregnancy.

Clarithromycin is a relatively new macrolide antibiotic with an action spectrum similar to that of erythromycin. Its main indications for use are for upper and lower respiratory and skin and soft tissue infections. Little is known about its safety in pregnancy, although animal reproductive studies found an increased rate of cardiovascular anomalies, cleft palate, and embryonic loss. Human data, limited to case reports and one small uncontrolled study, cannot allow evidence based counseling of pregnant women who were exposed to the drug before finding out they were pregnant. Pregnant women who had been counseled on the use of clarithromycin by five centers, were matched for age, smoking, and alcohol use with a control group of pregnant women who were exposed to nonteratogenic antibiotics. A total of 157 women were followed up. Of these, 122 were exposed to the drug in the first trimester. There were no significant differences found between the two groups in the rates of major and minor malformations; 2.3 versus 1.4% for major (p = 0.86) and 5.4 versus 4.9% for minor (p = 0.96). Spontaneous abortion rates in the exposed group was significantly different, higher (14%) than in the control group (7%) (p = 0.04). This first prospective controlled study of exposure to clarithromycin in pregnancy suggests that this agent does not increase the rate of major malformations above the baseline risk of 1-3%. The higher rate of reported spontaneous abortions, although still within the expected baseline rate, may warrant further study.

Cisapride use during human pregnancy: a prospective, controlled multicenter study.

The objective of this prospective multicenter study was to determine whether cisapride is associated with increased risk of malformations, spontaneous abortions, or decreased birthweight when used during pregnancy. Cases were paired for age, smoking, and alcohol consumption with controls exposed to nonteratogens, as well as with disease-paired controls. One hundred and twenty-nine pregnant women were exposed to cisapride during pregnancy, including 88 during the period of fetal organogenesis. There were no differences in maternal history, birthweight, gestational age at delivery, and rates of livebirths, spontaneous or therapeutic abortions, fetal distress, and major or minor malformations among groups. It is concluded that exposure to cisapride during pregnancy is not associated with a major increased risk of malformations or spontaneous abortions or with decreased birthweight.

Assessment of the palatability of beta-lactamase-resistant antibiotics in children.

OBJECTIVES: To evaluate the palatability of antibiotics effective against beta-lactamase-producing bacteria in children and to compare the results obtained with those obtained in adults. DESIGN: A taste test of 4 antibiotic suspensions: a combination of amoxicillin and clavulanic acid (banana), azithromycin (cherry), clarithromycin (wild fruit), and a combination of erythromycin and sulfisoxazole (strawberry-banana). SETTING: Outpatient setting. SUBJECTS: A volunteer sample of 50 healthy children (mean +/- SD age, 6.3 +/- 1.3 years) and 20 adults. MAIN OUTCOME MEASURES: After each antibiotic test dose, subjects rated its taste on a 10-cm visual analog scale incorporating a facial hedonic scale. RESULTS: The mean +/- SD taste scores of the antibiotics as rated by the children were as follows: amoxicillin-clavulanic acid, 5.7 +/- 3.6 cm; azithromycin, 6.8 +/- 3.2 cm; clarithromycin, 3.7 +/- 3.6 cm; and erythromycin-sulfisoxazole, 4.9 +/- 3.5 cm. The mean +/- SD taste score for erythromycin-sulfisoxazole (ie, 2.7 +/- 2.3) assigned by the adults was significantly different than that given by the children (P = .01) with no difference noted for the other 3 drugs. Children and adults both selected azithromycin most often as best tasting. There was a significant difference in the proportions selecting each antibiotic as worst tasting, with the children tending to dislike clarithromycin and the adults tending to dislike erythromycin-sulfisoxazole (P = .03). CONCLUSIONS: The taste of azithromycin was rated most highly by both children and adults, who also selected this antibiotic most often as best tasting. Differences in taste-testing results between children and adults suggest that evaluation of the palatability of medications intended for use in pediatrics should be conducted in children.