Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring.

OBJECTIVES: Low birth weight (LBW) has been associated with common adult-onset chronic diseases, including obesity, cardiovascular disease, type II diabetes and some cancers. The etiology of LBW is multi-factorial. However, recent evidence suggests exposure to antibiotics may also increase the risk of LBW. The mechanisms underlying this association are unknown, although epigenetic mechanisms are hypothesized. In this study, we evaluated the association between maternal antibiotic use and LBW and examined the potential role of altered DNA methylation that controls growth regulatory imprinted genes in these associations. METHODS: Between 2009-2011, 397 pregnant women were enrolled and followed until delivery. Prenatal antibiotic use was ascertained through maternal self-report. Imprinted genes methylation levels were measured at differentially methylated regions (DMRs) using bisulfite pyrosequencing. Generalized linear models were used to examine associations among antibiotic use, birth weight and DMR methylation fractions. RESULTS: After adjusting for infant gender, race/ethnicity, maternal body mass index, delivery route, gestational weight gain, gestational age at delivery, folic acid intake, physical activity, maternal smoking and parity, antibiotic use during pregnancy was associated with 138 g lower birth weight compared with non-antibiotic use (ß-coefficient=-132.99, s.e.=50.70, P=0.008). These associations were strongest in newborns of women who reported antibiotic use other than penicillins (ß-coefficient=-135.57, s.e.=57.38, P=0.02). Methylation at five DMRs, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) and PEG3 (P=0.08), was associated with maternal antibiotic use; among these, only methylation at the PLAGL1 DMR was also associated with birth weight. CONCLUSION: We report an inverse association between in utero exposure to antibiotics and lower infant birth weight and provide the first empirical evidence supporting imprinted gene plasticity in these associations.

Abdominal wall hernia repair with a composite ePTFE/polypropylene mesh: clinical outcome and quality of life in 152 patients.

PURPOSE: No consensus has yet been reached regarding the optimal mesh for the repair of small ventral hernias. A composite polytetrafluoroethylene/polypropylene mesh (Ventralex(®)) is designed for this purpose, and this paper reports its use in a larger series of patients. METHODS: Open repair for a small ventral hernia was undertaken in 152 patients between April 2006 and June 2008. Data from medical files were gathered, and follow-up questionnaires were retrieved. Patients were asked about pain, intake of analgesics and various physical capabilities. Patients with postoperative complaints were offered a follow-up visit. Ultrasonography was performed if recurrence was suspected. RESULTS: Median surgery time was 39 min (range 16-129 min). Junior surgeons performed 63% of the operations. Questionnaires were returned by 81.6% with a mean follow-up of 15.6 months. Eighteen patients (11.8%) had complications. Pain score was significantly lower and the physical capabilities of the patients were significantly enhanced after the operation. Recurrent hernia was reported in four patients (2.6%). Five patients (3.3%) had the mesh removed due to deep infection, chronic pain or early recurrence. The training level of the surgeon had no influence on the incidence of complications. A 93.8% majority of the patients would recommend this specific procedure to others. CONCLUSIONS: The intraperitoneal placement of this composite mesh is associated with a high level of patient satisfaction as well as low rates of both recurrence and infection.

Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction.

Caloric restriction (CR) is a reduction of total caloric intake without a decrease in micronutrients or a disproportionate reduction of any one dietary component. While CR attenuates age-related cognitive deficits in tasks of hippocampal-dependent memory, the cellular mechanisms by which CR improves this cognitive decline are poorly understood. Previously, we have reported age-related decreases in key synaptic proteins in the CA3 region of the hippocampus that are stabilized by lifelong CR. In the present study, we examined possible age-related changes in the functional microcircuitry of the synapses in the stratum lacunosum-molecular (SL-M) of the CA3 region of the hippocampus, and whether lifelong CR might prevent these age-related alterations. We used serial electron microscopy to reconstruct and classify SL-M synapses and their postsynaptic spines. We analyzed synapse number and size as well as spine surface area and volume in young (10 months) and old (29 months) ad libitum fed rats and in old rats that were calorically restricted from 4 months of age. We limited our analysis to SL-M because previous work demonstrated age-related decreases in synaptophysin confined to this specific layer and region of the hippocampus. The results revealed an age-related decrease in macular axo-spinous synapses that was not reversed by CR that occurred in the absence of changes in the size of synapses or spines. Thus, the benefits of CR for CA3 function and synaptic plasticity may involve other biological effects including the stabilization of synaptic proteins levels in the face of age-related synapse loss.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Isolation and phylogenetic characterization of acidophilic microorganisms indigenous to acidic drainage waters at an abandoned Norwegian copper mine.

The biodiversity of culturable acidophilic microbes in three acidic (pH 2.7-3.7), metal-rich waters at an abandoned subarctic copper mine in central Norway was assessed. Acidophilic bacteria were isolated by plating on selective solid media, and dominant isolates were identified from their physiological characteristics and 16S rRNA gene sequences. The dominant iron-oxidizing acidophile in all three waters was an Acidithiobacillus ferrooxidans-like eubacterium, which shared 98% 16S rDNA identity with the type strain. A strain of Leptospirillum ferrooxidans was obtained from one of the waters after enrichment in pyrite medium, but this iron oxidizer was below detectable levels in the acidic waters themselves. In two sites, there were up to six distinct heterotrophic acidophiles, present at 10(3) ml(-1). These included Acidiphilium-like isolates (one closely related to Acidiphilium rubrum, a second to Acidiphilium cryptum and a third apparently novel isolate), an Acidocella-like isolate (96% 16S rDNA identity to Acidocella facilis) and a bacterium that shared 94.5% 16S rDNA identity to Acidisphaera rubrifaciens. The other numerically significant heterotrophic isolate was not apparently related to any known acidophile, with the closest match (96% 16S rDNA sequence identity) to an acetogen, Frateuria aurantia. The results indicated that the biodiversity of acidophilic bacteria, especially heterotrophs, in acidic mine waters may be much greater than previously recognized.

The impact of affectivity dispositions, self-efficacy and locus of control on psychosocial adjustment in patients with epilepsy.

The main hypothesis of this study was that negative and positive affectivity, self-efficacy and health-related locus of control are important for psychosocial adjustment in patients with epilepsy. These dimensions are rarely examined directly in relation to the psychosocial adjustment in these patients. Correlations between measures of these constructs and measures of psychosocial adjustment in epilepsy were investigated. One hundred and one patients answered the Washington psychosocial seizure inventory (WPSI), the positive and negative affect schedule (PANAS-X), the multidimensional health locus of control scales (MHLC), the generalized self-efficacy scale and a scale measuring self-efficacy in epilepsy. Reliability analyses, correlational analyses and multiple stepwise regression analyses were performed. Negative affectivity (NA), positive affectivity (PA) and generalized self-efficacy showed high correlations with the WPSI scales emotional adjustment, overall psychosocial adjustment and quality of life. The epilepsy self-efficacy measures showed high, but lower correlations with the same WPSI scales. The MHLC scales showed low correlations with the WPSI scales. Multiple regression analyses showed that PA, NA and measures of self-efficacy explained more than 50% of the variances on emotional adjustment, overall psychosocial functioning and quality of life. In conclusion, positive and negative affectivity and self-efficacy are important predictors of perceived emotional adjustment, psychosocial adjustment and quality of life in patients with epilepsy. NA is the best predictor, but PA and self-efficacy measures give unique predictions independent of NA.

A convenient route to higher sugars by two-carbon chain elongation using Wittig/dihydroxylation reactions.

The combination of a Wittig olefination and a dihydroxylation reaction constitutes a facile synthetic protocol for the transformation of unprotected carbohydrates into higher sugars. The Wittig reaction is carried out with tert-butyl or diphenylmethyl ester stabilized phosphoranes to give (E)-configured alpha,beta-unsaturated esters as the only products in most cases. These are dihydroxylated in a diastereoselective fashion using OsO(4)/NMO. The stereochemical outcome in the dihydroxylation follows Kishi's empirical rule and gives high diastereoselectivity (5:1-8:1) when starting from sugars with the 2,3-threo configuration. When starting from sugars with the 2,3-erythro configuration, the diastereoselectivity in the dihydroxylation is low (2:1-2.5:1). As a result, the Wittig/dihydroxylation protocol is most effective for producing higher sugars with the galacto configuration at the reducing end. The two steps can either be carried out individually or, more efficiently, as a one-pot procedure.

Efficient synthesis of enantiopure conduritols by ring-closing metathesis.

Two short synthetic approaches to enantiopure conduritols are described starting from the chiral pool. In both cases, the cyclohexene ring is assembled via ring-closing olefin metathesis. The terminal diene precursers for the metathesis reaction are prepared either from octitols or from tartaric acids. The former route involves a new method for selective bromination of the primary positions in long-chain carbohydrate polyols. Subsequent reductive elimination with zinc then generates the diene. The latter route uses a highly diastereoselective addition of divinylzinc to tartaric dialdehydes for preparation of the dienes.

Up-regulation of hippocampal glutamate transport during chronic treatment with sodium valproate.

Excessive glutamatergic neurotransmission has been implicated in some neurodegenerative disorders. It would be of value to know whether glutamate transport, which terminates the glutamate signal, can be up-regulated pharmacologically. Here we show that chronic treatment of rats with the anti-epileptic drug sodium valproate (200 mg or 400 mg/kg bodyweight, twice per day for 90 days) leads to a dose-dependent increase in hippocampal glutamate uptake capacity as measured by uptake of [(3)H]glutamate into proteoliposomes. The level of glutamate transporters EAAT1 and EAAT2 in hippocampus also increased dose-dependently. No effect of sodium valproate on glutamate transport was seen in frontal or parietal cortices or in cerebellum. The hippocampal levels of glial fibrillary acidic protein and glutamine synthetase were unaffected by valproate treatment, whereas the levels of synapsin I and phosphate-activated glutaminase were reduced by valproate treatment, suggesting that the increase in glutamate transporters was not caused by astrocytosis or increased synaptogenesis. A direct effect of sodium valproate on the glutamate transporters could be excluded. The results show that hippocampal glutamate transport is an accessible target for pharmacological intervention and that sodium valproate may have a role in the treatment of excitotoxic states in the hippocampus.

Effect of terbutaline on exercise capacity and pulmonary function in patients with chronic obstructive pulmonary disease.

The objective of this study was to investigate the effects of a single dose of a beta2-agonist, terbutaline (Bricanyl Turbuhaler), on resting lung function and exercise capacity in patients with chronic obstructive lung disease. Using a double-blind, placebo-controlled, randomized crossover study and outpatients from a department of pulmonary medicine at a major inner-city hospital, we examined 26 individuals with chronic obstructive lung disease who met the criteria of 40%

Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history.

BACKGROUND: The discovery of BRCA1 and BRCA2 has led to a reassessment of the association between family history of breast/ovarian cancer and breast cancer risk after controlling for carrier status for mutations in the BRCA1 and BRCA2 genes. We examined whether family history of breast cancer remains a predictive risk factor for this disease after carrier status for BRCA1 and/or BRCA2 mutations is taken into consideration. METHODS: The data are from 4730 case subjects with breast cancer and 4688 control subjects enrolled in the Cancer and Steroid Hormone Study. The probability of being a BRCA1 and/or BRCA2 gene carrier was calculated for each woman. Among predicted noncarriers, logistic regression was used to assess the relationship (odds ratios and 95% confidence intervals [CIs]) between case or control status and family history of breast or ovarian cancer. Estimates of age-specific breast cancer risk are presented by predicted carrier status. RESULTS: Among predicted noncarriers, case subjects were 2.06 times (95% CI = 1.69-2.50) and 1.24 times (95% CI = 1.17-1.32) more likely to report a first-degree or second-degree family history of breast cancer, respectively, than were control subjects. Case subjects were 1.99 times (95% CI = 1.63-2.44), 1.66 times (95% CI = 1.18-2.38), and 2.23 times (95% CI = 0.21-24.65) more likely to report an affected mother, sister, or both, respectively, than were control subjects. A family history of ovarian cancer was not statistically significantly associated with breast cancer risk. Noncarriers were predicted to have a lifetime risk of 9% of developing breast cancer compared with a 63% risk for carriers. CONCLUSIONS: Among women with a moderate family history of breast cancer, i.e., predicted noncarriers of BRCA1 and/or BRCA2 mutations, family history remains a factor in predicting breast cancer risk. In families with breast and ovarian cancers, the aggregation of these two cancers appears to be explained by BRCA1/BRCA2 mutation-carrier probability.

Effect of salmeterol is independent of previously inhaled salbutamol: a clinical controlled study.

The objective of this study was to examine the bronchodilating effect of an inhaled long acting beta2-agonist (salmeterol) after a high dose of an inhaled short acting beta2-agonist (salbutamol) in asthma patients. We used a randomized double-blind, placebo-controlled, crossover design, studying seven subjects with moderate asthma, treated with inhaled steroids and highly reversible to salbutamol and salmeterol. 1.5 h after salmeterol inhalation, the mean difference in FEV1 between salbutamol and placebo pretreatment days was 6.31% and ranged from 0.02 to 1.05%, 2.5-10.5 h after salmeterol inhalation. We concluded that the effect measured as the duration of bronchodilation of salmeterol is not decreased by previously inhaled salbutamol. We only found a trend toward an additive effect of combining salbutamol and salmeterol, probably because the high dose of salbutamol did not give room for further improvement in FEV1. In accordance with other clinical studies we were unable to demonstrate any clinical implications of the salmeterol partial beta2-antagonism known from animal and in vitro studies.

Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark.

Thyroid abnormalities are common in all populations, but it is difficult to compare results of epidemiological studies, because different methods have been used for evaluation. We studied the importance of the population iodine intake level for the prevalence rate of various thyroid abnormalities in elderly subjects. Random samples of elderly subjects (68 yr) were selected from the central person registers in Jutland, Denmark, with low (n = 423) and, in Iceland, with longstanding relatively high (n = 100) iodine intake. Females from Jutland had a high prevalence of goiter or previous goiter surgery (12.2%), compared with males from Jutland (3.2%) and females (1.9%) and males (2.2%) from Iceland. Abnormal thyroid function was very common in both areas, with serum TSH outside the reference range in 13.5% of subjects from Jutland and 19% of those from Iceland. In Jutland, it was mainly thyroid hyperfunction (9.7% had low, 3.8% had high serum TSH), whereas in Iceland, it was impaired thyroid function (1% had low, 18% had high serum TSH). All subjects with serum TSH more than 10 mU/L had autoantibodies in serum, but antibodies were, in general, more common in Jutland than in Iceland. Thus, thyroid abnormalities in populations with low iodine intake and those with high iodine intake develop in opposite directions: goiter and thyroid hyperfunction when iodine intake is relatively low, and impaired thyroid function when iodine intake is relatively high. Probably, mild iodine deficiency partly protects against autoimmune thyroid disease. Thyroid autoantibodies may be markers of an autoimmune process in the thyroid or secondary to the development of goiter.

Homeless youth and their exposure to and involvement in violence while living on the streets.

PURPOSE: The purpose of this research were to explore homeless youths' histories of exposure to violence, perpetration of violence, and fear of violent victimization, and to examine the extent to which these constructs are associated with demographic variables. METHODS: A sample of 432 youth (between 13 and 23 years old) who were homeless or at imminent risk for homelessness were sampled from both service and street sites. The percentage of youth who reported exposure to each type of violence was calculated. Multiple regression analyses were used to examine differences in the risk of exposure to violence across gender, ethnicity, age, and length of time homeless. RESULTS: Respondents reported a high rate of exposure to violence. Female respondents reported levels of exposure to violence that were as high as those reported by males. Females were more likely to report having been sexually assaulted and fearing victimization, and tended to be less likely to report perpetrating violence. With a few exceptions, ethnic identity was not a significant predictor of exposure to violence or fear of victimization. Age tended to be inversely associated with risk of exposure to violence. Length of time homeless was not associated with fear of victimization. CONCLUSIONS: Homeless youth are at high risk for exposure to a variety of forms violence as both witnesses and victims. The overall rates of exposure to violence and patterns of association with demographic variables are significantly higher than those reported in national samples of adolescents.

Modulatory treatment of NMDA receptors in neonatal rats affects cognitive behavior in adult age.

The glutamatergic NMDA receptor is probably involved in establishing functional connections during development, and interference may promote or impair cognitive functions in adult age. In the present study, rat pups received one daily injection of the NMDA receptor partial agonist D-cycloserine in various concentrations (3, 10, 50 mg/kg), the NMDA receptor antagonist (+/-)-HA-966 (30 mg/kg), or saline throughout postnatal days 10-20 (Experiment 1). In Experiment 2, effects of the (+)-enantiomer of HA-966 were similarly examined. The rats were tested in a novelty task in adult age (postnatal days 98-112). The results from Experiment 1 show that injections of D-cycloserine in the concentration of 10 mg/kg or (+/-)-HA-966 caused a slight increase in locomotor activity only. The results from Experiment 2 show that (+)-HA-966-treated rats displayed reduced preference for novelty, a slight reduction in exploratory activity and locomotor behavior, and increased rate of grooming. These results suggest that neonatal treatment with (+)-HA-966 can impair cognitive behavior in adult life. It was not possible to record any effects on cognitive function after neonatal administration of the glutamatergic agonist D-cycloserine.

The effect of ephedrine plus caffeine on smoking cessation and postcessation weight gain.

OBJECTIVES: To evaluate the efficacy of a combination of ephedrine and caffeine on smoking cessation rates, postcessation weight gain, and withdrawal symptoms and to examine changes in glycosylated hemoglobin (HbA1c) after smoking cessation. METHODS: This randomized double-blind placebo-controlled study with a 1-year follow-up period was carried out at the Department of Pulmonary Medicine in Denmark. Study subjects were 225 heavy smokers who wanted to quit smoking without gaining weight. Two-thirds of the subjects were randomized to receive 20 mg ephedrine plus 200 mg caffeine three times a day; one-third of the subjects received placebo treatment. The dosage was gradually decreased from week 12 to discontinuation at week 39. Group support and control were performed at entry and after 1, 3, 6, 12, 26, 39, and 52 weeks. Main outcome measures were (1) self-reported abstinence with validation by carbon monoxide in expired air and serum cotinine and (2) weight gain. RESULTS: The success rates after 1 year were 17% in the group treated with ephedrine plus caffeine and 16% in the group treated with placebo; the success rates were not significantly different at any time. The success rates for the four counseling physicians varied between 7% and 27% after 1 year (p < 0.05). The weight gain was significantly lower in the ephedrine plus caffeine-treated group during the first 12 weeks, but weight gains were similar after 1 year. No differences in the smoking withdrawal symptoms could be observed between the treatment groups. HbA1c was lower 6 weeks and 1 year after smoking cessation (p < 0.05). CONCLUSIONS: We found an effect of this combination of ephedrine and caffeine on weight gain during the first 12 weeks, but we found no effect on the success rates or craving for cigarettes.

[Salmeterol improves the control of disease in patients with moderate asthma. A comparative study of inhaled salmeterol 50 mg and salbutamol depot tablets 8 mg, both administered twice daily]. / Salmeterol forbedrer sygdomskontrollen hos patienter med moderat astma. En sammenlignende undersøgelse af inhaleret salmeterol 50 mg og salbutamol depottabletter 8 mg, begge doseret to gange daglig.

In a randomized, double-blind, double-dummy, cross-over study the efficacy and safety of inhaled salmeterol 50 mcg (b.i.d.) was compared with oral salbutamol controlled release 8 mg (b.i.d.). Fifty-nine patients with moderate asthma were randomized to two four-week periods of treatment with a two-week washout period. During the study period the patients were allowed to use inhaled Salbutamol on a prn. basis. Inhaled steroids, if any, were continued. On diary cards patients recorded peak expiratory flow rate (PEFR) morning and evening before medication, asthma symptom score, and use of inhaled salbutamol. Salmeterol was more effective than salbutamol CR in decreasing daily symptoms (p = 0.001) and increasing morning-PEFR (p = 0.004). Salmeterol resulted in significantly more days without symptoms (p = 0.0004) and days and nights without need for rescue medication (p = 0.01 and p = 0.01). Salmeterol was better tolerated than salbutamol CR.

Changes in plasma volume during prolonged restriction of motor activity: effect of chronic hyperhydration.

Prolonged reduction of number of steps taken per day by healthy subjects (hypokinesia), is associated with a decrease in plasma volume (PV), which may contribute to the development of several so-called hypokinetic disorders seen immediately during exposure to hypokinesia (HK). The purpose of this study was to determine whether a daily intake of fluid and salt supplementation (FSS), would attenuate this loss of PV. Thirty male long distance runners (20-25 years of age) completed this investigation. Ten volunteers placed under a normal ambulatory life (control subjects), ten volunteers were subjected to continuous restriction of motor activity without using FSS (hypokinetic subjects) and ten volunteers were submitted to continuous restriction of motor activity and took daily FSS (hyperhydrated subjects). For the simulation of the hypokinetic effect the hypokinetic and hyperhydrated volunteers were kept under 2.7 km/day (3,000 steps/day). Plasma volume decreased significantly (p < 0.05) in the hypokinetic volunteers during HK, from 3.010 +/- 81 to 2.693 +/- 52 ml. The volunteers who were submitted to combined HK and FSS, had a significant (p < 0.05) increase in PV during HK, from 2.940 +/- 72 to 3.327 +/- 72 ml. There were demonstrable significant differences in PV between the hyperhydrated and hypokinetic groups of volunteers. Thus, prolonged restriction of motor activity appears to have significant effects on the loss of PV, whereas chronic hyperhydration significantly increases PV.