Pseudomonas aeruginosa quorum sensing molecules correlate with clinical status in cystic fibrosis.

Pseudomonas aeruginosa produces quorum sensing signal molecules that are potential biomarkers for infection.A prospective study of 60 cystic fibrosis patients with chronic P. aeruginosa, who required intravenous antibiotics for pulmonary exacerbations, was undertaken. Clinical measurements and biological samples were obtained at the start and end of the treatment period. Additional data were available for 29 of these patients when they were clinically stable.Cross-sectionally, quorum sensing signal molecules were detectable in the sputum, plasma and urine of 86%, 75% and 83% patients, respectively. They were positively correlated between the three biofluids. Positive correlations were observed for most quorum sensing signal molecules in sputum, plasma and urine, with quantitative measures of pulmonary P. aeruginosa load at the start of a pulmonary exacerbation. Plasma concentrations of 2-nonyl-4-hydroxy-quinoline (NHQ) were significantly higher at the start of a pulmonary exacerbation compared to clinical stability (p<0.01). Following the administration of systemic antibiotics, plasma 2-heptyl-4-hydroxyquinoline (p=0.02) and NHQ concentrations (p<0.01) decreased significantly.In conclusion, quorum sensing signal molecules are detectable in cystic fibrosis patients with pulmonary P. aeruginosa infection and are positively correlated with quantitative measures of P. aeruginosa. NHQ correlates with clinical status and has potential as a novel biomarker for P. aeruginosa infection.

A longitudinal study assessing the impact of elexacaftor/tezacaftor/ivacaftor on gut transit and function in people with cystic fibrosis using magnetic resonance imaging (MRI).

BACKGROUND: Gastrointestinal (GI) symptoms in cystic fibrosis (CF) are common and disruptive. The effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the GI tract is not fully understood. The aim was to use magnetic resonance imaging (MRI) to determine if elexacaftor/tezacaftor/ivacaftor (ETI) changed GI function and transit. METHODS: This was an 18 month prospective, longitudinal, observational study. We enrolled 24 people with CF aged 12 years or older to undergo MRI scans before starting ETI and 3, 6, and 18 months after starting ETI. The primary outcome measure was change in oro-caecal transit time (OCTT) at 6 and 18 months. Secondary outcome measures included change in small bowel water content (SBWC), change in the reduction in small bowel water content following a meal (DeltaSBWC) and change in total colonic volume (TCV). RESULTS: A total of 21 participants completed MRI scans at 6 months and 11 completed at 18 months. After 18 months of ETI, median OCTT significantly reduced, from >360 min [IQR 240->360] to 240 min [IQR 180-300] (p = 0.02, Wilcoxon signed-rank). Both SBWC and DeltaSBWC increased after starting ETI. TCV reduced significantly after 18 months (p = 0.005, Friedman). CONCLUSIONS: Our findings suggest an improvement in small bowel transit, small bowel response to food and a reduction in colonic volume after starting ETI. These effects may relate to CFTR activation in the small bowel. To our knowledge this is the first study to show a physiological change in GI transit and function in response to CFTR modulator use through imaging studies.

A grumbling concern: an international survey of gastrointestinal symptoms in cystic fibrosis in the modulator era.

Background: Gastrointestinal symptoms in cystic fibrosis (CF) are common and intrusive to daily life. Relieving gastrointestinal symptoms was identified as an important research priority and previously explored in an international survey in 2018. However, following the widespread introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators in 2019, the landscape of CF treatment has changed. We repeated an online survey to further describe gastrointestinal symptoms and their effect on quality of life (QoL) in the CFTR modulator era. Methods: An electronic survey consisting of closed questions and free text responses was distributed via social media and professional networks for a period of one month between March - April 2022. People with CF (pwCF), their family and friends, and healthcare professionals (HCPs) were invited to take part. Results: There were 164 respondents: 88 pwCF (54%), 22 (13%) family, and 54 (33%) healthcare professionals (HCPs). A total of 89/110 (81%) pwCF or family members reported CFTR modulator treatment. The most commonly reported symptoms were wind / gas, rumbling stomach noises, loose motions (modulator) and bloating (no modulator). Abdominal pain and bloating had the greatest impact on QoL.For those on a CFTR modulator, the proportion of pwCF reporting "no change" or "worse" for all of the symptoms surveyed was greater than the proportion reporting an improvement. Following modulator introduction, dietary changes were recommended by 28/35 (80%) of HCPs and reported by 38/76 (50%) lay respondents. Changes in medication were recommended by 19/35 (54%) HCPs and reported by 44/76 (58%) of patients and family members. Conclusion: This survey has shown that gastrointestinal symptoms remain prevalent in pwCF in the CFTR modulator era, though the nature of these symptoms may have changed. A better understanding of the underlying pathophysiology of these symptoms is essential. Future clinical studies should focus on improving symptoms and QoL.

WHAT IS ALREADY KNOWN: Gastrointestinal symptoms are common and intrusive to everyday life for people with cystic fibrosis (CF), however the majority of studies reporting gastrointestinal symptoms in CF are published prior to the widespread introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies. These are medications which target the underlying defect in CF rather than the consequences of CFTR failure. WHAT THIS STUDY ADDS: Through this survey, we describe the similarities and differences of gastrointestinal symptoms for people with CF on modulator therapy compared to those not receiving modulators. Comparisons were also made to our previous work which was completed in 2018 prior to the licencing of the newest, and most widely used modulator, Elexacaftor / Tezacaftor / Ivacaftor (ETI). How this study might affect future research: This survey provides a snapshot into gastrointestinal symptoms for people with CF which will be of benefit for researchers as well as clinicians caring for people with CF. These results will inform the development of a CF-specific gastrointestinal patient reported outcome measure for people with CF that can be used in clinical trials.

A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study.

Background: People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. Methods: We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results: We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions: Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrialsgov registration: NCT04006873 (02/07/2019).

Novel detection of specific bacterial quorum sensing molecules in saliva: Potential non-invasive biomarkers for pulmonary Pseudomonas aeruginosa in cystic fibrosis.

Pseudomonas aeruginosa produces specific signalling molecules, 2-alkyl-4-quinolones (AQs) that are detectable in the sputum of adults with cystic fibrosis (CF) and who have pulmonary infection with this opportunistic pathogen. This study aimed to determine whether AQs could be detected in saliva of patients with CF and known infection with Pseudomonas aeruginosa. Saliva and sputum samples were obtained from 89 adults with CF and analyzed using liquid chromatography-tandem mass spectrometry. AQs were detected in 39/89 (43.8%) saliva samples and 70/77(90.9%) sputum samples. Salivary AQs had a sensitivity of 50% (95%CI; 37.8; 62.2), specificity of 100% (95%CI; 47.8; 100), when compared to a molecular microbiological measure of P. aeruginosa in sputum as measured using polymerase chain reaction. Specific AQs produced by P. aeruginosa can be detected in the saliva and warrant investigation as potential non-invasive biomarkers of pulmonary P. aeruginosa.

Porphyromonas pasteri and Prevotella nanceiensis in the sputum microbiota are associated with increased decline in lung function in individuals with cystic fibrosis.

Although anaerobic bacteria exist in abundance in cystic fibrosis (CF) airways, their role in disease progression is poorly understood. We hypothesized that the presence and relative abundance of the most prevalent, live, anaerobic bacteria in sputum of adults with CF were associated with adverse clinical outcomes. This is the first study to prospectively investigate viable anaerobic bacteria present in the sputum microbiota and their relationship with long-term outcomes in adults with CF. We performed 16S rRNA analysis using a viability quantitative PCR technique on sputum samples obtained from a prospective cohort of 70 adults with CF and collected clinical data over an 8 year follow-up period. We examined the associations of the ten most abundant obligate anaerobic bacteria present in the sputum with annual rate of FEV1 change. The presence of Porphyromonas pasteri and Prevotella nanceiensis were associated with a greater annual rate of FEV1 change; -52.3 ml yr-1 (95 % CI-87.7;-16.9), -67.9 ml yr-1 (95 % CI-115.6;-20.1), respectively. Similarly, the relative abundance of these live organisms were associated with a greater annual rate of FEV1 decline of -3.7 ml yr-1 (95 % CI: -6.1 to -1.3, P=0.003) and -5.3 ml yr-1 (95 % CI: -8.7 to -1.9, P=0.002) for each log2 increment of abundance, respectively. The presence and relative abundance of certain anaerobes in the sputum of adults with CF are associated with a greater rate of long-term lung function decline. The pathogenicity of anaerobic bacteria in the CF airways should be confirmed with further longitudinal prospective studies with a larger cohort of participants.

Magnetic resonance imaging of the gastrointestinal tract shows reduced small bowel motility and altered chyme in cystic fibrosis compared to controls.

People with cystic fibrosis (CF) experience digestive symptoms but the mechanisms are incompletely understood. Here we explore causes and consequences of slower gastrointestinal transit using magnetic resonance imaging (MRI). Twelve people with CF and 12 healthy controls, matched for age and gender, underwent MRI scans, both fasted and after standardised meals, over 6.5 h. Fasted small bowel motility scores were lower in CF than in controls. No difference in ascending colon chyme T1 was detected. The difference in texture between small bowel and colon contents, seen in health, was diminished in CF. The ascending colon in CF participants had an abnormal appearance compared to controls. MRI offers unique potential to evaluate gut luminal content, colonic mucosa and intestinal motor activity. These new data support the theoretical cycle of desiccation, dysmotility and delayed transit as a cause of gastrointestinal symptoms in CF.

Using a learning health system to understand the mismatch between medicines supply and actual medicines use among adults with cystic fibrosis.

BACKGROUND: Studies in separate cohorts suggest possible discrepancies between inhaled medicines supplied (median 50-60%) and medicines used (median 30-40%). We performed the first study that directly compares CF medicine supply against use to identify the cost of excess medicines supply. METHODS: This cross-sectional study included participants from 12 UK adult centres with ≥1 year of continuous adherence data from data-logging nebulisers. Medicine supply was measured as medication possession ratio (MPR) for a 1-year period from the first suitable supply date. Medicine use was measured as electronic data capture (EDC) adherence over the same period. The cost of excess medicines was calculated as whole excess box(es) supplied after accounting for the discrepancy between EDC adherence and MPR with 20% contingency. RESULTS: Among 275 participants, 133 (48.4%) were females and mean age was 30 years (95% CI 29-31 years). Median EDC adherence was 57% (IQR 23-86%), median MPR was 74% (IQR 46-96%) and the discrepancy between measures was median 14% (IQR 2-29%). Even with 20% contingency, mean potential cost of excess medicines was £1,124 (95% CI £855-1,394), ranging from £183 (95% CI £29-338) for EDC adherence ≥80% to £2,017 (95% CI £1,507-2,526) for EDC adherence <50%. CONCLUSIONS: This study provides a conservative estimate of excess inhaled medicines supply cost among adults with CF in the UK. The excess supply cost was highest among those with lowest EDC adherence, highlighting the importance of adherence support and supplying medicine according to actual use. MPR provides information about medicine supply but over-estimates actual medicine use.

Postprandial changes in gastrointestinal function and transit in cystic fibrosis assessed by Magnetic Resonance Imaging.

BACKGROUND: Cystic fibrosis (CF) is a multi-system genetic disorder affecting >72,000 people worldwide. Most CF patients experience gastrointestinal symptoms and can develop complications. However, the mechanisms of CF gut disease are not well understood. We evaluated gut function and transit in CF using magnetic resonance imaging (MRI). We hypothesised oro-caecal transit time (OCTT) is longer in CF; with lower small bowel water content (SBWC). METHODS: Twelve CF patients aged 12-40 years and 12 age and sex-matched controls underwent serial MRIs over 1 day with standardised meals. The primary endpoint was OCTT, assessed by the appearance of a food bolus in the caecum. Other measures included corrected SBWC and corrected colonic volume (both area under the curve, AUC), gastric half-emptying time and gastrointestinal symptoms. RESULTS: OCTT was longer in CF (CF 330 mins [270, >360] vs. controls 210 mins [173, 315], p = 0.04), with no difference in gastric half-emptying times. Corrected SBWC was higher in CF (CF 62 L.min/m2 [36, 80] vs. controls 34 L.min/m2 [28, 41], p = 0.021); minimal postprandial decrease between T240 and T300 (CF 13 mL/m2 [-13, 57] vs. controls 102 mL/m2 [67, 108], p = 0.002) suggests impaired ileal emptying. Corrected colonic volumes were higher in CF (CF 186 L.min/m2 [167, 206] vs. controls 123 L.min/m2 [89, 146], p = 0.012). There were no differences in gastrointestinal symptoms. CONCLUSIONS: MRI provides novel insights into CF pathophysiology. Sub-clinical ileal obstruction may be more prevalent than previously thought. Gastrointestinal MRI shows promise as an investigational tool in CF.

2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis.

Introduction. Pseudomonas aeruginosa produces quorum sensing signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence factor production in the cystic fibrosis (CF) airways.Hypothesis/Gap statement. Culture can lead to condition-dependent artefacts which may limit the potential insights and applications of AQs as minimally-invasive biomarkers of bacterial load.Aim. We aimed to use culture-independent methods to explore the correlations between AQ levels and live P. aeruginosa load in adults with CF.Methodology. Seventy-five sputum samples at clinical stability and 48 paired sputum samples obtained at the beginning and end of IV antibiotics for a pulmonary exacerbation in adults with CF were processed using a viable cell separation technique followed by quantitative P. aeruginosa polymerase chain reaction (qPCR). Live P. aeruginosa qPCR load was compared with the concentrations of three AQs (HHQ, NHQ and HQNO) detected in sputum, plasma and urine.Results. At clinical stability and the beginning of IV antibiotics for pulmonary exacerbation, HHQ, NHQ and HQNO measured in sputum, plasma and urine were consistently positively correlated with live P. aeruginosa qPCR load in sputum, compared to culture. Following systemic antibiotics live P. aeruginosa qPCR load decreased significantly (P<0.001) and was correlated with a reduction in plasma NHQ (plasma: r=0.463, P=0.003).Conclusion. In adults with CF, AQ concentrations correlated more strongly with live P. aeruginosa bacterial load measured by qPCR compared to traditional culture. Prospective studies are required to assess the potential of systemic AQs as biomarkers of P. aeruginosa bacterial burden.

Mbd2 contributes to DNA methylation-directed repression of the Xist gene.

Transcription of the Xist gene triggers X chromosome inactivation in cis and is therefore silenced on the X chromosome that remains active. DNA methylation contributes to this silencing, but the mechanism is unknown. As methylated DNA binding proteins (MBPs) are potential mediators of gene silencing by DNA methylation, we asked whether MBP-deficient cell lines could maintain Xist repression. The absence of Mbd2 caused significant low-level reactivation of Xist, but silencing was restored by exogenous Mbd2. In contrast, deficiencies of Mbd1, MeCP2, and Kaiso had no detectable effect, indicating that MBPs are not functionally redundant at this locus. Xist repression in Mbd2-null cells was hypersensitive to the histone deacetylase inhibitor trichostatin A and to depletion of the DNA methyltransferase Dnmt1. These synergies implicate Mbd2 as a mediator of the DNA methylation signal at this locus. The presence of redundant mechanisms to enforce repression at Xist and other loci is compatible with the hypothesis that "stacking" of imperfect repressive tendencies may be an evolutionary strategy to ensure leakproof gene silencing.

Alcohol use before and during pregnancy in western Washington, 1989-2004: implications for the prevention of fetal alcohol spectrum disorders.

OBJECTIVE: We examined trends in rates of self-reported pregnancy alcohol use among women in western Washington. STUDY DESIGN: Between 1989 and 2004, we conducted 3 studies in western Washington State on problems that are associated with maternal prenatal alcohol or drug abuse (n = 12,526). To determine study eligibility, we screened hospitalized postpartum women for alcohol and drug use in the month before and during pregnancy. We examined trends in alcohol use rates and identified characteristics that were associated with any drinking and binge drinking (> or = 5 drinks on any occasion). RESULTS: We found a substantial decrease in pregnancy alcohol use between 1989 and 2004 (from 30-12%) across almost all demographic categories. Binge drinking in the month before pregnancy increased significantly among all race categories, except Native American. CONCLUSION: Increased prepregnancy binge drinking rates may estimate alcohol use during very early gestation and warrant clinical attention because of the potential for fetal alcohol spectrum disorders.

Clinical significance of Pseudomonas aeruginosa 2-alkyl-4-quinolone quorum-sensing signal molecules for long-term outcomes in adults with cystic fibrosis.

Introduction. Pseudomonas aeruginosa is an important respiratory pathogen in cystic fibrosis (CF), which is associated with an accelerated decline in lung function, frequent pulmonary exacerbations and increased mortality. P. aeruginosa produces intercellular signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence-factor production and biofilm formation in the CF airways. Studies have shown that AQs are detectable in the sputum and plasma of adults with CF and chronic pulmonary P. aeruginosa.Aim. We tested the hypothesis that the presence of six AQs in plasma or sputum obtained from adults with CF was associated with long-term adverse clinical outcomes.Methodology. We analysed clinical data over an 8 year follow period for 90 people with CF who had previously provided samples for AQ analysis at clinical stability. The primary outcome was all cause mortality or lung transplantation. Secondary outcomes were the rate of lung-function decline and the number of intravenous (IV) antibiotic days for pulmonary exacerbations.Results. There was no statistical association between the presence of any of the six measured AQs and the primary outcomes or the secondary outcome of decline in lung function. One of the six AQs was associated with IV antibiotic usage. The presence of 2-nonyl-3-hydroxy-4(1 h)-quinolone (C9-PQS) in sputum was associated with an increase in the number of IV antibiotic days in the follow-up period (Mann-Whitney; P=0.011).Conclusion. Further investigation to confirm the hypothesis that C9-PQS may be associated with increased antibiotic usage for pulmonary exacerbations is warranted as AQ-dependent signalling is a potential future target for anti-virulence therapies.

MBD2-mediated transcriptional repression of the p14ARF tumor suppressor gene in human colon cancer cells.

OBJECTIVE: The p14(ARF) and p16(INK4A) tumor suppressor genes are commonly inactivated by aberrant methylation of their promoter regions in human colon cancer. The methyl-CpG-binding domain protein MBD2 is physically associated with the methylated promoters of the p14(ARF) and p16(INK4A) genes in specific tumor cell lines. Moreover, deficiency of MBD2 strongly inhibits intestinal tumorigenesis in the Min mouse, raising the possibility that the protein might be involved in transcriptional repression of methylated tumor suppressor genes. The aim of this study was to evaluate the role of MBD2 in the silencing of p14(ARF) and p16(INK4A) in cancer. METHODS: The MBD2 protein was stably knocked down by RNA interference in RKO, a colon cancer cell line in which both p14(ARF) and p16(INK4A) are silenced by methylation. RESULTS: We demonstrate here that MBD2 associates with the methylated promoter of the p14(ARF) gene in the RKO colon cancer cell line. Depletion of MBD2 by RNAi leads to selective upregulation of the p14(ARF) but not the p16(INK4A) gene transcript. In addition, p14(ARF) repression can be restored by expressing mouse MBD2 protein in MBD2-deficient RKO cells. CONCLUSION: These findings implicate MBD2 in transcriptional repression of the methylated p14(ARF) tumor suppressor gene and suggest that repression by MBD2 selectively affects a subset of methylated promoters.

Weight gain during acute treatment of an initial pulmonary exacerbation is associated with a longer interval to the next exacerbation in adults with cystic fibrosis.

Weight gain during treatment for a cystic fibrosis exacerbation http://ow.ly/f1zl30dU9AO.

Diagnostic and prognostic significance of systemic alkyl quinolones for P. aeruginosa in cystic fibrosis: A longitudinal study.

BACKGROUND: Pulmonary P. aeruginosa infection is associated with poor outcomes in cystic fibrosis (CF) and early diagnosis is challenging, particularly in those who are unable to expectorate sputum. Specific P. aeruginosa 2-alkyl-4-quinolones are detectable in the sputum, plasma and urine of adults with CF, suggesting that they have potential as biomarkers for P. aeruginosa infection. AIM: To investigate systemic 2-alkyl-4-quinolones as potential biomarkers for pulmonary P. aeruginosa infection. METHODS: A multicentre observational study of 176 adults and 68 children with CF. Cross-sectionally, comparisons were made between current P. aeruginosa infection using six 2-alkyl-4-quinolones detected in sputum, plasma and urine against hospital microbiological culture results. All participants without P. aeruginosa infection at baseline were followed up for one year to determine if 2-alkyl-4-quinolones were early biomarkers of pulmonary P. aeruginosa infection. RESULTS: Cross-sectional analysis: the most promising biomarker with the greatest diagnostic accuracy was 2-heptyl-4-hydroxyquinoline (HHQ). In adults, areas under the ROC curves (95% confidence intervals) for HHQ analyses were 0.82 (0.75-0.89) in sputum, 0.76 (0.69-0.82) in plasma and 0.82 (0.77-0.88) in urine. In children, the corresponding values for HHQ analyses were 0.88 (0.77-0.99) in plasma and 0.83 (0.68-0.97) in urine. Longitudinal analysis: Ten adults and six children had a new positive respiratory culture for P. aeruginosa in follow-up. A positive plasma HHQ test at baseline was significantly associated with a new positive culture for P. aeruginosa in both adults and children in follow-up (odds ratio (OR)=6.67;-95% CI:-1.48-30.1;-p=0.01 and OR=70; 95% CI: 5-956;-p<0.001 respectively). CONCLUSIONS: AQs measured in sputum, plasma and urine may be used to diagnose current infection with P. aeruginosa in adults and children with CF. These preliminary data show that plasma HHQ may have potential as an early biomarker of pulmonary P. aeruginosa. Further studies are necessary to evaluate if HHQ could be used in clinical practice to aid early diagnosis of P. aeruginosa infection in the future.

Binge drinking during pregnancy as a predictor of psychiatric disorders on the Structured Clinical Interview for DSM-IV in young adult offspring.

OBJECTIVE: This study explored the extent to which the high frequency of psychiatric problems reported in clinical groups with fetal alcohol spectrum disorders might also be observed in a nonclinical group of young adults and the psychiatric conditions that are related to prenatal alcohol exposure in this group. METHOD: From a longitudinal prospective study beginning with interviews of 1,529 pregnant women, a birth cohort of about 500 newborns was chosen to include all of the most heavily alcohol exposed plus a sampling of the continuum of alcohol exposures from total abstinence through heavy drinking. At an average age of 25.7 years, 400 members of this birth cohort were administered valid Structured Clinical Interviews for DSM-IV (SCID), including both the SCID for axis I disorders and the SCID for axis II personality disorders. RESULTS: The odds of the appearance of six psychiatric disorders and traits were more than double in adults exposed to one or more binge alcohol episodes in utero. Three of these six odds ratios were uniformly stable against confounding: axis I substance dependence or abuse disorders and axis II passive-aggressive and antisocial personality disorders or traits. CONCLUSIONS: Prenatal exposure to alcohol may be a risk factor for specific psychiatric disorders and traits in early adulthood, even in a nonclinical group.

Effects of prenatal alcohol exposure on fine motor coordination and balance: A study of two adult samples.

Motor coordination was assessed in two samples of adult subjects: one sample (n = 90) included adults previously diagnosed with one of a number of Fetal Alcohol Spectrum Disorders (FASD) and comparison peers, the second was a prospective longitudinal study of adults who were exposed to varying levels of alcohol as fetuses (n = 402). This comparative analysis sought to determine whether motor effects seen in both clinical and nonclinical children persist into adulthood, whether any individual motor tasks show significant effects of prenatal alcohol exposure across the age range, and whether motor assessments of adults have any role in diagnostic strategies for adults suspected of FASD. Motor tests included balance and unilateral, bilateral, finger, hand and foot coordination. Three-quarters of the subjects with FASD demonstrated deficits in motor function outside the range of comparison subjects. Adults with FASD performed more poorly, on average, on all individual tests including balance and fine motor control. In the prospective longitudinal sample, only subjects who had been previously identified in childhood as having a possible diagnosis on the Fetal Alcohol Spectrum were still in deficit as adults on motor tasks, relative to comparison subjects. Thus, the dose-dependent motor coordination effects of alcohol previously found in children do not appear to persist into adulthood, except in those most highly exposed children who also have other accompanying neuropsychological effects in childhood.

Glutamine supplementation in cystic fibrosis: A randomized placebo-controlled trial.

RATIONALE: Pulmonary infection and malnutrition in cystic fibrosis are associated with decreased survival. Glutamine has a possible anti-microbial effect, with a specific impact against Pseudomonas aeruginosa. We aimed to test the hypothesis that oral glutamine supplementation (21 g/day) for 8 weeks in adults with cystic fibrosis would decrease pulmonary inflammation and improve clinical status. METHODS: The study design was a randomized double-blind placebo-controlled study design with an iso-nitrogenous placebo. The primary analysis was intention to treat, and the primary outcome was change in induced sputum neutrophils. RESULTS: Thirty-nine individuals were recruited and thirty-six completed the study. Glutamine supplementation had no impact on any of the outcome measures in the intention-to-treat analysis. In the per protocol analysis, glutamine supplementation was associated with an increase in induced sputum neutrophils (P = 0.046), total cells (P = 0.03), and in Pseudomonas isolation agar colony forming units (P = 0.04) compared to placebo. CONCLUSIONS: There was no effect of glutamine supplementation on markers of pulmonary inflammation in the intention-to-treat analysis.