A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI) = 0.76-0.86, P(combined) = 3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Frequent occurrence of multidrug-resistant CC17 Enterococcus faecium among clinical isolates in Sweden.

AIMS: To screen for the globally spread cluster of Enterococcus faecium, clonal complex 17 (CC17) and characterize the genetic profile of Swedish clinical Ent. faecium isolates. METHODS: A total of 203 consecutive isolates collected from 2004 to 2007 from patients with bacteraemia in Sweden. All isolates were genotyped using multiple-locus variable-number tandem repeat analysis (MLVA) and 20 isolates representing different MLVA types (MT) were chosen for multilocus sequence typing (MLST). Minimal inhibitory concentrations against clinically relevant antibiotics were determined with agar dilution. Presence of the virulence genes esp and hyl was investigated using PCR. RESULTS: A total of 65% (n = 109) of all isolates belonged to MT-1, and the second most common MLVA type was MT-159 (13%, n = 21). MLST analysis confirmed the presence of CC17 during the entire study period. The number of isolates resistant to gentamicin and vancomycin, as well as the presence of hyl, increased significantly during the investigation period. CONCLUSIONS: The present study demonstrates that nosocomial infections caused by Ent. faecium CC17 are commonly occurring in Sweden. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of CC17 Ent. faecium in Sweden. The increase of antibiotic resistance and virulence indicates that these strains are further adapting to the hospital environment.

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.

Increased conjugation frequencies in clinical Enterococcus faecium strains harbouring the enterococcal surface protein gene esp.

This study compared the in-vitro ability of Enterococcus faecium isolates of different origin to acquire vanA by conjugation in relation to the occurrence of the esp gene. In total, 29 clinical isolates (15/29 esp+), 30 normal intestinal microflora isolates (2/30 esp+) and one probiotic strain (esp-) were studied with a filter-mating assay. Conjugation events were confirmed by PCR and pulsed-field gel electrophoresis. Among the infection-derived isolates, the esp+ isolates had higher conjugation frequencies compared with esp- isolates (p < 0.001), with a median value of 6.4 x 10(-6) transconjugants/donor. The probiotic strain was shown to acquire vanA vancomycin resistance in in-vitro filter mating experiments.

Continent cutaneous urinary diversion in patients with spinal cord injury.

STUDY DESIGN: Retrospective study. OBJECTIVE: To examine the functional results and effect on quality of life of continent cutaneous urinary diversion in spinal cord injured patients. SETTING: Department of Urology, Sahlgrenska University Hospital, Göteborg, Sweden. SUBJECTS: A total of 10 patients with spinal cord injury (SCI). METHOD: The patients were operated on with an ileal reservoir (Kock reservoir or T-pouch), Cr-EDTA clearance was determined preoperatively and at follow-up. The patients answered a questionnaire concerning reservoir function, various activities and quality of life. The patient charts were reviewed. RESULTS: One patient died of pulmonary embolism 3 years after surgery. Two patients were reoperated on for reservoir perforation. All patients were satisfied/very satisfied with their reservoirs. Half of them reported improved ability to perform various activities. Eight out of nine patients reported improved quality of life. CONCLUSION: For a selected group of patients with SCI, continent cutaneous urinary diversion provides successful outcome with improved quality of life.

Sacral nerve stimulation for refractory urge symptoms in elderly patients.

OBJECTIVE: The presence of an overactive detrusor (OD) is becoming more prevalent in the elderly and may severely influence the social life and activities of daily living in the senior, otherwise healthy, person. There is a marked age-dependent increase in OD above the age of 65 years, which is mainly attributed to dysfunction, with loss of voluntary control, of the micturition reflex and decreased perception of bladder fullness. MATERIAL AND METHODS: Herein, we evaluate the outcome of sacral nerve stimulation in five patients aged >65 years derived from a large, multinational, randomized, prospective study. RESULTS: The effect on symptoms was excellent in two subjects. There was a moderate improvement in another subject and a variable but eventually small effect in the remaining two patients. The results appeared to be more favourable in younger patients. CONCLUSION: Our findings suggest that the outcome of sacral nerve stimulation is more unpredictable in the elderly, a fact that should be considered when counselling the patient. However, it should be remembered that, even for the older, active person, urge incontinence may have a severe impact on quality of life and that the majority of patients treated with an implant will benefit from this treatment.

Mechanism of quinolone resistance in anaerobic bacteria.

Several recently developed quinolones have excellent activity against a broad range of aerobic and anaerobic bacteria and are thus potential drugs for the treatment of serious anaerobic and mixed infections. Resistance to quinolones is increasing worldwide, but is still relatively infrequent among anaerobes. Two main mechanisms, alteration of target enzymes (gyrase and topoisomerase IV) caused by chromosomal mutations in encoding genes, or reduced intracellular accumulation due to increased efflux of the drug, are associated with quinolone resistance. These mechanisms have also been found in anaerobic species. High-level resistance to the newer broad-spectrum quinolones often requires stepwise mutations in target genes. The increasing emergence of resistance among anaerobes may be a consequence of previous widespread use of quinolones, which may have enriched first-step mutants in the intestinal tract. Quinolone resistance in the Bacteroides fragilis group strains is strongly correlated with amino acid substitutions at positions 82 and 86 in GyrA (equivalent to positions 83 and 87 of Escherichia coli). Several studies have indicated that B. fragilis group strains possess efflux pump systems that actively expel quinolones, leading to resistance. DNA gyrase seems also to be the primary target for quinolones in Clostridium difficile, since amino acid substitutions in GyrA and GyrB have been detected in resistant strains. To what extent other mechanisms, such as mutational events in other target genes or alterations in outer-membrane proteins, contribute to resistance among anaerobes needs to be further investigated.

Anaerobic bacteria commonly colonize the lower airways of intubated ICU patients.

OBJECTIVES: To investigate respiratory tract colonization by aerobic and anaerobic bacteria in mechanically ventilated patients. METHODS: Bacterial colonization of the stomach and the respiratory tract was qualitatively and quantitatively analyzed over time in 41 consecutive mechanically ventilated patients in a Swedish intensive care unit (ICU), with special emphasis on elucidation of the role of anaerobic bacteria in the lower respiratory tract. Samples were taken from the oropharynx, gastric juice, subglottic space and trachea within 24 h (median 14 h) of intubation, and then every third day until day 18 and every fifth day until day 33. RESULTS: The patients were often heavily colonized with microorganisms not considered to belong to a healthy normal oropharyngeal and gastric flora on admission to the ICU. A majority harbored enterococci, coagulase-negative staphylococci and Candida spp. in at least one site on day 1. Anaerobic bacteria, mainly peptostreptococci and Prevotella spp., were isolated from subglottic and/or tracheal secretions in 59% of the patients. Different routes of tracheal colonization for different groups of microorganisms were found. Primary or concomitant colonization of the oropharynx with staphylococci, enterococci, enterobacteria and Candida was often seen, while Pseudomonas spp., other non-fermenting Gram-negative rods and several anaerobic species often primarily colonized the trachea, indicating exogenous or direct gastrointestinal routes of colonization. CONCLUSIONS: Mechanically ventilated patients were heavily colonized in their lower airways by potential pathogenic microorganisms, including a high load of anaerobic bacteria. Different routes of colonization were shown for different species.

The treatment of sphincter incontinence with periurethral silicone implants (macroplastique).

OBJECTIVE: Patients with genuine stress urinary incontinence (GSI) refractory to conservative measures often undergo a colposuspension when the reason for urine leakage is hypermobility of the bladder neck. Patients who suffer from an insufficiency of the intramural sphincter are instead often suitable for pubovaginal sling procedures, implantation of an artificial sphincter or peri/intraurethral injection of some expansion substance. Here, we present our experience of periurethral injection of silicone microimplants (Macroplastique). METHOD: We studied 8 men and 22 women with urodynamically stable detrusor, and validated GSI on a standardized quantification test. Under direct endoscopic control Macroplastique was injected. Follow-up was performed by a questionnaire and a new standardized quantification test. RESULTS: Nineteen of the 22 patients with follow-up in excess of 2 years reported a considerable amelioration and their subjective impressions were also validated by the postoperative standardized quantification test (preoperative 147 g, postoperative 9 g; p < 0.001). No side effects were reported except for mild dysuria for practically all the patients, in all cases transient. A few patients also reported a short initial sensation of incomplete bladder emptying. CONCLUSION: Considering the difficulty in treating sphincter insufficiency, particularly iatrogenic, the results in this study appear to justify the attempt of injection therapy. It may very well be performed as an outpatient procedure and, moreover, side effects are rare. If silicone microimplants are used there is no obstacle to proceed with artificial sphincter implantation, should the patient's symptoms remain unaffected by the injection procedure.

Clam ileocystoplasty: successful treatment of severe bladder overactivity.

OBJECTIVE: When conservative treatment for bladder overactivity fails the "clam" ileocystoplasty has been proposed to restore continence and preserve urethral voiding. This study presents our experience with this technique. MATERIALS AND METHODS: Thirty patients, 4 men and 26 women, with a mean age of 50.3 years (range 21-71 years) were operated upon. Five patients had an incomplete spinal lesion and detrusor hyperreflexia, 25 subjects had an idiopathic, unstable detrusor. The ileocystoplasty was combined with a colposuspension procedure in 8 patients. In one patient simultaneous repair of an urethro-vaginal fistula was performed using omentum flap interposition. The mean follow-up was 60 months (range 4-127). RESULTS: To the surgeon, 27 patients (90%) reported satisfaction with bladder control and relief of symptoms at follow-up. When asked by a nurse in a written questionnaire, 18 out of 23 patients (78%) were quite happy with their bladder function postoperatively. No serious complications to surgery were noted. Postoperatively, 11 patients used self-intermittent catheterization and one, by choice, preferred an indwelling catheter. Due to failure, two patients later underwent reoperation with urinary diversion and one further patient required an additional artificial sphincter. Metabolic consequences owing to enteric malabsorption were infrequent and of a mild nature. No malignant change was identified. CONCLUSION: In patients with refractory overactive bladder, we found the "clam" ileocystoplasty to be an effective technique for symptom reduction and increased quality of life.

Effect of perorally administered pivmecillinam on the normal oropharyngeal, intestinal and skin microflora.

To study the ecological effects of pivmecillinam on the human oropharyngeal, intestinal and skin microflora, 15 healthy volunteers were given pivmecillinam tablets 400 mg twice daily for 7 days. Saliva, stool and skin specimens were taken before (days -3 and 0) and on the 2nd, 4th and 7th days during the administration period and 14 and 21 days after the start of administration. Mecillinam caused no major changes in the aerobic or anaerobic oropharyngeal microflora. In the aerobic intestinal microflora there was a decrease in the numbers of Escherichia coli while no changes occurred in the anaerobic microflora. In the skin microflora there was a transient decrease in the numbers of Propionibacterium spp. underneath the wing of the nose. The major effect of pivmecillinam was seen on E. coli and to some extent on Propionibacterium spp. No further ecological disturbances were noticed in the oropharyngeal, intestinal or skin microflora.

gyrA mutations associated with quinolone resistance in Bacteroides fragilis group strains.

Mutations in the gyrA gene contribute considerably to quinolone resistance in Escherichia coli. Mechanisms for quinolone resistance in anaerobic bacteria are less well studied. The Bacteroides fragilis group are the anaerobic organisms most frequently isolated from patients with bacteremia and intraabdominal infections. Forty-four clinafloxacin-resistant and-susceptible fecal and clinical isolates of the B. fragilis group (eight Bacteroides fragilis, three Bacteroides ovatus, five Bacteroides thetaiotaomicron, six Bacteroides uniformis, and 22 Bacteroides vulgatus) and six ATCC strains of the B. fragilis group were analyzed as follows: (i) determination of susceptibility to ciprofloxacin, levofloxacin, moxifloxacin, and clinafloxacin by the agar dilution method and (ii) sequencing of the gyrA quinolone resistance-determining region (QRDR) located between amino acid residues equivalent to Ala-67 through Gln-106 in E. coli. Amino acid substitutions were found at hotspots at positions 82 (n = 15) and 86 (n = 8). Strains with Ser82Leu substitutions (n = 13) were highly resistant to all quinolones tested. Mutations in other positions of gyrA were also frequently found in quinolone-resistant and -susceptible isolates. Eight clinical strains that lacked mutations in their QRDR were susceptible to at least two of the quinolones tested. Although newer quinolones have good antimicrobial activity against the B. fragilis group, quinolone resistance in B. fragilis strains can be readily selected in vivo. Mutational events in the QRDR of gyrA seem to contribute to quinolone resistance in Bacteroides species.

BPH with coexisting overactive bladder dysfunction--an everyday urological dilemma.

The aim of this study was to use a systematic schedule, including urodynamics, to describe the rate of coexisting overactive bladder (OB) in patients with bladder outlet obstruction (BOO) caused by benign prostatic hyperplasia (BPH). We also identified differences between the patients with pure BOO compared with those with BOO combined with OB (BOO + OB). One hundred and sixty-two men referred to our clinic due to LUTS were included. Patients with a history that might affect their bladder function were excluded. After cystometry and pressure-flow studies, the patients were divided into pure BOO and BOO + OB. Of the 162 men, 55% had pure BOO. BOO + OB was found in 45%. Age, s-PSA, voided volume, and obstruction grade differed significantly between the groups. The patients with BOO + OB were older, had a higher s-PSA, voided smaller volumes, and were more obstructed. We found no differences in TRUS-volume, Q-max, IPS score, or PVR. There was a strong association between OB and BOO, the percentage of OB increasing with increased obstruction. TRUS-volume, Q-max, IPS score, and PVR did not predict whether the patients had a combined BOO + OB or not. These findings indicate that BOO is a progressive disease, which in time causes pronounced obstruction and perhaps in itself contributes to the development of OB.

Ecological effects on the oro- and nasopharyngeal microflora in children after treatment of acute otitis media with cefuroxime axetil or amoxycillin-clavulanate as suspensions.

OBJECTIVE: To evaluate if the extent of normal microflora disturbances differed between treatment with amoxycillin-clavulanate administered in an active form and cefuroxime axetil administered as an inactive prodrug. METHODS: Twenty-eight children, 0.5-5 years old, diagnosed with acute otitis media (AOM), were treated with either amoxycillin-clavulanate (13.3 mg/kg 3 times daily) or cefuroxime axetil (15 mg/kg twice daily) for 7 days. Saliva samples and nasopharyngeal swabs were collected before, directly after and 2 weeks after treatment. The saliva samples were quantitatively and qualitatively analyzed and the nasopharyngeal swabs were qualitatively analyzed. All isolated strains were tested for beta-lactamase production. RESULTS: Both treatment regimens gave rise to similar alterations of the normal oropharyngeal microflora. In both groups, the amount of Streptococcus salivarius was significantly reduced (P < 0.05). The most common causative pathogens of acute otitis were S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. On the day of enrollment, approximately half of the patients, in both groups, were infected with more than one pathogen. The rate of infection or colonization with more than one potential pathogen was low on day 7 but recurred 2 weeks after treatment to similar levels as on day 0. The total number of patients with reinfection, recolonization or recurrence of pathogens on day 21 was 11/12 in the amoxycillin-clavulanate group and 4/7 in the cefuroxime axetil group. The most common beta-lactamase producer was M. catarrhalis. CONCLUSION: The local high concentration of antibiotics in the oropharynx immediately after intake of antibiotic suspensions seem to have little or no impact on the extent of disturbance of the microflora in this region. Children of this age group seem prone to either reinfection, recolonization or persistence of pathogens within 2 weeks after treatment. Furthermore, co-infection with more than one pathogen seems common in children with AOM and infection with beta-lactamase producing microorganisms occurs frequently.

Probiotic Enterococcus faecium strain is a possible recipient of the vanA gene cluster.

The characteristics of Enterococcus faecium have led to concern regarding the safety of probiotics that contain this bacterium. The results of an in vitro filter mating assay indicate that a probiotic E. faecium strain might be a potential recipient of vancomycin resistance genes.

Lidocaine cystometry in the diagnosis of bladder overactivity.

The effect of intravesical lidocaine was studied in a group of patients with symptoms of urinary urgency with or without incontinence. Provocative water cystometry failed to demonstrate signs of unstable detrusor but all patients presented a continuous, steep rise of detrusor pressure at the end phase of filling. Repeat cystometry was performed after the bladder had been treated with 3 g lidocaine intravesically for 20 minutes. In the majority of patients, no change in configuration of the cystometrogram was noted. In a group of patients, a decrease of detrusor pressure occurred and there was also an influence on phasic bladder contractions. In three patients, phasic detrusor contractions developed after lidocaine. Thus, intravesical lidocaine seems to be a useful tool to increase the precision of the urodynamic diagnosis in bladder overactivity.

Effect of antimicrobial agents on the ecological balance of human microflora.

The normal microflora acts as a barrier against colonisation of potentially pathogenic microorganisms and against overgrowth of already present opportunistic microorganisms. Control of growth of opportunistic microorganisms is termed colonisation resistance. Administration of antimicrobial agents, therapeutically or as prophylaxis, causes disturbances in the ecological balance between the host and the normal microflora. Most studies on the impact of antimicrobial agents on normal microflora have been carried out on the intestinal flora. Less is known on the effects on oropharyngeal, skin, and vaginal microflora. Disturbances in the microflora depend on the properties of the agents as well as of the absorption, route of elimination, and possible enzymatic inactivation and/or binding to faecal material of the agents. The clinically most common disturbances in the intestinal microflora are diarrhoea and fungal infections that usually cease after the end of treatment. A well-balanced microflora prevents establishment of resistant microbial strains. By using antimicrobial agents that do not disturb colonisation resistance, the risk of emergence and spread of resistant strains between patients and dissemination of resistant determinants between microorganisms is reduced. In this article, the potential ecological effects of administration of antimicrobial agents on the intestinal, oropharyngeal, and vaginal microflora are summarised. The review is based on clinical studies published during the past 10 years.