Sperm count in Swedish clinical stage I testicular cancer patients following adjuvant treatment.

BACKGROUND: Little is known regarding sperm production following adjuvant treatment in testicular cancer (TC) clinical stage I (CS I) patients. PATIENTS AND METHODS: A total of 182 TC patients aged 18-50 years were prospectively included during 2001-2006 at any given time within 5 years of orchiectomy. Semen samples were delivered postorchiectomy but before further treatment, 6, 12, 24, 36 and 60 months (T0-T60) after completed therapy. Total sperm number (TSN) and sperm concentration (SC) were used as measurements of testicular function. Four groups according to treatment modality were identified; Radiotherapy; To a total dose of 25.2 Gy to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes (RT, N = 70), one cycle of adjuvant BEP (bleomycin, etoposide, cisplatin, 5 day regimen) (BEP, N = 62), one cycle of adjuvant carboplatin AUC 7 (Carbo, N = 22), and patients managed by surveillance (SURV, N = 28). RESULTS: In the cross-sectional analysis, a significant but transient drop in mean TSN and mean SC (T0-T60) was seen at T6 after radiotherapy. Apart from a significant increase in mean SC at T12 compared with baseline, no significant differences were observed in the other treatment groups. In 119 patients delivering 3 or more samples, values in TSN and SC were rather stable over time. Azoospermic patients (N = 11) were observed in most treatment groups except for in the BEP group. During follow-up, one azoospermic patient belonging to the Carbo group became normospermic. CONCLUSIONS: No clinically significant long-term effect on TSN or SC associated with adjuvant treatment in TC CSI patients was found. However, as patients may have low sperm counts before orchiectomy as well as after adjuvant treatment, we offer sperm banking before orchiectomy as assisted reproductive measures may be necessary regardless of treatment given.

Depression is associated with enhanced aversive Pavlovian control over instrumental behaviour.

The dynamic modulation of instrumental behaviour by conditioned Pavlovian cues is an important process in decision-making. Patients with major depressive disorder (MDD) are known to exhibit mood-congruent biases in information processing, which may occur due to Pavlovian influences, but this hypothesis has never been tested directly in an unmedicated sample. To address this we tested unmedicated MDD patients and healthy volunteers on a computerized Pavlovian-Instrumental Transfer (PIT) task designed to separately examine instrumental approach and withdrawal actions in the context of Pavlovian appetitive and aversive cues. This design allowed us to directly measure the degree to which Pavlovian cues influence instrumental responding. Depressed patients were profoundly influenced by aversive Pavlovian stimuli, to a significantly greater degree than healthy volunteers. This was the case for instrumental behaviour both in the approach condition (in which aversive Pavlovian cues inhibited 'go' responses), and in the withdrawal condition (in which aversive Pavlovian cues facilitated 'go' responses). Exaggerated aversive PIT provides a potential cognitive mechanism for biased emotion processing in major depression. This finding also has wider significance for the understanding of disrupted motivational processing in neuropsychiatric disorders.

The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats.

PURPOSE: Metabolic surgery alters the secretion of gastrointestinal hormones that influence glycemic control. Elevated gastrin has been suggested to benefit patients with type 2 diabetes and has been reported following sleeve gastrectomy in rats. The present study compares the effect of hypergastrinemia following sleeve gastrectomy with proton-pump inhibitor therapy on glycemic control and beta-cell mass in lean, diabetic animals. METHODS: Thirty-three diabetic Goto-Kakizaki rats were randomized into pantoprazole + sham operation (GK-PPI), sleeve gastrectomy (GK-SG) and vehicle + sham operation (GK-V). Body weight, glucose parameters, HbA1c, glucagon-like peptide 1, gastrin, insulin and lipids were evaluated for eighteen postoperative weeks. Total beta-cell mass was quantified by optical projection tomography. RESULTS: After surgery, body weight development was equal among groups (P g = 0.75). Fasting and stimulated gastrin increased for GK-PPI and GK-SG vs. GK-V (p < 0.05 for all). Fasting blood glucose was decreased for GK-PPI and GK-SG vs. GK-V (p < 0.05 and p = 0.052). HbA1c was lower for GK-SG vs. GK-V at 6 weeks and for GK-PPI vs. GK-V at twelve- and eighteen weeks postoperative (p < 0.05 for all); a borderline difference was observed for GK-SG vs. GK-V at 18 weeks (p = 0.054). Total- and LDL cholesterol was elevated for GK-PPI compared to the other two groups (p < 0.05 for all). Beta-cell mass did not differ among groups (p = 0.35). CONCLUSIONS: Hypergastrinemia following sleeve gastrectomy and pantoprazole has a similar, modest effect on glycemic control in Goto-Kakizaki rats but does not enhance beta-cell mass after 18 weeks. Hypergastrinemia in the setting of T2DM might be of clinical relevance.

Unreliability of putative fMRI biomarkers during emotional face processing.

There is considerable need to develop tailored approaches to psychiatric treatment. Numerous researchers have proposed using functional magnetic resonance imaging (fMRI) biomarkers to predict therapeutic response, in particular by measuring task-evoked subgenual anterior cingulate (sgACC) and amygdala activation in mood and anxiety disorders. Translating this to the clinic relies on the assumption that blood-oxygen-level dependent (BOLD) responses in these regions are stable within individuals. To test this assumption, we scanned a group of 29 volunteers twice (mean test-retest interval=14.3 days) and calculated the within-subject reliability of the amplitude of the amygdalae and sgACC BOLD responses to emotional faces using three paradigms: emotion identification; emotion matching; and gender classification. We also calculated the reliability of activation in a control region, the right fusiform face area (FFA). All three tasks elicited robust group activations in the amygdalae and sgACC (which changed little on average over scanning sessions), but within-subject reliability was surprisingly low, despite excellent reliability in the control right FFA region. Our findings demonstrate low statistical reliability of two important putative treatment biomarkers in mood and anxiety disorders.

Disrupted habenula function in major depression.

The habenula is a small, evolutionarily conserved brain structure that plays a central role in aversive processing and is hypothesised to be hyperactive in depression, contributing to the generation of symptoms such as anhedonia. However, habenula responses during aversive processing have yet to be reported in individuals with major depressive disorder (MDD). Unmedicated and currently depressed MDD patients (N=25, aged 18-52 years) and healthy volunteers (N=25, aged 19-52 years) completed a passive (Pavlovian) conditioning task with appetitive (monetary gain) and aversive (monetary loss and electric shock) outcomes during high-resolution functional magnetic resonance imaging; data were analysed using computational modelling. Arterial spin labelling was used to index resting-state perfusion and high-resolution anatomical images were used to assess habenula volume. In healthy volunteers, habenula activation increased as conditioned stimuli (CSs) became more strongly associated with electric shocks. This pattern was significantly different in MDD subjects, for whom habenula activation decreased significantly with increasing association between CSs and electric shocks. Individual differences in habenula volume were negatively associated with symptoms of anhedonia across both groups. MDD subjects exhibited abnormal negative task-related (phasic) habenula responses during primary aversive conditioning. The direction of this effect is opposite to that predicted by contemporary theoretical accounts of depression based on findings in animal models. We speculate that the negative habenula responses we observed may result in the loss of the capacity to actively avoid negative cues in MDD, which could lead to excessive negative focus.

Susceptibility of Clostridium difficile isolates from a Phase 2 clinical trial of cadazolid and vancomycin in C. difficile infection.

OBJECTIVES: The aim of this study was to evaluate the susceptibilities of Clostridium difficile isolates to cadazolid, a novel antibiotic for the treatment of C. difficile infection. METHODS: Ribotyping and susceptibilities were determined for C. difficile isolates from a multicentre, double-blind, Phase 2 study of oral cadazolid in patients with C. difficile infection (NCT01222702, ClinicalTrials.gov; EudraCT 2010-020941-29, European Clinical Trials Database). Patients were randomized to receive 250, 500 or 1000 mg of cadazolid twice daily or 125 mg of vancomycin four times daily, for 10 days. MICs of cadazolid, vancomycin, fidaxomicin, linezolid and moxifloxacin were determined at baseline for all patients and post-baseline for patients with clinical failure or recurrence, using the agar dilution method. RESULTS: Seventy-eight of 84 patients had an evaluable toxigenic C. difficile isolate at baseline. The most frequent PCR ribotype was 027 (15.4%). Cadazolid MICs for baseline isolates (including epidemic strain 027) ranged from 0.06 to 0.25 mg/L. Baseline cadazolid MICs were similar to those of fidaxomicin and lower than those of vancomycin, linezolid and moxifloxacin. For each clinical outcome group (clinical cure, clinical failure, sustained clinical response and clinical failure or recurrence), the baseline cadazolid MIC range was 0.06-0.25 mg/L. Mean (min-max) cadazolid faecal concentration (µg/g) on day 5 was 884 (101-2710), 1706 (204-4230) and 3226 (1481-12 600) for the doses 250, 500 and 1000 mg, respectively. CONCLUSIONS: For all cadazolid doses, the faecal concentration was in excess of several thousand-fold the MIC90 for C. difficile. The MIC of cadazolid for all C. difficile isolates, including epidemic strains, was low and in the same narrow range regardless of treatment outcome.

Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle.

The water-soluble prodrug MCB3837 is rapidly converted to MCB3681, active against Gram-positive bacterial species, after intravenous infusion. The aim of this study was to prove the principle that MCB3681 is efficacious in vivo by demonstrating its effect on the resident microflora or colonizers of the human skin, nose, oropharynx and intestine. MCB3837 was infused at a daily dose of 6 mg/kg for 5 days. MCB3681 was active against clostridia, bifidobacteria, lactobacilli, enterococci and Staphylococcus aureus, thus proving the principle that MCB3681 is antibacterially efficacious in vivo without affecting the Gram-negative microflora.

Impact of 2011 French guidelines on antibiotic prescription for acute otitis media in infants.

OBJECTIVE: In 2011, new guidelines on antibiotic prescription for acute otitis media (AOM) were published in France to decrease the use of third generation cephalosporins that promote the carriage of extended-spectrum beta-lactamase producing Escherichia coli. Our objective was to assess the impact of the 2011 French recommendations on the type of antibiotics prescribed for AOM. METHODS: Fourteen thousand six hundred and sixty-one children, 6 to 24 months of age, presenting with AOM were included in 2 studies, between November 1, 2009 and October 31, 2012. The first one was conducted with the support of 62 private practice pediatricians; the second one was conducted in 7 pediatric emergency departments. Three periods of 1 year each were defined. RESULTS: Antibiotics were prescribed in 12,471 (85.1%) of cases of AOM during the study period. Amoxicillin prescriptions was multiplied by 25, between the first year (2.6%) and the last year (66.1%). Conversely, prescriptions of cefpodoxime proxetil and amoxicillin-clavulanic acid decreased from 33.6% and 62.0% in the first year to 5.2% and 27.7% in the last year, respectively. This trend was observed in both private practices and in the pediatric emergency departments. CONCLUSION: Amoxicillin became the most frequently prescribed antibiotic for AOM in 2012, complying with the 2011 French guidelines, while the proportion of prescribed broad-spectrum antibiotics decreased. Our study highlights the importance of guidelines to decrease the prescription of broad-spectrum antibiotics, a crucial factor in the prevention of antibiotic resistance.

Antibiotic resistance patterns of Escherichia coli isolates from different aquatic environmental sources in León, Nicaragua.

Antibiotic-resistant bacteria have emerged due to the selective pressure of antimicrobial use in humans and animals. Water plays an important role in dissemination of these organisms among humans, animals and the environment. We studied the antibiotic resistance patterns among 493 Escherichia coli isolates from different aquatic environmental sources collected from October 2008 to May 2009 in León, Nicaragua. High levels of antibiotic resistance were found in E. coli isolates in hospital sewage water and in eight of 87 well-water samples. Among the resistant isolates from the hospital sewage, ampicillin, chloramphenicol, ciprofloxacin, nalidixic acid, trimethoprim-sulphamethoxazole was the most common multi-resistance profile. Among the resistant isolates from the wells, 19% were resistant to ampicillin, ceftazidime, ceftriaxone, cefotaxime, chloramphenicol, ciprofloxacin, gentamicin, nalidixic acid and trimethoprim-sulphamethoxazole. E. coli producing ESBL and harbouring bla(CTX-M) genes were detected in one of the hospital sewage samples and in 26% of the resistant isolates from the well-water samples. The bla(CTX-M-9) group was more prevalent in E. coli isolates from the hospital sewage samples and the bla(CTX-M-1) group was more prevalent in the well-water samples.

Cellulose and PapG are important for Escherichia coli causing recurrent urinary tract infection in women.

PURPOSE: To identify Escherichia coli factors associated with bacterial persistence in the human urogenital tract using well-defined clinical isolates from women with cystitis. METHODS: E. coli were isolated from women suffering from recurrent cystitis. For comparison, isolates from sporadically infected patients and healthy volunteers were included in the analysis. Samples were taken on three occasions from the urine, periurethra, and vagina. Isolates were typed by pulsed-field gel electrophoresis, and virulence factors were detected by PCR and morphotypic analysis. RESULTS: In all patients, the original E. coli strain was isolated repeatedly and from different regions. The presence of papG coding for a P fimbriae subtype linked to pyelonephritis was associated with strains isolated from patients with recurrent cystitis, including both among urinary and vaginal isolates. The biofilm component cellulose was detected at a higher frequency in urinary isolates from recurrent versus sporadic cystitis. CONCLUSION: The hypothesis of a periurethral/vaginal E. coli reservoir is supported by the results of this study. Our results also indicate an impact of cellulose on E. coli persistence in the human urogenital tract.

Comparative effects of the immediate and the extended release formulations of ciprofloxacin on normal human intestinal microflora.

Ciprofloxacin is a well-known fluoroquinolone, active in vitro against most Gram-negative and Gram-positive bacteria. The purpose of the present study was to evaluate the ecological effects of an orally administered extended-release formulation of ciprofloxacin in comparison with an immediate-release formulation of ciprofloxacin on the normal human intestinal microflora. Thirty-six healthy female subjects were included in the study. the extended-release formulation of ciprofloxacin was given as 500 mg once daily and the immediate-release formulation as 250 mg twice daily. The treatment period was 3 days. the microbiological investigation was blinded with respect to treatment. Mean fecal concentration in the volunteers receiving the extended-release formulation ciprofloxacin was 453 mg/kg and in the immediate-release formulation ciprofloxacin volunteers, the mean fecal concentration was 392 mg/kg. The numbers of Escherichia coli were significantly suppressed while the enterococci decreased moderately in both treatment groups. No toxigenic Clostridium difficile strains were found. No major differences were observed between the two studied formulations on the normal human intestinal microflora.

Antibiotic resistance patterns in gram-negative and gram-positive bacteria causing septicemia in newborns in León, Nicaragua: correlation with environmental samples.

The aim of this study was to identify the bacteria causing neonatal septicemia in a neonatal intensive care unit (NICU) in León, Nicaragua and its relation with bacteria isolated from the environment at the NICU. Our data showed that 74% (34/46) of the bacteria related to newborns with septicemia were Gram-negative and highly resistant to beta-lactams (>85%) and aminoglycosides (80%), leading to treatment failure in 10 neonates with fatal outcome. Although, the prevalence of Gram-positive bacteria (26%) was lower than Gram-negative bacteria, Staphylococcus epidermidis was related to the death of three newborns. No clonal similarity was found among Enterobacter cloacae , Escherichia coli and Serratia liquefaciens isolated from the neonates with septicemia and the NICU environment. However, in order to improve the outcome for neonates with septicemia, infection control practices and appropriate empirical therapy should be considered to reduce the high prevalence of extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria isolated from neonates with septicemia (80%) and from the NICU environment (34%).

Distinct ribotypes and rates of antimicrobial drug resistance in Clostridium difficile from Shanghai and Stockholm.

Seventy-five clinical isolates of Clostridium difficile from Shanghai and 80 from Stockholm were investigated. The prevalence of toxin A-negative, toxin B-positive isolates of C. difficile among isolates from Shanghai (33.3%) was significantly higher than among isolates from Stockholm (0%). Both sets of isolates were fully susceptible to metronidazole and vancomycin. However, the MICs of fluoroquinolones, erythromycin-clindamycin, tetracycline, rifampin and fusidic acid were significantly higher for the Shanghai isolates than for the Stockholm isolates. Thirty-three PCR ribotypes were identified; a dominant clone, 017, accounted for 18.7% of Shanghai isolates, whereas clone 005 dominated among Stockholm isolates, accounting for 11.3%. Strains 027 and 078 were not detected. No outbreak occurred during the study period.

Genetic diversity of community-associated methicillin-resistant Staphylococcus aureus in southern Stockholm, 2000-2005.

This study investigated the molecular epidemiology of 104 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates from southern Stockholm during the period 2000-2005. The isolates were analysed by pulsed-field gel electrophoresis (PFGE), multilocus sequence typing, staphylococcal chromosomal cassette (SCC) mec typing and detection of genes encoding Panton-Valentine leukocidin (PVL). Overall, 28 distinct PFGE patterns and 13 sequence types (STs) were identified. ST80, ST8, ST88 and ST150 were the major CA-MRSA clones in the area, and these accounted for 75% (78/104) of all CA-MRSA isolates. ST150 isolates, which have, to date, been found only in Sweden, were isolated exclusively from a group of homeless individuals. Eighty-six (83%) of the 104 isolates in the study possessed SCCmecIV, found in ten different STs, while 16 isolates possessed SCCmecV. The PVL genes were detected in 56% (58/104) of the isolates. Strain ST80-MRSA-IV carrying PVL genes predominated over the 6-year period and accounted for 38% of all isolates. However, a polyclonal tendency was observed among the CA-MRSA isolates recovered in recent years.

European surveillance study on antimicrobial susceptibility of Gram-positive anaerobic cocci.

Gram-positive anaerobic cocci (GPAC) are a heterogeneous group of microorganisms frequently isolated from local and systemic infections. In this study, the antimicrobial susceptibilities of clinical strains isolated in 10 European countries were investigated. After identification of 299 GPAC to species level, the minimum inhibitory concentrations of penicillin, imipenem, clindamycin, metronidazole, vancomycin and linezolid were determined by the agar dilution method according to the Clinical and Laboratory Standards Institute. The majority of isolates were identified as Finegoldia magna and Parvimonas micra (formerly Peptostreptococcus micros), isolated from skin and soft tissue infections. All isolates were susceptible to imipenem, metronidazole, vancomycin and linezolid. Twenty-one isolates (7%) were resistant to penicillin (n=13) and/or to clindamycin (n=12). Four isolates were resistant to both agents. The majority of resistant isolates were identified as F. magna and originated from blood, abscesses and soft tissue infections.

Emergence of VanD-type vancomycin-resistant Enterococcus faecium in Stockholm, Sweden.

A vancomycin-resistant Enterococcus faecium isolate from the urine of a liver transplant patient in Stockholm was found to contain a vanD gene. The sequence of the vanD PCR product shared 100% identity with the vanD5 allele. The isolate was resistant to a relatively high level of vancomycin (128 mg/L) and a low level of teicoplanin (4 mg/L). This is the first VanD-type vancomycin-resistant E. faecium isolate reported in Sweden. The emergence of this strain reinforces the necessity of infection control efforts to interrupt the spread of these organisms.

Examination of cfiA-mediated carbapenem resistance in Bacteroides fragilis strains from a European antibiotic susceptibility survey.

Of 1284 Bacteroides strains collected in Europe in 2000 for antibiotic susceptibility surveillance, 65 isolates displayed imipenem minimum inhibitory concentrations (MICs) > or =1 mg/L and were chosen for a thorough analysis of their resistance mechanism. Twenty-five of the isolates were positive for the cfiA carbapenem resistance gene. The resistance rates were 0.8% and 1.3% for imipenem and meropenem, respectively. In six of the strains, insertion sequence (IS) elements (IS613, IS614B, IS1186 and IS1187) activated the cfiA gene. However, other strains displayed at least elevated carbapenem MICs or were carbapenem resistant and produced measurable carbapenemase activities but did not harbour IS elements in the region upstream of the cfiA gene. The major determinant of carbapenem resistance in Bacteroides fragilis is production of CfiA metallo-beta-lactamase via activation of the cfiA gene by IS elements (higher level resistance) or by activation of its putative own promoter.

European surveillance study on the antibiotic susceptibility of Propionibacterium acnes.

Propionibacterium acnes strains are recovered from infections linked to surgical procedures, foreign bodies and septicaemia. This study investigated the antibiotic susceptibility patterns of P. acnes isolates from different systemic infections and determined the genomic diversity among resistant P. acnes isolates with low-frequency restriction analysis of chromosomal DNA by pulsed-field gel electrophoresis (PFGE). In total, 304 P. acnes isolates from 13 laboratories in 13 European countries were tested against six antimicrobial agents by the NCCLS reference agar dilution method and the breakpoints recommended by the European Committee on Antimicrobial Susceptibility Testing. Blood isolates were encountered most frequently, followed by those from skin and soft tissue infections, and abdominal infections. Of the isolates examined, 2.6% were resistant to tetracycline, 15.1% to clindamycin, and 17.1% to erythromycin. No resistance was observed to linezolid, benzylpenicillin or vancomycin. There was considerable variation between countries in the proportion of resistant strains, ranging from 83% in Croatia and 60% in Italy to 0% in The Netherlands. Isolates from blood were predominant among the resistant isolates. Seventeen clones and 78 banding patterns were identified among the resistant isolates. It was concluded that antimicrobial resistance has now emerged among P. acnes isolates from systemic infections.

Probiotics and gastrointestinal diseases.

There is increasing evidence indicating health benefits by consumption of foods containing microorganisms, i.e. probiotics. A number of clinical trials have been performed to evaluate the effects in the prevention and treatment of gastrointestinal diseases caused by pathogenic microorganisms or by disturbances in the normal microflora. Gastrointestinal infections caused by Helicobacter pylori, traveller's diarrhoea, rotavirus diarrhoea, antibiotic-associated diarrhoea (AAD) and Clostridium difficile-induced diarrhoea are conditions that have been studied. There are also studies performed on the preventive effect of probiotics on radiation-induced diarrhoea and diarrhoea in tube-fed patients. Inflammatory bowel disease and irritable bowel syndrome, two idiopathic conditions where alterations in the normal microflora have been implicated as responsible for initiation, are two further areas where the use of probiotics has been regarded as promising. The results from clinical studies have not been conclusive in that the effects of probiotics have been strain-dependent and different study designs have been used. Treatment of acute diarrhoea in children and prevention of AAD are the two most justified areas for the application of probiotics.