Abnormal P600 in obsessive-compulsive disorder. A comparison with healthy controls

Recently, the P600 component of the event-related potential (ERP), a waveform that is thought to be generated and/or modulated by the anterior cingulate gyrus and basal ganglia has been considered as an index of second pass-parsing processes of information processing, having much in common with working memory (WM) operation. Moreover, dysfunction of these brain structures as well as WM deficits have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). The present study is focused on P600 elicited during a WM test in OCD patients compared with healthy controls. Twenty drug-free OCD patients and an equal number of normal subjects matched for age, sex and educational level were studied via a computerized version of the Wechsler digit span test. Auditory P600 was measured during the anticipatory period of this test. The patient group, as compared with healthy controls, showed significantly enhanced amplitudes of P600 at the right temporoparietal area and prolonged latencies at the right parietal region. Moreover, the memory performance of patients was significantly impaired. These findings may indicate that OCD patients manifest abnormal aspects of second pass-parsing processes of information processing as they are reflected by P600 amplitudes and latencies.     

Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor.

Human infants are relatively resistant to Clostridium difficile-associated diarrhea and colitis compared to adults. In that toxin A is the major cause of intestinal damage with this organism, we compared toxin A receptor binding and biological effects in newborn vs adult rabbit ileum. Purified toxin A (M(r) 308 kD) was labeled with tritium or biotin with full retention of biologic activity. Appearance of specific toxin A brush border (BB) binding was strongly age dependent with minimal [3H]toxin A specific binding at 2 and 5 d of life, followed by gradual increase in binding to reach adult levels at 90 d. Absence of toxin A binding sites in newborn and presence in adult rabbits was confirmed by immunohistochemical studies using biotinylated toxin A. Toxin A (50 ng to 20 micrograms/ml) inhibited protein synthesis in 90-d-old rabbit ileal loops in a dose-dependent fashion. In contrast, inhibition of protein synthesis in 5-d-old rabbit ileum occurred only at the highest toxin A doses (5 and 20 micrograms/ml) and at all doses tested was significantly less than the adult rabbit ileum. In addition, toxin A (5 micrograms/ml) caused severe mucosal damage in adult rabbit ileal explants but had no discernable morphologic effect on 5-d-old rabbit intestine. Our data indicate that newborn rabbit intestine lacks BB receptors for toxin A. The absence of the high-affinity BB receptor for toxin A in the newborn period may explain lack of biologic responsiveness to purified toxin, and the absence of disease in human infants infected with this pathogen.     

Effect of handedness on the Stroop Colour Word Task

Handedness is associated with cerebral organisation, but its relationship with cognition remains unclear. Since the Stroop task is believed to measure aspects of executive control, this study aims to investigate the effect of handedness on Stroop interference. We used the Stroop task with 90 young adults with university education, of whom 47 (23 males) were right-handed and 43 (21 males) were left-handed. Main dependent variables were Stroop baseline (SB), Stroop incongruent (SI), and the proportional derivative Stroop reduction (SR) [SR=(SB ? SI)/SB×100%] (Bugg, Delosh, Davalos, & Davis, 2007; Graf, Uttl, &Tuokko, 1995) scores. The analysis revealed that SI is significantly affected by both handedness and the interaction of sex×handedness, whereas SR is only affected by handedness. After controlling for the effect of SB on SI, only the effect of handedness remained statistically significant [F(1, 83) = 6.44, p=.013]. Post-hoc comparisons showed that left-handed females performed significantly better than right-handed females on both SI (p=.003) and SR (p=.007). The data suggest that handedness is associated with cognitive function alterations, which lead to a smaller Stroop interference of left-handers irrespectively of sex, an effect that is more pronounced in the female subpopulation.     

Rifalazil treats and prevents relapse of clostridium difficile-associated diarrhea in hamsters

Although vancomycin and metronidazole effectively treat Clostridium difficile-associated diarrhea and colitis (CDAD), their use is associated with a high incidence of relapsing C. difficile infection. Rifalazil is a new benzoxazinorifamycin that possesses activity against Mycobacterium tuberculosis and gram-positive bacteria. Here we compared rifalazil and vancomycin for effectiveness in preventing or treating clindamycin-induced cecitis in a hamster model of CDAD. Golden Syrian hamsters were injected subcutaneously with clindamycin phosphate (10 mg/kg), followed 24 h later by C. difficile gavage. Hamsters received by gavage for 5 days vehicle, vancomycin (50 mg/kg), or rifalazil (20 mg/kg) either simultaneously with (prophylactic protocol) or 24 h after C. difficile administration (treatment protocol). While all vehicle-administered animals became moribund within 48 h of C. difficile administration, no rifalazil- or vancomycin-treated animals in either protocol showed signs of morbidity after 7 days. Ceca of rifalazil-treated animals showed absence of epithelial cell damage, significantly reduced congestion and edema, and less, but not statistically significantly less, neutrophil infiltration compared to those of vehicle-treated animals. In contrast, vancomycin-treated animals demonstrated severe epithelial cell damage and mildly reduced congestion and edema. Moreover, hamsters relapsed and tested C. difficile toxin positive (by enzyme-linked immunosorbent assay) 10 to 15 days after discontinuation of vancomycin treatment. None of the rifalazil-treated hamsters showed signs of disease or presence of toxins in their feces 30 days after discontinuation of treatment. Our results indicate that once daily rifalazil may be superior to vancomycin for curative treatment of CDAD.     

Fidaxomicin Inhibits Clostridium difficile Toxin A-Mediated Enteritis in the Mouse Ileum

Clostridium difficile infection (CDI) is a common, debilitating infection with high morbidity and mortality. C. difficile causes diarrhea and intestinal inflammation by releasing two toxins, toxin A and toxin B. The macrolide antibiotic fidaxomicin was recently shown to be effective in treating CDI, and its beneficial effect was associated with fewer recurrent infections in CDI patients. Since other macrolides possess anti-inflammatory properties, we examined the possibility that fidaxomicin alters C. difficile toxin A-induced ileal inflammation in mice. The ileal loops of anesthetized mice were injected with fidaxomicin (5, 10, or 20 μM), and after 30 min, the loops were injected with purified C. difficile toxin A or phosphate-buffered saline alone. Four hours after toxin A administration, ileal tissues were processed for histological evaluation (epithelial cell damage, neutrophil infiltration, congestion, and edema) and cytokine measurements. C. difficile toxin A caused histologic damage, evidenced by increased mean histologic score and ileal interleukin-1β (IL-1β) protein and mRNA expression. Treatment with fidaxomicin (20 μM) or its primary metabolite, OP-1118 (120 μM), significantly inhibited toxin A-mediated histologic damage and reduced the mean histology score and ileal IL-1β protein and mRNA expression. Both fidaxomicin and OP-1118 reduced toxin A-induced cell rounding in human colonic CCD-18Co fibroblasts. Treatment of ileal loops with vancomycin (20 μM) and metronidazole (20 μM) did not alter toxin A-induced histologic damage and IL-1β protein expression. In addition to its well known antibacterial effects against C. difficile, fidaxomicin may possess anti-inflammatory activity directed against the intestinal effects of C. difficile toxins.     

Hepatopancreatoduodenectomy for metastatic duodenal gastrointestinal stromal tumor

BACKGROUND: Duodenal gastrointestinal stromal tumors, which are rare, comprise 3%-5% of all gastrointestinal stromai tumors. We present a case of a metastatic duodenal gastrointestinal stromal tumor that was successfully treated by simultaneous tight hemihepatectomy and pancreaticoduodenectomy. METHODS: A 50-year-old woman was admitted to our department for the treatment of a possible metastatic duodenal gastrointestinal stromal tumor (GIST). At laparotomy a large duodenal tumor was found displacing the head of the pancreas. A 3 cm in diameter lesion in the posterior aspect of segment Ⅷ of the liver was also noted. Simultaneous right hepatectomy and pancreaticoduodenectomy were performed. RESULTS: Histological examination revealed a high grade metastatic duodenal GIST strongly positive for c-kit, CD34, and vimentin. The patient had no additional therapy. A follow-up of 21 months showed that the patient is very well and there is no evidence of recurrent diseases. CONCLUSIONS: Malignant stromai tumors of the duodenum are rarely encountered. They are usually slow growing, and may be amenable to curative surgery, even after occurrence of metastases. Resection of localized liver metastasis is still advocated when feasible, since imatinib does not provide a complete or long-term response. Combined surgical resection is an efficacious treatment for patients with metastatic duodenal gastrointestinal stromal tumor.     

Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea

BACKGROUND & AIMS: Recurrent C difficile -associated diarrhea (CDAD) is associated with a lack of protective immunity to C difficile toxins. A parenteral C difficile vaccine containing toxoid A and toxoid B was reported previously to be safe and immunogenic in healthy volunteers. Our aim was to examine whether the vaccine is also well tolerated and immunogenic in patients with recurrent CDAD. METHODS: Subjects received 4, 50-microg intramuscular inoculations of the C difficile vaccine over an 8-week period. Serum antitoxin antibodies were measured by ELISA, and toxin neutralizing activity was evaluated using the tissue culture cytotoxin assay. RESULTS: Three patients with multiple episodes of recurrent CDAD were vaccinated. Two of the 3 showed an increase in serum IgG antitoxin A antibodies (3-fold and 4-fold increases, respectively) and in serum IgG antitoxin B antibodies (52-fold and 20-fold, respectively). Both also developed cytotoxin neutralizing activity against toxin A and toxin B. Prior to vaccination, the subjects had required nearly continuous treatment with oral vancomycin for 7, 9, and 22 months, respectively, to treat recurrent episodes of CDAD. After vaccination, all 3 subjects discontinued treatment with oral vancomycin without any further recurrence. CONCLUSIONS: A C difficile toxoid vaccine induced immune responses to toxins A and B in patients with CDAD and was associated with resolution of recurrent diarrhea. The results of this study support the feasibility of active vaccination against C difficile and its toxins in high-risk individuals but must be validated in larger, randomized, controlled trials.