A Structured Training for Trans Anal Irrigation in Pediatric Patients Improves Outcomes and Reduce Failures: Results of an Interventional Multicenter Prospective Study.

BACKGROUND: Continence issues due to organic causes including previous colorectal surgery or neurological issues might benefit from Transanal irrigation (TAI) that proved to be highly effective but with a number of limitations including a relatively high discontinuation rates. Our study was aimed at evaluating the efficacy of an advanced protocol tailored to each patient to prevent dropout and increase satisfaction, independence, and quality of life. MATERIALS AND METHODS: This was a prospective, interventional, multicenter, nonrandomized study involving children aged 4-18 years with bowel dysfunction unresponsive to conventional treatments who required TAI. TAI was performed in accordance to the best standards of care with a total irrigation volume that was determined based on low emission X-Ray barium enemas performed at the very beginning of the study. All patients underwent training and assessments of continence, patients' perspectives and quality of life were performed at different timepoints from enrollment (T0) up to 6 months since TAI was introduced (T3). RESULTS: A total of 78 patients were enrolled. Male to female ratio was 1.4:1. Mean age at enrollment was 106.1 ± 42.8 months. Discontinuation was reported by 3 patients (3.8 %). Continence, satisfaction and a number of other outcome measures increased from baseline (T0) to the last visit (T3). In particular, mean Rintala total score increased linearly from 7.8 to 14.8 during the study period (T0 to T3 timepoints). On a multivariate analysis, the only parameter that proved to be inversely associated with continence as well as with other outcome measures was the use of laxatives at enrollment and during the study. CONCLUSIONS: This study has demonstrated the high efficacy of this innovative patient-tailored TAI protocol across all assessed scores. Of note, given the negative impact of laxatives, our findings suggest limiting their use in this patient population to further increase the efficacy of the procedure.

Prognostic evaluation of biofeedback response in patients treated for anorectal malformation.

PURPOSE: Functional bowel outcome in patients with anorectal malformation often is poor. For fecal incontinence resulting from sphincter dysfunction, biofeedback (BFB) training appears to be effective. The aim of study was to investigate the bowel function in incontinent children treated for ARM, using a clinical score, a manometric and pelvic magnetic resonance evaluation, in order to establish predictive parameters of response after BFB. METHODS: 25 children (median age of 6.5 years) with true fecal incontinence were evaluated by clinical score, anorectal manometry and magnetic resonance imaging (MRI). According to these evaluations patients were divided in 4 groups: group 1 (favorables manometry and MRI); group 2 (favorable manometry and unfavorable MRI); group 3 (unfavorable manometry and favorable MRI); group 4 (unfavorables manometry and MRI). All groups started a cycle of BFB and six months after end of BFB, were reevaluated by clinical score and manometry. RESULTS: The overall response to BFB was excellent in 44%, discrete in 40% and poor in 16%; a better response was found in groups 1 and 2 than groups 3 and 4. The differences between groups before BFB proportionally correlated with values after BFB; a correlation with genitourinary and spinal anomalies was found. CONCLUSIONS: Our results showed that BFB is an effective for fecal incontinence when the assessment pretreatment (functional and morphologic) is favorable; the manometry can evaluate the potential sphincterial recovery after BFB with a further prognostic benefit if correlated to morphologic evaluation with MRI.

Focus on paediatric and adolescent varicocoele: a single institution experience.

The aim of this study was to report our long-term diagnostic and surgical outcome during the last 18 years, in paediatric and adolescent management of varicocoele. The present retrospective study enrols 374 patients observed at our institution between 1994 and 2011. Patients were divided into three groups: Group A includes 142 youngsters and adolescents treated with open surgery for left varicocoele, in which a pre-operative CDUS was not performed; Group B includes 65 patients treated with open surgery in which a pre-operative CDUS evaluation was carried out, to assess varicocoele haemodynamic pattern and testicular volume. Group C includes 167 patients treated by laparoscopy and with pre-operative CDUS assessment. For all groups post-operative follow-up consisted of CDUS evaluation performed 1, 3, 6, 12 months after surgical treatment, than every year. Persistence/recurrence of varicocoele, testicular volume and presence of hydrocele were evaluated. Recurrence rate was significatively higher in group A (11.2%) than B (no recurrence, p = 0.003) or C (no recurrence, p = 0.000). Post-operative hydrocele was not significantly observed overall in group A in 9.8% of cases (13% if tunica vaginalis was left untouched, 4.2% if everted or resected p = 0.005), in group B in 3% and in group C in 7.1% of cases (p = NS). In conclusion, open and laparoscopic surgery offers similar results. In our opinion, the key-point in paediatric and adolescent varicocoele is not the surgical approach to use, but the exact diagnosis. Careful CDUS evaluation is, in our opinion, a valid, safe, cost-effective and immediate tool to accurately detect all refluxing venous system and for achieving a comprehensive evaluation of the vascular anatomy of varicocoele in paediatric and adolescent age. Laparoscopic Palomo or open subinguinal microsurgical varicocelectomy offer similar results in terms of recurrence; meanwhile the use of a lymphatic sparing surgery with or without blue-dye is recommended to reduce post-operative hydroceles.

Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis.

CD4 T cells are important in the protective immune response against tuberculosis. Two mouse models deficient in CD4 T cells were used to examine the mechanism by which these cells participate in protection against Mycobacterium tuberculosis challenge. Transgenic mice deficient in either MHC class II or CD4 molecules demonstrated increased susceptibility to M. tuberculosis, compared with wild-type mice. MHC class II-/- mice were more susceptible than CD4-/- mice, as measured by survival following M. tuberculosis challenge, but the relative resistance of CD4-/- mice did not appear to be due to increased numbers of CD4-8- (double-negative) T cells. Analysis of in vivo IFN-gamma production in the lungs of infected mice revealed that both mutant mouse strains were only transiently impaired in their ability to produce IFN-gamma following infection. At 2 wk postinfection, IFN-gamma production, assessed by RT-PCR and intracellular cytokine staining, in the mutant mice was reduced by >50% compared with that in wild-type mice. However, by 4 wk postinfection, both mutant and wild-type mice had similar levels of IFN-gamma mRNA and protein production. In CD4 T cell-deficient mice, IFN-gamma production was due to CD8 T cells. Thus, the importance of IFN-gamma production by CD4 T cells appears to be early in infection, lending support to the hypothesis that early events in M. tuberculosis infection are crucial determinants of the course of infection.

Dishevelled proteins lead to two signaling pathways. Regulation of LEF-1 and c-Jun N-terminal kinase in mammalian cells.

Dishevelled (Dsh/Dvl) proteins are known to mediate Wnt signaling by up-regulating beta-catenin levels and stimulating T cell factor (TCF)/LEF-1-dependent transcription. We have identified a new Dvl-mediated signaling pathway in that mouse Dvl proteins, when expressed in COS-7 cells, stimulate c-Jun-dependent transcription activity and the kinase activity of the c-Jun N-terminal kinase (JNK). The DEP domain of Dvl1 is essential for JNK activation. By contrast, all three conserved domains of Dvl, including DIX, PDZ, and DEP, are required for up-regulation of beta-catenin and for stimulation of LEF-1-mediated transcription in mammalian cells. Thus, Dvl can lead to two different signaling pathways. Furthermore, the small G proteins of Cdc42 or Rac1, which are involved in JNK activation by many stimuli, do not appear to play a major role in Dvl-mediated JNK activation, because the dominant negative mutants of Cdc42 and Rac1 could not inhibit Dvl-induced JNK activation. This suggests that Dvl may activate JNK via novel pathways.