Region-specific remodeling of the enteric nervous system and enteroendocrine cells in the colon of spinal cord injury patients.

Patients with spinal cord injury (SCI) suffer from major bowel dysfunction, whose exact pathophysiology, particularly the involvement of the enteric nervous system or epithelial dysfunction is poorly understood. Herein, we aimed to characterize the mucosal biopsies of the right and left colon in SCI patients vs controls (CT): (1) remodeling of key enteric neurotransmitters, (2) remodeling of enteroendocrine cells, and (3) mucosal inflammation compared to those in controls. In SCI, mucosal ACh concentration was lower in the right colon as compared to CT, but no change was observed in the left colon, and AChE expression was lower in both the right and left colons than in CT. While the VIP concentration was similar in the right and left colons, VIP mRNA expression was increased in the right colon and decreased in the left colon, in SCI patients as compared to CT. Interestingly, 5-HT concentration was reduced in the left colon but not in the right colon in SCI patients. Moreover, in SCI patients, as compared to CT, SERT mRNA expression was selectively increased in the left colon while TPH1 mRNA expression was increased in the right and left colons. Although mucosal TNFα and IL-1ß mRNA expression did not significantly differ between SCI and CT groups, we identified a significant positive correlation between TNFα and IL-1ß mRNA expression and left colon transit time in the SCI group. In conclusion, region-specific changes occur in the enteric neurotransmitter, serotonergic, and inflammatory pathways in the colon of SCI patients. The significant correlations between these pathways and clinical parameters in the left colon further set a scientific basis for designing therapeutic targets to improve colonic motor dysfunction in patients.Biobank information: Spinal cord injury patients: PHRC ConstiCAPE-clinical trial NCT02566746. Controls: Anosain-clinical trial NCT03054415 and biobank of the "Institut des Maladies de l'Appareil Digestif (IMAD)" registered under number DC-2008-402.

Synthetic Mid-urethral Sling for the Treatment of Urinary Incontinence in Women With Neurogenic Lower Urinary Tract Dysfunction: A Multicentric Retrospective Study.

PURPOSE: We assess the efficacy, safety, and predictive factors for failure of synthetic mid-urethral slings for the treatment of urinary incontinence in a large cohort of women with neurogenic lower urinary tract dysfunction. MATERIALS AND METHODS: Women aged 18 years or older who received a synthetic mid-urethral sling for stress urinary incontinence or mixed urinary incontinence in 3 centers between 2004 and 2019 and who had a neurological disorder were included. Exclusion criteria were less than 1 year of follow-up, concomitant pelvic organ prolapse repair, previous synthetic sling implantation, and no baseline urodynamics. The primary outcome was surgical failure, defined as recurrence of stress urinary incontinence during follow-up. Kaplan-Meier analysis was used to estimate the 5-year failure rate. Adjusted Cox proportional hazard model was used to identify factors associated with surgical failure. Complications and reoperations during the follow-up have also been reported. RESULTS: A total of 115 women with a median age of 53 years were included. The median follow-up duration was 75 months. The 5-year failure rate was 48% (95 CI 46%-57%). Age above 50 years, negative tension-free vaginal tape test and transobturator route were associated with surgical failure. Thirty-six patients (31.3%) underwent at least 1 reoperation for complications or failure, and 2 required definitive intermittent catheterization. CONCLUSIONS: Synthetic mid-urethral slings may be an acceptable alternative to autologous slings or artificial urinary sphincters for the treatment of stress urinary incontinence in a selected group of patients with neurogenic lower urinary tract dysfunction.

Robot-assisted laparoscopic cystectomy with non-continent urinary diversion for neurogenic lower urinary tract dysfunction: Midterm outcomes.

OBJECTIVES: The aim of this study was to assess midterm functional outcomes and complications of robot-assisted laparoscopic cystectomy with non-continent urinary diversion in patients with neurogenic lower urinary tract dysfunction. MATERIALS AND METHODS: We performed a retrospective single center study including all patients who underwent robot-assisted laparoscopic cystectomy with non-continent urinary diversion between January 2008 and December 2018 for neurogenic lower urinary tract dysfunction. Perioperative data, early and late complications, reoperation rate, renal function, and patient satisfaction (PGI-I) were evaluated. RESULTS: One hundred and forty patients were included (70 multiple sclerosis, 37 spinal cord injuries, 33 others) with a median follow-up of 29 months (12-49). The main indication for surgery was an inability to perform intermittent self-catheterization (n = 125, 89%). The early complication rate (<30 days) was 41% (n = 58), including 72% (n = 45) minor complications (Clavien I-II) and 29% (n = 17) major complications (Clavien III-V). Three patients died in the early postoperative period. Late complications appear in 41% (n = 57), with 9% (n = 13) being ureteroileal anastomotic stricture. The overall reintervention rate was 19% (n = 27), mainly for lithiasis surgery. Pre- and postoperative renal function were comparable. Most of patients reported an improvement in their quality of life following their surgery (PGI-I 1-2). CONCLUSION: Robot-assisted laparoscopic cystectomy with non-continent urinary diversion may be of particular interest in patients with neurogenic lower urinary tract dysfunction who are unable to benefit from conservative treatment, as it provides midterm protection of the upper urinary tract and an improvement in quality of life.

Altered epithelial barrier functions in the colon of patients with spina bifida.

Our objectives were to better characterize the colorectal function of patients with Spina Bifida (SB). Patients with SB and healthy volunteers (HVs) completed prospectively a standardized questionnaire, clinical evaluation, rectal barostat, colonoscopy with biopsies and faecal collection. The data from 36 adults with SB (age: 38.8 [34.1-47.2]) were compared with those of 16 HVs (age: 39.0 [31.0-46.5]). Compared to HVs, rectal compliance was lower in patients with SB (p = 0.01), whereas rectal tone was higher (p = 0.0015). Ex vivo paracellular permeability was increased in patients with SB (p = 0.0008) and inversely correlated with rectal compliance (r = - 0.563, p = 0.002). The expression of key tight junction proteins and inflammatory markers was comparable between SB and HVs, except for an increase in Claudin-1 immunoreactivity (p = 0.04) in SB compared to HVs. TGFß1 and GDNF mRNAs were expressed at higher levels in patients with SB (p = 0.02 and p = 0.008). The levels of acetate, propionate and butyrate in faecal samples were reduced (p = 0.04, p = 0.01, and p = 0.02, respectively). Our findings provide evidence that anorectal and epithelial functions are altered in patients with SB. The alterations in these key functions might represent new therapeutic targets, in particular using microbiota-derived approaches.Clinical Trials: NCT02440984 and NCT03054415.

Adherence to long-term medical follow-up: A qualitative, experience-focused study of people with spinal cord injury.

BACKGROUND: Scientific evidence indicates the presence of secondary conditions (such as pressure injuries) after spinal cord injury (SCI). Treatment methods focusing on the management of paraplegia and tetraplegia include systematic preventive follow-up. These advances have significantly improved the functional and vital prognosis of people with SCI, but some people may not have access to these specialized organizations or may not adhere closely to this medicalized vision. We used a narrative approach to explore the perceptions of people with SCI to better understand their adherence to follow-up. OBJECTIVES: We aimed to determine the "common denominators" that lead to adherence or non-adherence to long-term follow-up after SCI. METHODS: People with SCI who had completed their first rehabilitation period for > 1 year were included with regard to 2 variables: 1) an actual medical follow-up or not and 2) a history of pressure injury or not. A review of the literature was used as preparation for semi-directive interviews, which were prospectively analysed by using qualitative analysis software. Thematic saturation was reached at 28 interviews, and 32 interviews were ultimately completed. RESULT: Three main areas concerning participants' perceptions emerged: people's readiness, appropriation and modulation of the systematic follow-up. We developed a broad conceptual framework representing follow-up and the promotion of the long-term health of people with SCI from their perspectives. CONCLUSIONS: The medical environment should ensure that people with SCI are ready to actively consider the implementation of prevention strategies and should take into account their ability to establish their own truth, to integrate various life stages after SCI and to negotiate systematic follow-up. The implementation of data about functioning should be conducted using the concept of the Learning Health System.

The functioning of social support in long-term prevention after spinal cord injury. A qualitative study.

BACKGROUND: The impact of social support on the long-term condition after a spinal cord injury (SCI) varies across studies mainly involving self-report questionnaires. OBJECTIVE: We aimed to establish the common factors associated with social support leading individuals with an SCI to the effective prevention of secondary complications, including via adherence to medical follow-up. METHODS: Inclusion criteria were a history of acquired SCI of any etiology, wheelchair use, and age≥18 years at the time of the study. Participants should have completed their initial rehabilitation program in France≥1 year earlier and were also enrolled according to 2 related study variables: routine medical follow-up (patients were or were not followed up) and the medically supervised reporting of a pressure ulcer after the initial rehabilitation session (0 or≥1 pressure ulcers). We performed a preparatory quantitative and qualitative literature review to identify factors affecting long-term follow-up after SCI, then adopted a narrative design with semi-structured interviews, transcribed and analyzed progressively by using qualitative analysis software. RESULTS: We included 32 participants. We categorized our results based on the knowledge, attitudes, beliefs and practices of participants with respect to pressure ulcer prevention and long-term medical follow-up. Our narrative approach allowed us to identify 3 main domains relevant to social support: reciprocity, self-management and timing related to social support. CONCLUSIONS: Our study showed social support as a dynamic process, a reciprocal phenomenon evolving in variations over time. These findings should be central to short- and long-term therapeutic education programs for patients and for people providing social support. Effective changes should also be implemented through the concept of the Learning Health System.

Analysis of enteric nervous system and intestinal epithelial barrier to predict complications in Hirschsprung's disease.

In Hirschsprung's disease (HSCR), postoperative course remains unpredictable. Our aim was to define predictive factors of the main postoperative complications: obstructive symptoms (OS) and Hirschsprung-associated enterocolitis (HAEC). In this prospective multicentre cohort study, samples of resected bowel were collected at time of surgery in 18 neonates with short-segment HSCR in tertiary care hospitals. OS and HAEC were noted during postoperative follow-up. We assessed the enteric nervous system and the intestinal epithelial barrier (IEB) in ganglionic segments by combining immunohistochemical, proteomic and transcriptomic approaches, with functional ex vivo analysis of motility and para/transcellular permeability. Ten HSCR patients presented postoperative complications (median follow-up 23.5 months): 6 OS, 4 HAEC (2 with OS), 2 diarrhoea (without OS/HAEC). Immunohistochemical analysis showed a significant 41% and 60% decrease in median number of nNOS-IR myenteric neurons per ganglion in HSCR with OS as compared to HSCR with HAEC/diarrhoea (without OS) and HSCR without complications (p = 0.0095; p = 0.002, respectively). Paracellular and transcellular permeability was significantly increased in HSCR with HAEC as compared to HSCR with OS/diarrhoea without HAEC (p = 0.016; p = 0.009) and HSCR without complications (p = 0.029; p = 0.017). This pilot study supports the hypothesis that modulating neuronal phenotype and enhancing IEB permeability may treat or prevent postoperative complications in HSCR.

Enteric Nervous System Remodeling in a Rat Model of Spinal Cord Injury: A Pilot Study.

The physiopathology of digestive disorders in patients with spinal cord injury (SCI) remains largely unknown, particularly the involvement of the enteric nervous system (ENS). We aimed in a rat model of chronic thoracic SCI to characterize (1) changes in the neurochemical coding of enteric neurons and their putative consequences upon neuromuscular response, and (2) the inflammatory response of the colon. Ex vivo motility of proximal and distal colon segments of SCI and control (CT) rats were studied in an organ chamber in response to electrical field stimulation (EFS) and bethanechol. Immunohistochemical analysis of proximal and distal segments was performed using antibodies again Hu, neuronal nitric oxide synthase, (nNOS), and choline acetyltransferase. Colonic content of acetylcholine and acetylcholinesterase was measured; messenger RNA (mRNA) expression of inflammatory cytokines was measured using reverse transcription quantitative polymerase chain reaction (RT-qPCR) approaches. Compared with the CT rats, the contractile response to bethanechol was significantly decreased in the proximal colon of SCI rats but not in the distal colon. The proportion of nNOS immunoreactive (IR) neurons was significantly reduced in the proximal but not distal colon of SCI rats. No change in proportion of choline acetyltransferase (ChAT)-IR was reported; the tissue concentration of acetylcholine was significantly decreased in the proximal colon of SCI rats. The expression of tumor necrosis factor alpha (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) was significantly reduced in the proximal and distal colon of SCI rats. This study demonstrates that functional motor and enteric neuroplastic changes affect preferentially the proximal colon compared with the distal colon. The underlying mechanisms and factors responsible for these changes remain to be discovered.

Management of urethrocutaneous fistulae complicating sacral and perineal pressure ulcer in neurourological patients: A national multicenter study from the French-speaking Neuro-urology Study Group and the Neuro-urology committee of the French Association of Urology.

PURPOSE: To describe the epidemiologic characteristics of urethrocutaneous fistulae (UCF) in sacro-perineal pressure ulcer (SPPU) in neurourological patients and to assess outcomes after surgical urinary diversion. MATERIALS AND METHODS: Through the French-speaking Neurourology Study Group and Association of Urology network, a retrospective multicenter study in nine major urology and physical medicine and rehabilitation (PMR) units was conducted. All patients with SPPU associated with UCF between 2000 and 2016 were included. Data concerning: sociodemography, clinical, medical and biological comorbidities, neurological and urological history, pressure ulcer characteristics, and finally urinary diversion surgery were collected. Complications and SPPU healing/relapse were assessed. RESULTS: In all, 74 patients were included. The median age on diagnosis: 45.9 years (interquartile range [IQR], 38.7-53.4) and median follow-up: 15.1 months (IQR, 5.7-48.8). A psychiatric disorder was the most frequent comorbidity (44.6%). Only 59.5% and 50% had regular PMR and urologic follow-up, respectively. Seventy-one patients (95.9%) underwent urinary diversion surgery. Among those, relapse occurred in 15 (21.1%) at the end of the follow-up. The diversion was noncontinent in 85.9%. The major complications rate was 26.8%. A total of 30 late complications in 21 patients were reported. The most frequent was obstructive pyelonephritis (n = 9). All of the patients who underwent surgical diversion without cystectomy (n = 5) developed a pyocyst. Finally, the pressure ulcer healing rate when patients underwent both urinary diversion and pressure ulcer surgery was 74.4%. CONCLUSIONS: Our retrospective data suggest that UCF complicating SPPU is a rare and severe pathology. The combination of radical urinary diversion with cystectomy and pressure ulcer surgery should be performed as often as possible.

Anterograde colonic irrigations by percutaneous endoscopic caecostomy in refractory colorectal functional disorders.

PURPOSE: In case reports or small studies, percutaneous endoscopic caecostomy (PEC) has been proposed as an alternative to the Malone intervention to perform antegrade colonic enemas. Our goal was to assess the feasibility, efficacy, and tolerance of PEC in a large group of patients with refractory colorectal functional disorders. METHODS: From September 2006 to April 2014, all patients undergoing PEC for constipation, fecal incontinence, and incontinence after rectal resection in two expert centers were studied. The PEC procedure consisted in anchoring the caecum to the abdominal wall (caecopexy) and placing a specifically designed tube in the colonic lumen to perform antegrade enemas. The quality of life (GIQLI), constipation (Kess), and incontinence (Cleveland) scores were assessed before PEC and at 3, 6, 12, and 24 months. RESULTS: A total of 69 patients were included. GIQLI scores were significantly improved in constipation group (n = 43), incontinence group (n = 19), and rectal resection group (n = 10). In the constipation group, Kess score decreased from 25.9 before PEC to 20.6 at 2 years (p = 0.01). In the incontinence and post-rectal resection groups, Cleveland scores decreased from 14.3 before PEC to 2.7 at 6 months (p = 0.01) and to 10.4 at 2 years (p = 0.04). Overall, PEC was considered successful by patients in 58%, 74%, and 90% of cases, in constipation, incontinence, and rectal resection groups, respectively. Chronic pain (52%) at the catheter site was the most frequent complication. CONCLUSIONS: Percutaneous endoscopic caecostomy for antegrade colonic enemas improves significantly the quality of life of patients with colorectal disorder refractory to medical treatment.

Ten years of myocutaneous flaps for pressure ulcers in patients with spinal lesions: Analysis of complications in the framework of a specialised medical-surgical pathway.

INTRODUCTION: The objective of the study is to analyse complications associated with surgery for pelvic pressure ulcers in terms of their frequency, nature and rate of surgical revisions. The secondary aims are to analyse the rate of recurrence, length of stay and time to healing, and to determine factors associated with complications and recurrence. METHODS: It is a single-centre, retrospective cohort study with a 10-year follow-up setting in Nantes University Hospital, France, a specialist centre for spinal cord injury (SCI). All patients who were admitted to the Neurological Physical Medicine and Rehabilitation (PMR) department for surgery (flap coverage) for pelvic pressure ulcers between 1st of January 2004 and 30th September 2014 were included. The main outcome measures were the rate of complications, rate of recurrence, length of stay and time to healing, as well as factors associated with complications and recurrence. RESULTS: One hundred and sixty-six patients underwent 252 flap procedures in 239 operations. The majority of patients had SCI (78.3%). The ulcer sites were mainly ischial (67%), sacral (20%) and trochanteric (12%). Gluteus maximus was used most often (75.3% of flaps) (ischial and sacral ulcers), followed by tensor fascia lata (16.2%) (trochanteric ulcers). The rate of complications that delayed return to wheelchair at 6 weeks was 34.5%. The factors associated with complications were more than one surgical ulcer and drainage time greater than 10 days. The rate of recurrence was 20.04%. The factors related to recurrence were young age, scoliosis and an oblique pelvis. CONCLUSIONS: Management within a specialised medical-surgical pathway limited post-operative complications and recurrences in this sample of subjects who mostly had SCI.

Risk of pressure ulcers in tetraplegic people: a French survey crossing regional experience with a long-term follow-up.

Background: Pressure ulcer risk assessment provides an indicator of quality of care in French health establishments. The reliability and validity of assessment tools have been shown to be lower for people with spinal cord injury (SCI). We hypothesized that skin complications would be less frequent in people with traumatic SCI and tetraplegia (TSCIt), who were initially managed in French regions with a high level of specialized SCI rehabilitation experience. Methods: First, we used the most recent French territorial survey about SCI to determine a 'Level of Regional Experience (LRE) in Specialized Physical Medicine and Rehabilitation'. We then studied the individual variables reported in the Tetrafigap survey (which compiled a cohort of TSCIts people to assess their trajectory and life conditions following their return to community life by questionnaires) using univariate analysis according to these LREs (chi2 test using a significance threshold of P < 0.05). Finally, we performed a series of logistic regressions to determine the link between LREs and pressure ulcers. Results: Management in high-LRE regions was linked with a lower declaration of pressure ulcers during early treatment and in the long term (on average, 8 years post-trauma). Conclusions: Using pressure ulcers as a marker, our study showed the protective element of regional experience in the early management of TSCIts patients. A dilution effect between SCI specialized units and more polyvalent physical medicine and rehabilitation departments should be prevented within each region within the scope of a regional organization that would link referral centres and local health care networks.

Premature senescence of vascular cells is induced by HIV protease inhibitors: implication of prelamin A and reversion by statin.

OBJECTIVE: To determine whether and how protease inhibitors (PIs) could affect vascular aging. METHODS AND RESULTS: HIV therapy with PIs is associated with an increased risk of premature cardiovascular disease. The effect of ritonavir and a combination of lopinavir and ritonavir (for 30 days) on senescence, oxidative stress, and inflammation was evaluated in human coronary artery endothelial cells (HCAECs). These HCAECs were either cotreated or not cotreated with pravastatin or farnesyl transferase inhibitor (FTI)-277 or with 2 antioxidants (manganese [III] tetrakis [4-benzoic acid] porphyrin [MnTBAP] and N-acetyl cysteine). Senescence markers were evaluated in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients under PI treatment. PIs induced senescence markers, prelamin A accumulation, oxidative stress, and inflammation in HCAECs. Senescence markers and prelamin A were also observed in PBMCs from HIV-infected patients under ritonavir-boosted PIs. Pravastatin, FTI-277, and antioxidants improved PI adverse effects in HCAECs. Senescence markers were lower in PBMCs from PI-treated patients cotreated with statins. CONCLUSIONS: PIs triggered premature senescence in endothelial cells by a mechanism involving prelamin A accumulation. Accordingly, circulating cells from HIV-infected patients receiving PI therapy expressed senescence markers and prelamin A. Statin was associated with improved senescence in endothelial cells and patient PBMCs. Thus, PIs might promote vascular senescence in HIV-infected patients; and statins might exert beneficial effects in these patients.

HIV protease inhibitors activate the adipocyte renin angiotensin system.

BACKGROUND: HIV-infected patients under antiretroviral therapy that includes HIV protease inhibitors (PIs) are prone to develop a complex metabolic syndrome including insulin resistance, lipodystrophy and hypertension. Whether hypertension and cardiovascular events could result from the adipocyte renin angiotensin system (RAS) overactivation has never been investigated. METHODS: Primary human adipocytes and 3T3-F442A murine adipocytes were incubated with lopinavir or atazanavir boosted with ritonavir, with or without the angiotensin II type-1 receptor (AT1R) blockers (ARBs), irbesartan or telmisartan, and the peroxysome proliferator-activated receptor-gamma (PPAR-gamma) regulators, rosiglitazone and GW9662. Adipose RAS activation and adipocyte functions were evaluated. RESULTS: The ritonavir-boosted PIs activated the adipose RAS in human and murine adipocytes as shown by the overexpression of AT1R protein, angiotensinogen messenger RNA and the amplified effect of angiotensin II on extracellular signal-regulated kinase 1/2 activity. ARBs prevented the PI effect on RAS activation (AT1R overexpression and signalling) and adipocyte functions (dedifferentiation, insulin resistance, oxidative stress and inflammation). Consistent with a role of PPAR-gamma signalling in PI-induced RAS activation, the PPAR-gamma agonist (rosiglitazone) normalized PI-induced AT1R overexpression and adipocyte dysfunction. Conversely, the PPAR-gamma antagonist (GW9662) induced AT1R overexpression and reduced the beneficial effect of telmisartan on PI toxicity. CONCLUSIONS: We report that two frequently prescribed PI combinations could activate the adipose RAS in cultured cells, in part through a PPAR-gamma-dependant signalling pathway. Our data suggest a role for the adipose RAS in the development of hypertension in HIV-infected patients under PI treatment, and point out the potential use of ARBs to decrease PI adverse effects.