Ageing with sacral nerve modulation for fecal incontinence: how many patients get benefit after more than 10 years?

Sacral nerve modulation (SNM) has represented a major advancement in the minimally invasive management of patients with fecal incontinence (FI). Although the success rate in the short-medium term has widely been demonstrated, the very long-term outcomes are poorly investigated. This study aims to assess the effectiveness of SNM in a cohort of patients with a follow-up longer than 10 years. Clinical records of patients submitted to SNM for FI in our tertiary referral colorectal Unit between 1998 and 2010 were retrospectively reviewed looking for status of the implantable pulse generator (IPG), follow-up duration, severity of FI by the St Marks' score and quality of life. 58 patients fulfilled the entry criteria and 36 (58%, median follow-up, 12 years) accepted to take part to the telephone interview, while 22 (38%) were lost to the follow-up. Nineteen patients had their IPG removed (Group A) while 17 (27%) had the SNM still active after a median follow-up of 13 years (Group B). In the group A, the median baseline St Marks' score was 13 and did not change after the IPG removal. In group B, the median baseline St Marks' score was 14, at last IPG substitution, it was of 7 and at the last follow-up dropped to 4. In the group A, the median SF-12 physical and mental scores did not change significantly while they improved significantly in group B. A progressive deterioration of the success rate of SNM with the time has been documented after a very long-term follow-up.

Effects of temporary sacral nerve stimulation on gastrointestinal motility and function in patients with chronic refractory slow-transit constipation.

BACKGROUND: The efficacy of sacral nerve stimulation (SNS) on patients with chronic refractory slow-transit constipation is controversial and its mechanism of action on gastrointestinal motility and transit is not fully understood. The aim of this study was to document the effects of temporary SNS on the gastrointestinal and biliary tract motility and on gastrointestinal transit in patients with refractory slow-transit constipation. METHODS: This was a prospective interventional study. Patients with slow-transit chronic constipation, unresponsive to any conservative treatment, were enrolled between January 2013 and December 2018. Patients' quality of life [patient assessment of constipation quality of life (PAC-QOL) questionnaire], constipation scores (Cleveland Clinic Constipation Score) colonic transit time (CTT), orocecal transit time (OCTT), gastric and gallbladder kinetics, together with the assessment of the autonomic nerve function were evaluated before and during temporary SNS. RESULTS: 14 patients (12 females, median age 38 years, range 24-42 years) had temporary SNS. The Cleveland Clinic Constipation Score did not change compared to baseline (23 ± 3 vs 21.4; p = 070). The PAC-QOL did not improve significantly during the stimulation period. Gallbladder/stomach motility (half-emptying time) did not change significantly before and after SNS. OCTT was delayed at baseline, as compared to standard internal normal values, and did not change during SNS. CTT did not improve significantly, although in two patients it decreased substantially from 97 to 53 h, and from 100 to 65 h. CONCLUSIONS: Temporary SNS did not have any effect on upper/lower gastrointestinal motility and transit in patients with severe constipation.

Incidence and treatment of lymphedema in heart transplant patients treated with everolimus.

BACKGROUND: Proliferation signal inhibitors are increasingly used as immunosuppressive drugs in solid organ transplantation. Among their side effects peripheral lymphedema is rarely described in literature. METHODS: All heart transplant patients treated with everolimus (de novo or maintenance) at our center (135 patients: age 50.72±11.1 y, 115 male) were retrospectively analyzed. We considered the incidence of adverse events, particularly the appearance of peripheral edema (13 patients, 9.6%), and the correlation with preoperative characteristics, concomitant medications, other possible causes of edema, as well as all the measures developed for its therapeutic treatment. RESULTS AND CONCLUSIONS: Edema appearance, especially in lower limbs, was considered to be one of the most frequent side effects in heart transplant patients treated with everolimus. In some cases its regression was possible with an adjustment of drug dosages associated with diuretics and lymphatic drainage, but more often a suspension of the drug itself was required for complete regression of the symptoms.

Correlation of susceptibility of Cryptococcus neoformans to amphotericin B with clinical outcome.

Testing of Cryptococcus neoformans for susceptibility to antifungal drugs by standard microtiter methods has not been shown to correlate with clinical outcomes. This report describes a modified quantitative broth macrodilution susceptibility method showing a correlation with both the patient's quantitative biological response in the cerebrospinal fluid (CSF) and the survival of 85 patients treated with amphotericin B (AMB). The Spearman rank correlation between the quantitative in vitro measure of susceptibility and the quantitative measure of the number of organisms in the patient's CSF was 0.37 (P < 0.01; 95% confidence interval [95% CI], 0.20, 0.60) for the first susceptibility test replicate and 0.46 (P < 0.001; 95% CI, 0.21, 0.62) for the second susceptibility test replicate. The median in vitro estimated response (defined as the fungal burden after AMB treatment) at 1.5 mg/liter AMB for patients alive at day 14 was 5 CFU (95% CI, 3, 8), compared to 57 CFU (95% CI, 4, 832) for those who died before day 14. These exploratory results suggest that patients whose isolates show a quantitative in vitro susceptibility response below 10 CFU/ml were more likely to survive beyond day 14.

Factors affecting the outcome of temporary sacral nerve stimulation for faecal incontinence. The value of the new tined lead electrode.

AIM: Sacral nerve stimulation (SNS) is an effective but expensive treatment for faecal incontinence. About 50% of the patients are unresponsive for unknown reasons, hence knowledge of any factors predictive of success would be highly desirable. The aim of this study was to analyse the potential factors associated with a successful outcome of the temporary test of electrostimulation. METHOD: Eighty-five patients with faecal incontinence were tested for SNS. The cause was idiopathic in 45, iatrogenic or obstetric in 28, spinal lesion or neurological diseases in nine and anal malformation in three patients; 43 were tested with a unipolar electrode and 42 with a quadripolar electrode. The severity of faecal incontinence was evaluated using the American Medical System (AMS) score and Wexner's score. RESULTS: A positive response was obtained in 45 patients (53%); 40 (47%) were implanted with a permanent pulse generator. Responders and nonresponders were comparable in age, duration of incontinence, anal manometry, pudendal nerve terminal motor latency and diabetes. Unipolar electrode test (PNE test) was able to elicit positive responses in 18 of 43 (42%) and the quadripolar in 27 of 42 patients (P < 0.001). Type of incontinence and gender did not affect the success rate. Patients with idiopathic incontinence had a significantly higher response rate (P =0.022). Multivariate regression analysis indicated use of a quadripolar electrode as the only independent variable predicting the success of SNS (OR = 5.58, P = 0.009). CONCLUSION: Use of the quadripolar electrode is the only factor significantly related to the success of SNS.

Azithromycin reduces pulmonary fibrosis in a bleomycin mouse model.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease without proper treatment. Despite intensive research, the exact underlying pathogenesis remains elusive. It is regarded as a continuous injury, resulting in inflammation, infiltration, and proliferation of fibroblasts and extracellular matrix deposition, leading to an irreversible restrictive lung function deterioration and death. In this study the effect of azithromycin, a macrolide antibiotic on bleomycin-induced pulmonary fibrosis was investigated. C57BL/6 mice were intratracheally instilled with bleomycin (0.5 mg/kg) or saline. In the bleomycin group, half of the animals received azithromycin every other day from day 1 on. Bronchoalveolar lavage and histology were performed at days 7 and 35, and pulmonary function tests on day 35. At day 35, fibrotic lesions (spindle cell proliferation/collagen I deposition) were paralleled by a restrictive lung function pattern. Alterations were found in neutrophils and macrophages (innate immunity) and in T(H)2, T(H)17, and Treg cytokines (adaptive immunity). Azithromycin significantly reduced both fibrosis and the restrictive lung function pattern. This study demonstrated a beneficial effect of azithromycin on bleomycin-induced pulmonary fibrosis. A possible mechanism could be a modulation of both innate immunity and adaptive immunity. These findings might suggest a potential role for azithromycin in the treatment of IPF.

Fecal incontinence: up to date on pathophysiology and treatment.

This study analyzes the most recent insight into the pathophysiology of fecal incontinence considering each of the factors contributing to the mechanism of fecal continence both during urgency to defecate and in resting state. In fact different types of incontinence are caused by different damage to one or more of these physiologic factors. The second part of the study focuses on the therapeutic choices of fecal incontinence. The recent introduction of sacral nerve electrostimulation and the progressive broadening of its clinical indications is progressively replacing and challenging other traditional surgical techniques because of their disappointing long-term results and because they are much more invasive. An emerging new treatment based on the injection of anal bulking agents is nowadays even more preferred for the less severe cases of fecal incontinence. An increasing number of materials is now proposed by the industry in order to identify the best biocompatible material to be injected trans-anally. Traditional surgery could be reserved for patients non-responding to these new treatments.

Does the choice of treatment influence survival of patients with small hepatocellular carcinoma in compensated cirrhosis?

OBJECTIVE: Untreated patients with small, single hepatocellular carcinoma (HCC) in compensated cirrhosis are characterized by a relatively good prognosis. METHODS: We report the findings generated in a retrospective study on a cohort of 186 consecutive patients with small (< 5 cm) HCC in Child A or B cirrhosis, who were transplanted (four), underwent surgery (15), or were treated with percutaneous ethanol injection (117), lipiodol chemoembolization (44) or best supportive care (six), depending on their clinical features. RESULTS: Overall survival was 26% at 5 years (31% Child A, 20% Child B), with a mean and median survival of 44 and 38 months, respectively. The longest survival was obtained with transplantation and surgery, and the worst with best supportive care. When untreated patients were not considered, no significant differences were observed between the different types of treatment, however, even when patients in the Child A group were considered alone. Almost all the patients who underwent surgery relapsed. No significant difference was observed in relation to the stage of the disease, while alpha-fetoprotein levels were singled out as the only relevant prognostic factor in a multivariate Cox's regression model. Costs per year of life saved were extremely high for transplantation and lowest for ethanol injection, with surgery being less expensive than chemoembolization. CONCLUSIONS: This study confirms that patients with single, small HCC nodules in well compensated cirrhosis should be treated. The choice of type of treatment should be based on the availability of local resources and expertise, and on the patients' preference, after they have been properly informed on the survival, morbidity and mortality related to each treatment option. The relative cost of the procedures should also be considered.

A study of the antidepressant activity of Hypericum perforatum on animal models.

The treatment of non-selected depressed patients with a hydro-alcoholic extract of Hypericum perforatum has been reported to have an efficacy similar to that of classical antidepressants. The effects of H. perforatum on three animal depression models have been studied: (a) an acute form of escape deficit (ED) induced by unavoidable stress; (b) a chronic model of ED, which can be maintained by the administration of mild stressors on alternate days; (c) a model of anhedonia based on the finding that repeated stressors prevent the development of appetitive behavior induced by vanilla sugar in satiated rats fed ad libitum. H. perforatum: (i) acutely protects animals from the sequelae of unavoidable stress; (ii) reverts the chronic escape deficit state maintained by repeated stressors and (iii) preserves the animal's capacity to acquire motivated appetitive behavior. Exposure to chronic stress not only induces escape deficit, but also decreases extraneuronal levels of dopamine in the nucleus accumbens shell; both behavioral and neurochemical effects are reverted by long-term treatment with antidepressants. Three-week treatment with H. perforatum reverted the chronic stress effect on extraneuronal dopamine in the nucleus accumbens. A consistent body of data in the literature suggests that, among the components of H. perforatum extract, hyperforin is the compound (or one of the compounds) responsible for the antidepressant activity. We compared the efficacy of the total extract with the efficacy of hyperforin after p.o. administration. In the acute-escape deficit model, hyperforin showed a potency of about ten times that of the total extract in protecting rats from the sequelae of unavoidable stress. Thus, hyperforin appears to be the most likely active component responsible for the antidepressant activity of H. perforatum.

Correlation between antifungal susceptibilities of Coccidioides immitis in vitro and antifungal treatment with caspofungin in a mouse model.

Caspofungin (Merck Pharmaceuticals) was tested in vitro against 25 clinical isolates of Coccidoides immitis. In vitro susceptibility testing was performed in accordance with the National Committee for Clinical Laboratory Standards document M38-P guidelines. Two C. immitis isolates for which the caspofungin MICs were different were selected for determination of the minimum effective concentration (MEC), and these same strains were used for animal studies. Survival and tissue burdens of the spleens, livers, and lungs were used as antifungal response markers. Mice infected with strain 98-449 (48-h MIC, 8 microg/ml; 48-h MEC, 0.125 microg/ml) showed 100% survival to day 50 when treated with caspofungin at > or =1 mg/kg. Mice infected with strain 98-571 (48-h MIC, 64 microg/ml; 48-h MEC, 0.125 microg/ml) displayed > or =80% survival when the treatment was caspofungin at > or =5 mg/kg. Treatment with caspofungin at 0.5, 1, 5, or 10 mg/kg was effective in reducing the tissue fungal burdens of mice infected with either isolate. When tissue fungal burden study results were compared between strains, caspofungin showed no statistically significant difference in efficacy in the organs of the mice treated with both strains. A better in vitro-in vivo correlation was noted when we used the MEC instead of the MIC as the endpoint for antifungal susceptibility testing. Caspofungin may have a role in the treatment of coccidioidomycosis.

Chilaiditi's syndrome. Successful surgical correction by colopexy.

We describe the case of a patient affected by the Chilaiditi's syndrome, the interposition of the small or large bowel between the inferior face of the diaphragm and the liver, a rare anomaly, often asymptomatic. A 50-year-old man came to our outpatients clinic because of persistent pain in the right abdominal region. Two attempts to perform colonoscopy failed because of the impossibility of passing through the transverse colon. A double contrast enema indicated only sigmoid diverticulitis. Only after abdominal radiography was the abnormal position of the right colon noted. At surgery the right colon was totally intraperitoneal and positioned between the diaphragm and liver, which was smaller than normal. The right colon was repositioned and fixed to the anterior abdominal wall. The postoperative course was uneventful and the right abdominal pain disappeared completely. In conclusion, surgical treatment of Chilaiditi's syndrome may be required in cases of persistent abdominal pain.

Efficacy of SCH56592 in a rabbit model of invasive aspergillosis.

SCH56592 (SCH) was evaluated in an immunosuppressed rabbit model of invasive aspergillosis. SCH was more effective than similar doses of itraconazole and as effective as amphotericin B in the clearance of Aspergillus spp. from tissues. Compared with controls, SCH regimens reduced mortality, improved survival, and significantly reduced tissue colony counts.

Clinical evaluation and microbiology of oropharyngeal infection due to fluconazole-resistant Candida in human immunodeficiency virus-infected patients.

Signs and symptoms of oropharyngeal candidiasis (OPC) were correlated with microbiology and clinical response to fluconazole in a cohort of patients with advanced human immunodeficiency virus (HIV) infection and recurrent OPC. Sixty-four HIV-infected patients with a median CD4 cell count of < 50/mm3 (range, 3-318/mm3) who presented with OPC were enrolled in a longitudinal study. Specimens for cultures were taken weekly until clinical resolution. Therapy with fluconazole was increased weekly as required to a maximum daily dose of 800 mg until resolution of symptoms and oral lesions. Resistant or dose-dependent susceptible yeasts, defined as a minimum inhibitory concentration of > or = 16 micrograms/mL, were detected in 48 (31%) of 155 episodes. Clinical resolution with fluconazole therapy occurred in 107 (100%) of 107 episodes with susceptible yeasts vs. 44 (92%) of 48 episodes with resistant or dose-dependent susceptible strains (P = .008). Patients from whom fluconazole-resistant yeasts were isolated required longer courses of therapy and higher doses of fluconazole for response, but overall, excellent responses to fluconazole were seen in patients with advanced HIV infection.

Evaluation of possible correlations between antifungal susceptibilities of filamentous fungi in vitro and antifungal treatment outcomes in animal infection models.

Nine isolates of filamentous fungi previously tested in 11 different laboratories for their susceptibilities to amphotericin B and itraconazole in vitro were injected intravenously into mice and guinea pigs, and responses to treatment with both agents were studied. The experiments were done in a single laboratory. Mean survival times, the percentages of animals surviving 12 days after infection, and culture results for samples of deep organs obtained postmortem were used as markers of antifungal efficacy. Because of variations in organism pathogenicity, interpretable test systems in vivo could not be established for Fusarium spp. in mice or guinea pigs or for Pseudallescheria boydii in mice, even with the use of immunosuppressive pretreatments. Among the infections that could be evaluated, some degree of response to the corresponding treatment in vivo was seen in animals infected with each of two Rhizopus arrhizus isolates susceptible to amphotericin B at < 0.5 microg/ml and Aspergillus spp. isolates susceptible to itraconazole at < 1.0 microg/ml. Conversely, no responses were apparent with infecting strains for which MICs were > or = 2 microg/ml (amphotericin B) or > or = 1 microg/ml (itraconazole). However, the limitations of the intravenous challenge systems studied mean that no firm conclusion relating MICs in vitro to the lowest effective doses in vivo could be drawn.

Do in vitro susceptibility data predict the microbiologic response to amphotericin B? Results of a prospective study of patients with Candida fungemia.

Outcome for 105 patients with candidemia treated with amphotericin B was correlated with amphotericin B in vitro susceptibility results. Thirty-three patients had microbiologic failure, which was defined as persistence of Candida in the bloodstream despite > or = 3 days of amphotericin B. Amphotericin B minimum inhibitory concentrations (MICs) were determined by the National Committee for Clinical Laboratory Standards methodology. After determination of MICs, the minimal lethal concentrations (MLCs) were determined. The isolates tested yielded a narrow range of amphotericin B MICs (0.06-2 microg/mL); only 5% (5/105) exhibited MICs > or = 1 microg/mL. The MLC range, on the other hand, was significantly broader (0.125 to > 16 microg/mL); 24% (25/105) exhibited MLCs > or = 1 microg/mL. The strongest predictor for microbiologic failure was 48-h MLC (P < .001), followed by 24-h MLC (P = .03) and 48-h MIC (P = .11). A resistant break point for amphotericin B of > 1 microg/mL for MLC and > or = 1 microg/mL for MIC could be inferred from this study.

Treatment of histoplasmosis with MK-991 (L-743,872).

BALB/c nu/+ immunocompetent and athymic (nu/nu) mice were infected intravenously with yeast cells of Histoplasma capsulatum. Mice were either given water (controls) intraperitoneally (i.p.) or given MK-991 i.p. once daily or twice daily. Protection was measured as prolonged survival or reduction in tissue counts. MK-991 was protective in immunocompetent mice, prolonging survival and reducing counts in spleen and livers at a dose as low as 0.05 mg/kg of body weight/day. MK-991 was modestly effective in athymic mice at a higher dose, 5 mg/kg/day. These studies suggest that MK-991 may be appropriate for clinical development in histoplasmosis.

Treatment of murine Candida krusei or Candida glabrata infection with L-743,872.

L-743,872 is a broad-spectrum pneumocandin antifungal drug developed by Merck Research Co., and in the present work it was evaluated in vivo in murine models of Candida krusei and Candida glabrata infection. Mice were infected intravenously with two isolates of C. krusei and treated with fluconazole or L-743,872. Fluconazole was beneficial only in immune-competent mice infected with isolate 94-2696. At > 0.5 mg/kg of body weight/day, L-743,872 was effective against both infecting isolates in immune-competent and immune-suppressed mice. Against C. glabrata, L-743,872 was effective, at doses > or = 0.5 mg/kg, in reducing fungal cell counts in the kidneys but not in the spleen. L-743,872 has significant potential for clinical development.

Discrepancy between in vitro and in vivo antifungal activity of albendazole.

Albendazole has in vitro activity against Cryptococcus neoformans and reduced in vitro activity for albendazole when compared with Candida albicans. The major metabolite of albendazole, albendazole sulphoxide showed no in vitro activity against isolates of either fungus. Immunocompetent mice infected intravenously (i.v.) with C. albicans were treated with albendazole doses of 20-600 mg kg-1 per day in noble agar or sesame oil for per oral (PO) administration, or 80 mg kg-1 per day in DMSO for intraperitoneal (i.p.) and i.v. administration for 10 days, and were observed for survival. Mice infected with C. neoformans intracranially received albendazole in daily doses of 600 mg kg-1 prepared in DMSO (i.p.) or peanut butter/rat chow (PO) for 10 days and were observed for survival. Mortality was not different between the treated and control animals in any study. Plasma samples from uninfected mice dosed with similar formulations and doses of albendazole were analysed by HPLC for albendazole and albendazole sulphoxide. No albendazole could be detected in any sample, while concentrations of albendazole sulphoxide (286-8697 ng ml-1) were observed in all samples. These data suggest that the absence of in vivo activity for albendazole is due to rapid conversion to the inactive albendazole sulphoxide metabolite.

Invasive Nattrassia mangiferae infections: case report, literature review, and therapeutic and taxonomic appraisal.

We report on a case of subcutaneous infection of the arm caused by the coelomycetous fungus Nattrassia mangiferae (formerly Hendersonula toruloidea) in a steroid-dependent diabetic man with chronic obstructive lung disease. The man was a resident of Arizona, where the fungus is known to be endemic on Eucalyptus camaldulensis and on citrus trees. Diagnosis of fungal infection was made by observation of narrow hyphal filaments by histopathology of biopsy specimens and isolation of a fast-growing black mold which demonstrated hyphae and arthroconidia of varying widths typical of the Scytalidium synanamorph (S. dimidiatum). The formation of pycnidia, which at maturity expressed conidia with a central median dark band, allowed for the confirmation of the isolate as N. mangiferae. Remission of the lesions occurred following intravenous therapy with amphotericin B, followed by topical clotrimazole treatment. We use this patient's case report as an opportunity to review the literature on cases of deep infection caused by Scytalidium species, to evaluate the antifungal susceptibilities of a spectrum of Scytalidium isolates, and to review the taxonomy of Scytalidium species isolated from human infections.

Electrostimulated gracilis neosphincter for faecal incontinence and in total anorectal reconstruction: still an experimental procedure?

The possibility of converting an easily fatiguable muscle like the gracilis muscle into a fatigue-resistant one using chronic electrostimulation has renewed interest in Pickrell's procedure. Between July 1991 and June 1996, 9 patients (2 M; 7 F) mean age = 45 y (range 14-72) underwent dynamic graciloplasty using Medtronic electrostimulators. Five patients had faecal incontinence (2 congenitally anomaly, 1 neurological, 2 post-operative) and 4 had a perineal colostomy performed either simultaneously (two cases) or at 3 to 4 years after abdominoperineal excision of the rectum. Early post-operative complications included distal tendon necrosis [1], perineal colostomy breakdown [1], detachment of the gracilis tendon [2] and seroma in the thigh [1]. Long-term complications included rectocele with faecal impaction in one patient with imperforate anus, anal stricture in one patient who had refashioning of a perineal colostomy, and displacement of the lead from the main nerve in 3 with external expulsion in 2. The patient with anal stricture was successfully treated with anoplasty but subsequently returned to an abdominal colostomy due to stricture recurrence 2 years later. The rectocele was successfully treated using a transvaginal approach. Electrical conversion of the muscle was completed in all patients but long term functional results are available for only 5 cases. Manometry revealed a significant improvement in anal pressure under electro-stimulation and the continence grading scale score significantly improved in 4 patients. The technique is applicable to a very selected group of patients with no other options but is still in the experimental phase and should not be performed outside controlled trials. Repeated hospitalisation and reoperations are often required although the complication rate may diminish and improve with experience.