Sacral Neuromodulation for Refractory Lower Urinary Tract Dysfunction: Results of a Nationwide Registry in Switzerland

OBJECTIVE: To assess the efficacy and safety of sacral neuromodulation (SNM) in patients with refractory lower urinary tract dysfunction in Switzerland based on a nationwide registry. PATIENTS AND METHODS: A total of 209 patients (181 females, 28 males) underwent SNM testing between July 2000 and December 2005 in Switzerland. Subjective symptom improvement, bladder/pain diary variables, adverse events, and their management were prospectively registered. RESULTS: SNM testing was successful (defined as improvement of more than 50% in bladder/pain diary variables) in 102 of 209 patients (49%). An implantable pulse generator (IPG) was placed in 91 patients (89% of all successfully tested and 44% of all tested patients). Of the IPG-implanted patients, 71 had urge incontinence, 13 nonobstructive chronic urinary retention, and 7 chronic pelvic pain syndrome. After a median follow-up of 24 mo, SNM was successful in 64 of the 91 IPG-implanted patients (70%) but failed in 27 patients. SNM was continued in 15 of the 27 patients considered failures, because following troubleshooting SNM response improved subjectively and the patients were satisfied. However, improvement in bladder/pain diary variables remained less than 50%. In the other 12 patients both the leads and the IPG were explanted. During the test phase and during/following IPG implantation, 6% (12 of 209) and 11% (10 of 91) adverse event rates and 1% (3 of 209) and 7% (6 of 91) surgical revision rates were reported, respectively. CONCLUSIONS: SNM is an effective and safe treatment for refractory lower urinary tract dysfunction. Adverse events are usually transient and can be treated effectively.

Evaluation of gastrointestinal permeability and mucosal absorptive capacity in dogs with chronic enteropathy

OBJECTIVE: To assess intestinal mucosal function by measuring permeability and absorptive capacity in dogs with chronic enteropathy (CE) before and after treatment and to determine whether those variables were correlated with clinical disease activity or histologic scoring of intestinal biopsy specimens. ANIMALS: 29 dogs with CE. PROCEDURE: Dogs were designated as having dietresponsive CE or CE requiring glucorticoid treatment. Severity of clinical signs was assessed by calculating the canine inflammatory bowel disease activity index (CIBDAI). Histologic severity of intestinal infiltration was assessed before and after 4 weeks of treatment in the diet-responsive group and before and after 10 weeks of treatment in the glucocorticoid group. Gastrointestinal permeability and mucosal absorptive capacity were assessed by use of intragastric administration of a solution containing lactulose, rhamnose, xylose, 3-O-methylglucose, and sucrose. Urine was collected 6 hours after administration of the sugar solution to determine urinary lactulose-to-rhamnose (L:R), xylose-to-methylglucose (X:M), and sucrose-to-methylglucose (S:M) ratios. RESULTS: Median CIBDAI scores decreased significantly in both groups of dogs after treatment. However, the median histologic grade of intestinal biopsy specimens did not change with treatment in either group. There were no significant differences in L:R, X:M, or S:M ratios after treatment in either group and no significant correlations between L:R, X:M, or S:M ratios and CIBDAI or histologic scores. CONCLUSIONS AND CLINICAL RELEVANCE: Results of tests for intestinal permeability and mucosal absorptive capacity were not useful indicators of clinical disease activity as assessed by the CIBDAI or the sever ity of infiltration as indicated by histologic evaluation.

Nuclear receptor and nuclear receptor target gene messenger ribonucleic acid levels at different sites of the gastrointestinal tract and in liver of healthy dogs

Nuclear receptors (NR) are ligand-activated transcription factors that regulate different metabolic pathways by influencing the expression of target genes. The current study examined mRNA abundance of NR and NR target genes at different sites of the gastrointestinal tract (GIT) and the liver of healthy dogs (Beagles; n = 11). Samples of GIT and liver were collected postmortem and homogenized, total RNA was extracted and reverse transcribed, and gene expression was quantified by real-time reverse-transcription PCR relative to the mean of 3 housekeeping genes (beta-actin, glyceraldehyde-3-phosphate dehydrogenase, and ubi-quitin). Differences were observed (P < or = 0.05) in the mRNA abundance among stomach (St), duodenum (Du), jejunum (Je), ileum (Il), and colon (Col) for NR [pregnane X receptor (Du, Je > Il, Col > St), peroxisome proliferator-associated receptor gamma (St, Du, Col > Je, Il), constitutive androstane receptor (Je, Du > Il, Col), and retinoid x receptor alpha (Du > Il)] and NR target genes [glutathione-S-transferase A3-3 (Du > Je > St, Il; St > Col), phenol-sulfating phenol sulfotransferase 1A1 (Du, Je > Il, St; Col > St), cytochrome P450 3A12 (Du, Je > St, Il, Col), multiple drug resistance gene 1 (Du, Je, Il, Col > St), multiple drug resistance-associated protein 2 (Je, Du > Il > St, Col), multiple drug resistance-associated protein 3 (Col > St > Il; Du > Je, Il; St > Il), NR corepressor 2 (St > Il, Col), and cytochrome P450 reductase (St, Du, Je > Il, Col)], but not for peroxisome proliferator-associated receptor alpha. Differences (P > 0.05) in mRNA abundance in the liver relative to the GIT were also observed. In conclusion, the presence of numerous differences in expression of NR and NR target genes in different parts of the GIT and in liver of healthy dogs may be associated with location-specific functions and regulation of GIT regions.

Nitazoxanide, a broad-spectrum thiazolide anti-infective agent for the treatment of gastrointestinal infections

Colonisation of the gastrointestinal tract by anaerobic bacteria, protozoa, trematodes, cestodes and/or nematodes and other infectious pathogens, including viruses, represents a major cause of morbidity and mortality in Africa, South America and southeast Asia, as well as other parts of the world. Nitazoxanide is a member of the thiazolide class of drugs with a documented broad spectrum of activity against parasites and anaerobic bacteria. Moreover, the drug has recently been reported to have a profound activity against hepatitis C virus infection. In addition, nitazoxanide exhibits anti-inflammatory properties, which have prompted clinical investigations for its use in Crohn's disease. Studies with nitazoxanide derivatives have determined that there must be significantly different mechanisms of action acting on intracellular versus extracellular pathogens. An impressive number of clinical studies have shown that the drug has an excellent bioavailability in the gastrointestinal tract, is fast acting and highly effective against gastrointestinal bacteria, protozoa and helminthes. A recent Phase II study has demonstrated viral response (hepatitis C) to monotherapy, with a low toxicity and an excellent safety profile over 24 weeks of treatment. Pre-clinical studies have indicated that there is a potential for application of this drug against other diseases, not primarily affecting the liver or the gastrointestinal tract.

[Acute lower gastrointestinal bleeding--an evidence-based algorithm for diagnosis and treatment]

Novel means to locate and treat lower gastrointestinal bleeding (lGB) allow to reduce the rate of required surgical interventions and help to limit the extend of resection. The risk stratification of patients with lGB is the primary step of our recommended treatment algorithm. Accordingly, risk stratifying instruments, which are only partly validated up to now, are gaining significance in lGB. Whereas, gastro-duodenoscopy and colonoscopy prior to angiography or scintigraphy are established diagnostic tools, capsule enteroscopy offers a novel approach to hemodynamic stable patients with lGB that are difficult to localize. With its every increasing sensitivity, Angio-Computer Tomography is likely to replace scintigraphy and diagnostic angiography in the very near future. In addition, recent advances in superselective microembolisation have been shown to have the potential rendering surgical interventions in a majority of patients with acute lGB unnecessary. The extend of required surgical resection is largely dependent on the success to localize the bleeding source of prior diagnostics. Only if the source is identified, a limited segmental resection should be performed. Should surgery be required, we suggest to maintain the effort to localize the bleeding, either by prior laparoscopy and/or by intraoperative entero-colonoscopy. Eventually, if the source of bleeding remains unclear total colectomy with ileorectal anastomosis represents the procedure of choice in patients with acute lGB.

International Society on Thrombosis and Haemostasis score for overt disseminated intravascular coagulation predicts organ dysfunction and fatality in sepsis patients

We evaluated the score for disseminated intravascular coagulation (DIC) recently published by the International Society for Thrombosis and Haemostasis (ISTH) in a well-defined series of sepsis patients. Thirty-two patients suffering from severe sepsis and eight patients with septic shock were evaluated following the ISTH DIC score. Fibrin monomer and D-dimer were chosen as fibrin-related markers (FRM), respectively. DIC scores for nonsurvivors (n = 13) as well as for septic shock patients were higher (P < 0.04) compared with survivors and patients with severe sepsis, respectively. Using fibrin monomer and D-dimer, 30 and 25% of patients suffered from overt DIC. Overt DIC was associated with significantly elevated thrombin-antithrombin complexes and plasminogen activator inhibitor type-1 levels as well as with significantly lower factor VII clotting activity. Patients with overt DIC had a significantly higher risk of death and of developing septic shock. Since more than 95% of the sepsis patients had elevated FRM, the DIC score was strongly dependent on prolongation of the prothrombin time and platelet counts. The ISTH DIC score is useful to identify patients with coagulation activation, predicting fatality and disease severity. It mainly depends on the prolongation of the prothrombin time and platelet counts.

[Erectile dysfunction in depression and under treatment with antidepressants -- current treatment options]

Erectile dysfunction (ED) is a common problem in the general population, but also a symptom of both treated and untreated depression. As a side effect of antidepressant medication, erectile dysfunction appears to be one of the principal reasons for discontinuing antidepressant treatment. Avoiding or switching antidepressants is problematic, as this may lead to an increase in depressive symptoms. Our review shows that oral phosphodiesterase inhibitors are an option in treating both ED resulting from depression and from antidepressant medication.

Messenger RNA levels and binding sites of muscarinic acetylcholine receptors in gastrointestinal muscle layers from healthy dairy cows

Acetylcholine interacts with muscarinic receptors (M) to mediate gastrointestinal (GI) smooth muscle contractions. We have compared mRNA levels and binding sites of M(1)to M(5) in muscle tissues from fundus abomasi, pylorus, ileum, cecum, proximal loop of the ascending colon (PLAC), and external loop of the spiral colon (ELSC) of healthy dairy cows. The mRNA levels were measured by quantitative RT-PCR. The inhibition of [(3)H]-QNB (1-quinuclidinyl-[phenyl-4-(3)H]-benzilate) binding by M antagonists [atropine (M(1 - 5)), pirenzepine (M(1)), methoctramine (M(2)), 4-DAMP (M(3)), and tropicamide (M(4))] was used to identify receptors at the functional level. Maximal binding (B(max)) was determined through saturation binding with atropine as a competitor. The mRNA levels of M(1), M(2), M(3), and M(5) represented 0.2, 48, 50, and 1.8%, respectively, of the total M population, whereas mRNA of M(4) was undetectable. The mRNA levels of M(2) and of M(3) in the ileum were lower (P < 0.05) than in other GI locations, which were similar among each other. Atropine, pirenzepine, methoctramine, and 4-DAMP inhibited [(3)H]-QNB binding according to an either low- or high-affinity receptor pattern, whereas tropicamide had no effect on [(3)H]-QNB binding. The [(3)H]-QNB binding was dose-dependent and saturable. B(max) in fundus, pylorus, and PLAC was lower (P < 0.05) than in the ELSC, and in the pylorus lower (P < 0.05) than in the ileum. B(max) and mRNA levels were negatively correlated (r = -0.3; P < 0.05). In conclusion, densities of M are different among GI locations, suggesting variable importance of M for digestive functions along the GI tract.

Mitochondrial neurogastrointestinal encephalomyopathy in three siblings: clinical, genetic and neuroradiological features

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder in which a nuclear mutation of the thymidine phosphorylase (TP) gene causes mitochondrial genomic dysfunction. Patients suffer from gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoparesis, myopathy and polyneuropathy. Magnetic resonance imaging (MRI) shows leukoencephalopathy. We describe clinical, genetic and neuroradiological features of three brothers affected with MNGIE. Clinical examination, laboratory analyses, MRI and magnetic resonance spectroscopy (MRS) of the brain, and genetic analysis have been performed in all six members of the family with the three patients with MNGIE. Two of them are monozygous twins. They all suffered from gastrointestinal dysmotility, cachexia, ophthalmoplegia, muscular atrophies, and polyneuropathy. Urinary thymidine was elevated in the patients related to the severity of clinical disease, and urinary thymidine (normally not detectable) was also found in a heterozygous carrier. Brain MRI showed leukoencephalopathy in all patients; however, their cognitive functioning was normal. Brain MRS demonstrated reduced N-acetylaspartate and choline in severely affected areas. MRI of heterozygous carriers was normal. A new mutation (T92N) in the TP gene was identified. Urinary thymidine is for the first time reported to be detectable in a heterozygous carrier. MRS findings indicate loss of neurons, axons, and glial cells in patients with MNGIE, but not in heterozygous carriers.

Local vascular dysfunction after coronary paclitaxel-eluting stent implantation

BACKGROUND: Paclitaxel-eluting stents (PES) have been shown to reduce the rate of restenosis and the need for repeated revascularization procedures compared with bare metal stents. However, long-term effects of paclitaxel on vascular function are unknown. The purpose of the present study was to assess coronary vasomotor response to exercise after paclitaxel-eluting stent implantation. METHODS: Coronary vasomotion was evaluated by biplane quantitative coronary angiography at rest and during supine bicycle exercise in 27 patients with coronary artery disease. Twelve patients were treated with a bare metal stent (controls), and fifteen patients with a paclitaxel-eluting stent. All patients were restudied 6+/-2 (range 2-12) months after stent implantation. Minimal luminal diameter, stent diameter, proximal, distal and a reference vessel diameter were determined. RESULTS: Reference vessels showed exercise-induced vasodilation in both groups (+20+/-5% controls; +26+/-3% PES group). Vasomotion within the stented vessel segments was abolished. In the controls, the adjacent segments proximal and distal to the stent showed exercise-induced vasodilation (+17+/-3% and +24+/-4%). In contrast, there was exercise-induced vasoconstriction of the proximal and distal vessel segments adjacent to the paclitaxel-eluting stent (-13+/-6% and -18+/-4%; p<0.005). After sublingual nitroglycerin, the proximal and distal vessel segments dilated in both groups. Exercise-induced vasoconstriction adjacent to paclitaxel-eluting stent correlated inversely with the time interval after stent implantation. CONCLUSIONS: Paclitaxel-eluting stent implantation is associated with exercise-induced vasoconstriction in the persistent region suggesting endothelial dysfunction as the underlying mechanism. Improvement of vascular function occurs over time, indicating delayed vascular healing.

Effects of vasopressin on microcirculatory blood flow in the gastrointestinal tract in anesthetized pigs in septic shock

BACKGROUND: Vasopressin increases arterial pressure in septic shock even when alpha-adrenergic agonists fail. The authors studied the effects of vasopressin on microcirculatory blood flow in the entire gastrointestinal tract in anesthetized pigs during early septic shock. METHODS: Thirty-two pigs were intravenously anesthetized, mechanically ventilated, and randomly assigned to one of four groups (n=8 in each; full factorial design). Group S (sepsis) and group SV (sepsis-vasopressin) were made septic by fecal peritonitis. Group C and group V were nonseptic control groups. After 300 min, group V and group SV received intravenous infusion of 0.06 U.kg.h vasopressin. In all groups, cardiac index and superior mesenteric artery flow were measured. Microcirculatory blood flow was recorded with laser Doppler flowmetry in both mucosa and muscularis of the stomach, jejunum, and colon. RESULTS: While vasopressin significantly increased arterial pressure in group SV (P<0.05), superior mesenteric artery flow decreased by 51+/-16% (P<0.05). Systemic and mesenteric oxygen delivery and consumption decreased and oxygen extraction increased in the SV group. Effects on the microcirculation were very heterogeneous; flow decreased in the stomach mucosa (by 23+/-10%; P<0.05), in the stomach muscularis (by 48+/-16%; P<0.05), and in the jejunal mucosa (by 27+/-9%; P<0.05), whereas no significant changes were seen in the colon. CONCLUSION: Vasopressin decreased regional flow in the superior mesenteric artery and microcirculatory blood flow in the upper gastrointestinal tract. This reduction in flow and a concomitant increase in the jejunal mucosa-to-arterial carbon dioxide gap suggest compromised mucosal blood flow in the upper gastrointestinal tract in septic pigs receiving low-dose vasopressin.

Vocal cord dysfunction: dealing with aggressivity

QUESTIONS UNDER STUDY: Vocal cord dysfunction (VCD) is characterised by recurrent attacks of paradoxical adduction of the vocal cords during inspiration, accompanied clinically by dyspnoea attacks with inspiratory stridor lasting between minutes and hours. The aim of the study is to evaluate the self-perception of patients suffering from VCD and how they deal with aggressivity. METHODS: The Giessen Test (GT) and the Picture Frustration Test (PFT) were used on 6 patients with VCD. RESULTS: Five variables show significant differences between the patients with VCD and the values of the normative groups. VCD-patients show an idealized image of themselves, ie relaxed, open, sociable, and capable of devotion. They do not reject accusations against them by others and rarely make self-criticism. In conflicts they behave passively, thus blocking their expression of aggressivity. CONCLUSIONS: In many cases organic disposition and trigger stimuli are thought to be responsible for provoking dyspnoea attacks in VCD. However, the self-perception of patients and their way of dealing with aggressivity strongly suggests that psychosocial factors play a great role in the development of VCD. This requires not only symptom-orientated therapy but also psychological counselling.

Vascular dysfunction and reduced circulating endothelial progenitor cells in young healthy UK South Asian men

OBJECTIVES: The objective of this study was to examine determinants of excess coronary artery disease risk in UK South Asians, more prevalent in this population than UK Caucasians, by examining differences in risk factors, vascular function, and endothelial progenitor cells (EPCs). METHODS AND RESULTS: 24 South Asian and 25 Caucasian healthy age-matched nonsmoking men were studied. Vascular function was assessed by flow-mediated and GTN brachial artery dilatation and blood flow responses to infusion of ACh, SNP, and L-NMMA. EPC number and function were measured by flow cytometry (CD34, CD133, and KDR positive cells), and CFU/migration assays. Traditional risk factors and anthropometric measurements were similar in the groups. South Asians had higher fasting insulin levels (6.01 versus 3.62 microU/mL; P = 0.02). South Asians had lower FMD (6.9 versus 8.5%; P = 0.003), L-NMMA response (0.8 versus 1.3 mL/min/100 mL; P = 0.03), mean SNP response (9.5+/-0.6 versus 11.6+/-0.6; P = 0.02), EPC number (0.046+/-0.005% versus 0.085+/-0.009%; P = < 0.001), and CFU ability (CFU 4.29+/-1.57 versus 18.86+/-4.00; P = 0.005). EPC number was the strongest predictor of FMD. Ethnicity was the strongest predictor of EPC number. CONCLUSIONS: Healthy South Asian men are more insulin resistant, and demonstrate endothelial dysfunction and reduced EPC number and function compared with Caucasians. These abnormalities may contribute to their increased CAD risk.