Changing paradigm of sacral neuromodulation and external anal sphincter repair for faecal incontinence in specialist centres.

AIM: The aim of this study was to determine whether the paradigm of surgical intervention for faecal incontinence (FI) has changed between 2000 and 2013. METHOD: This was a multi-centre retrospective study of patients who had undergone either sacral neuromodulation (SNM) or delayed sphincter repair or sphincteroplasty (SR) as a primary surgical intervention for FI in five centres in Europe and one in the United States. The flow of patients according to the intervention, sustainability of the treatment at a minimum follow-up of 5 years, complications and requirement for further interventions were recorded. RESULTS: A total of 461 patients (median age 56 years, range 24-90 years, 41 men) had either SNM or SR as an index operation during the study period [SNM 284 (61.6%), SR 177 (38.4%)]. Among SNM patients, there were 169 revisional operations (change of battery and/or lead, re-siting or removal). At the time of last follow-up 203 patients (71.4%) continued to use SNM. Among SR patients, 30 (16.9%) had complications, most notably wound infection (22, 12.4%). During follow-up 32 patients (18.1%) crossed over to SNM. Comparing two 4-year periods (2000-2003 and 2007-2010), the proportion of patients operated on who had a circumferential sphincter defect of less than 90° was 48 (68%) and 45 (46%), respectively (P = 0.03), while those who had SNM as the primary intervention increased from 29% to 89% (P < 0.05). CONCLUSION: The paradigm of surgical intervention for FI has changed with increasing use of SNM.

Oncological outcome after hyperthermic isolated limb perfusion for primarily unresectable versus locally recurrent soft tissue sarcoma of extremities.

INTRODUCTION: The management of locally advanced extremity soft tissue sarcomas, particularly in terms of a limb salvage strategy, represents a challenge, especially in recurrent tumors. In the context of a patient-tailored multimodal therapy, hyperthermic isolated limb perfusion (ILP) is a promising limb-saving treatment option. We report the outcome of patients with primarily irresectable and locally recurrent soft tissue sarcoma (STS) treated by ILP. PATIENTS AND METHODS: Data about patient demographics, clinical und histopathological characteristics, tumor response, morbidity and oncological outcome of all patients with STS, who underwent an ILP at our institution in a 10-year period, were retrospectively detected and analyzed. RESULTS: The cohort comprised 30 patients. Two patients were treated with ILP for palliative tumor control, 13 patients because of a local recurrent soft tissue sarcoma (rSTS) and 15 patients because of primarily unresectable soft tissue sarcoma (puSTS). 25 of the 28 patients with curative intention received surgery after ILP (11 pts with rSTS and 14 pts with puSTS). Histopathologically we observed complete response in 6 patients (24%) and partial responses in 19 patients (76%) with a significant better remission in patients with puSTS (p = 0,043). Limb salvage rate was 75%. Mean follow-up was 69 months [range 13-142 months]. Seven (7/11; 64%) patients with rSTS and one (1/14; 7%) patient with puSTS developed local recurrence after ILP and surgery, whereas eight (8/13; 62%) rSTS patients and seven (7/15; 47%) puSTS patients developed distant metastasis. During follow-up, eight patients (28.5%) died of disease (5/13; 38%) rSTS and 3/15 (20%) puSTS. ILP in the group of previously irradiated sarcoma patients (n = 13) resulted in a limb salvage rate of 69% and was not associated in an increased risk for adverse events. DISCUSSION: ILP for advanced extremity STS is a treatment option for both puSTS and rSTS resulting in good local control and should be considered in multimodal management. ILP is also a good option for patients after radiation history.

Effectiveness of sacral nerve stimulation in fecal incontinence after multimodal oncologic treatment for pelvic malignancies: a multicenter study with 2-year follow-up.

BACKGROUND: To assess whether sacral nerve stimulation (SNS) is an effective treatment for severe fecal incontinence (FI) after radiotherapy (RT)/chemoRT (CRT) in combination with pelvic surgery. METHODS: A multicenter study was conducted on patients with FI that developed after multimodal therapy for pelvic tumors and was refractory to non-operative management, who were treated with SNS between November 2009 and November 2012. Data were prospectively collected and retrospectively analyzed. Cleveland Clinic FI score (CCFIS), FI episodes per week, FI Quality of Life (FIQoL), anorectal manometry and pudendal nerve terminal motor latency were evaluated before and after SNS. RESULTS: Eleven patients (seven females, mean age 67.3 ± 4.8 years) were evaluated in the study period. Multimodal treatments included surgery and CRT (four rectal, two cervical and one prostate cancers), surgery and RT (one cervical and two endometrial cancers) and CRT (one anal cancer). The mean radiation dose was 5.3 Gy, and mean interval between the end of RT and onset of FI was 43.7 ± 23 months. Before SNS, the mean CCFIS and the mean number of FI episodes per week were 15.7 ± 2.8 and 12.3 ± 4.2, respectively. At 12-month follow-up, mean CCFIS improved to 3.6 ± 1.8 (p = 0.003) and the mean number of FI episodes decreased to 2.0 ± 1.9 per week (p = 0.003). These results persisted at 24-month follow-up. Significant improvement was also observed for each of the four domains of FIQoL at 12- and 24-month follow-up. Anorectal manometry values did not change significantly at follow-up. CONCLUSIONS: SNS is feasible and may be an effective therapeutic option for FI after multimodal treatment of pelvic malignancies.

Sacral nerve stimulation for faecal incontinence in patients with sacral malformation.

INTRODUCTION: Sacral nerve stimulation (SNS) is a common and effective treatment for faecal incontinence (FI), but accessibility of the sacral nerves is mandatory. In some cases, electrode placement fails for unknown reasons. A frequent cause could be sacral malformations, which have a high incidence (up to 24.1%) and can be unsuspected. METHODS AND RESULTS: We report two patients with FI consequent to congenital anorectal malformation and associated sacral malformation. Despite partial sacral agenesis, SNS was feasible in both. They benefitted greatly from SNS, with an improved ability to postpone the urge up to at least 15 min, reduced incontinence episodes (at least 50%), and significantly better quality of life. CONCLUSION: SNS may be feasible in patients with FI, even in the presence of sacral malformation. However, clinicians should be aware of the attendant technical difficulties. Preoperative imaging, preferably with MRI of the sacrum, is advisable. If the sacral spinal nerves are inaccessible technically, pudendal nerve stimulation could be considered, if anatomy permits.

Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects.

UNLABELLED: ESSENTIALS: It is unknown whether single rivaroxaban doses should best be administered in the morning or evening. Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban. Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations. Evening intake of rivaroxaban better matches the morning hypofibrinolysis. BACKGROUND: A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening. MATERIALS AND METHODS: Sixteen healthy male or female volunteers with a mean age of 26 ± 7 years were included in this randomized, controlled, analyst-blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an anti-activated factor X assay and liquid chromatography-mass spectrometry. MAIN RESULTS: Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL(-1) [95% confidence interval 46.0-67.8] vs. 23.3 ng mL(-1) [19.4-29.1, respectively]). Rivaroxaban intake in the evening reduced morning F1+2 concentrations better at 8:00 AM than did administration on awakening (85 ± 25 nmol L(-1) vs. 106 ± 34 nmol L(-1) , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake. CONCLUSIONS: Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment.

Control of ocular disease in mucous membrane pemphigoid.

BACKGROUND: Mucous membrane pemphigoid is a rare immune-mediated disease. It is characterised by an abnormal binding of immunoglobulins to the basement membrane zone of mucous membranes and the skin. Conjunctival involvement in mucous membrane pemphigoid may lead to cicatrising conjunctivitis and eventually to corneal blindness. The factors that determine mild or progressive disease are not fully understood and need to be clarified. This study examines the features, progression and risk factors of patients with ocular involvement in mucous membrane pemphigoid. METHODS: 36 eyes of 18 patients with the diagnosis of ocular disease associated with MMP were identified. Fornix depth and keratopathy were repeatedly assessed using a standardised protocol to identify progression. MMP was diagnosed based on the characteristic clinical and laboratory features. Endpoints of the study were the incidence of progressive disease and the development of keratopathy with and without systemic immunomodulatory therapy. RESULTS: 12 eyes of 6 patients (33%) showed progressive conjunctival cicatrisation. Obvious progression was observed in 2 patients who had refused systemic treatment at an early stage. 10 eyes showed progression while on systemic treatment. In these patients, however, systemic treatment was started at an advanced stage of the ocular disease. None of the patients receiving systemic treatment developed persistent keratopathy. CONCLUSION: Systemic treatment with diaminodiphenyl sulfone and/or cyclophosphamide allows one to control the further progression of cicatrising conjunctivitis. It prevents keratopathy. To be efficient, however, treatment has to be started at an early stage of the ocular disease.

Characterization of mice with a combined suppression of I(to) and I(K,slow).

Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenuates the slow inactivating outward K(+) current (I(K,slow)), increases action potential duration (APD) and Q-T intervals, and induces spontaneous ventricular arrhythmias. Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current (I(to)) and prolongs APDs and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mice, suggesting that APD and Q-T prolongation are not per se proarrhythmic. To test this hypothesis, the Kv1DN and Kv4DN lines were crossbred to produce animals (Kv1/Kv4DN) expressing both transgenes in an identical genetic background. Whole cell voltage-clamp recordings from left ventricular apex cells confirmed that in Kv1/Kv4DN left ventricular apex cells, both components (fast and slow) of I(to) and the 4-aminopyridine-sensitive component of I(K,slow) are eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, or Kv4DN cells. Telemetric electrocardiogram monitoring (n = 10 mice/group) revealed a significant prolongation of Q-Tc and P-R intervals in Kv1/Kv4DN animals compared with Kv1DN or Kv4DN animals. Spontaneous arrhythmias were observed mainly in Kv1DN mice. Thus the attenuation of fast I(to) in addition to I(K,slow) in Kv1/Kv4DN mice causes significant prolongation of APD and Q-T intervals and attenuation of spontaneous arrhythmias.

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

OBJECTIVE: Current guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered beta-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DESIGN: Prospective comparative study of two groups. SETTING: The intensive care unit and research ward of an university hospital. SUBJECTS: Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers. INTERVENTIONS: To measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 microg/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. CONCLUSION: The results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Inhibition of inducible nitric oxide synthesis by the herbal preparation Padma 28 in macrophage cell line.

Padma 28 is a mixture of herbs used in traditional Tibetan medicine with anti-inflammatory activities. We investigated the effects of Padma 28 on nitric oxide (NO) production by the inducible nitric oxide synthase (iNOS) in lipopolysaccharide stimulated mouse macrophages (RAW 264.7). Padma 28 (0-900 microg/mL) induced a concentration dependent inhibition of inducible nitric oxide synthesis. iNOS protein expression showed a concentration dependent reduction as revealed by immunoblotting when cells were incubated with increasing amounts of Padma 28. Padma 28 decreased iNOS mRNA levels as shown by RT-PCR. Aqueous extracts from costi amari radix (costus root, the dried root of Saussurea lappa) and the outer cover of myrobalani fructus (the dried fruit of Terminalia chebula), constituents of the complex herb preparation Padma 28, were found to inhibit inducible nitric oxide synthesis by decreasing iNOS protein and iNOS mRNA levels. The inhibition of inducible nitric oxide synthesis might contribute to the anti-inflammatory activities of Padma 28.

Visualization and registration of three-dimensional E-field distributions in annual-phased-array applicators.

A testing system is presented allowing registration, digitization, and evaluation of three-dimensional power distributions rendered by annular-phased-array applicators in homogeneous liquid media. The system is based on a lamp phantom originally developed to visualize power distributions. Now the brightness distribution is registered via a charge-coupled device camera and transferred to a PC-based evaluation system outside the shielding room. An appropriate mechanical coupling of camera and sensor matrix probing the phantom was built in order to keep optical image conditions constant under movement. For visualization and evaluation commercially customized software was employed. The evaluation of the system shows the linearity between sensor signal and power density magnitude to be sufficient for evaluation and graphical representation of three-dimensional data sets. In a first practical application the testing system was employed to evaluate dependencies of power distributions as a function of frequency and phase settings on temperatures and, subsequently, the relevance of those results for clinical hyperthermia in a SIGMA-60 applicator (BSD-2000 system). Now, the system is ready to evaluate more complex multiantenna array applicators like the SIGMA-Eye applicator. The measuring system is particularly suitable for a fast comparison of APA applicators applied for a homogeneous medium. Implications for heterogeneous structures (like in patients) are then possible via modeling calculations.

Comparative intravenous toxicity of cisplatin solution and cisplatin encapsulated in long-circulating, pegylated liposomes in cynomolgus monkeys.

The toxicity of cisplatin encapsulated in pegylated, long-circulating liposomes (SPI-077) was compared with nonliposomal cisplatin in male and female cynomolgus monkeys (n = 2-4 per sex per group) treated with intravenous infusions of 2.5 or 25 mg/kg SPI-077, 2.5 mg/kg cisplatin, placebo liposomes, or saline once every 3 weeks for total of five treatments. All animals survived until scheduled necropsy at 3 days after the final treatment or after a treatment-free 4-week recovery period. Emesis occurred after each treatment in all cisplatin-treated monkeys, but only once in one monkey treated with high-dose SPI-077. Dose-related mild decreases in red blood cell (RBC) count, hemoglobin, and hematocrit to or slightly below low normal range occurred in the high-dose SPI-077 and placebo liposome treatment groups after each treatment, with partial to complete recovery between treatments and no signs of correlating bone marrow toxicity. Decreases were similar in cisplatin-treated monkeys, but resolved only slightly between treatments and after the end of treatment (continuing to decrease in females) and were accompanied by bone marrow hypocellularity. Indirect, but not direct, bilirubin levels were cyclically elevated in the high-dose SPI-077 and placebo-treated animals, but not in the other treatment groups. Levels had either fully resolved or were near baseline and/or saline group values prior to the next treatment. Serum cholesterol levels were cyclically increased in SPI-077- and placebo liposome-treated animals, and minimally increased numbers of foam cells were seen in the liver, spleen, kidney, and other organs; both were considered related to the lipid dose administered. Cisplatin-treated monkeys exhibited sensory polyneuropathy and moderate irreversible toxic tubular nephrosis, but no neuropathy or nephrotoxicity was seen in either SPI-077 treatment group. Microscopically, treatment-related cell death was seen in dorsal root ganglia (DRG), affecting 15% of the cells in cisplatin-treated animals, compared to 8 and 12% in the low- and high-dose SPI-077 treatment groups. Neither drug was ototoxic. In summary, repeated administration of SPI-077 produced minimal, reversible effects related to the lipid dose administered, mostly limited to the 25 mg/kg dose group. The most notable effects in this group were cyclical decreases in hematology parameters thought to be related to increased recycling of a small fraction of RBCs and limited cell death in the DRG in the absence of any neurophysiological changes. Animals treated with a 10-fold lower dose of cisplatin (2.5 mg/kg), in contrast, exhibited myelo-, nephro-, and neurotoxicity, including sensory neuropathy, and were emetic after every dose. The SPI-077 liposomal formulation of cisplatin may provide a less toxic alternative to standard cisplatin solution.

Spectrophotometric determination of dehydroascorbic acid in biological samples.

We describe a method for accurately and precisely measuring dehydroascorbic acid in perchloric acid extracts prepared from human plasma, lymphocytes, and mammalian cells. Samples were assayed by spectrophotometrically monitoring the kinetics of the concentration-dependent absorbance changes of dehydroascorbic acid with phosphate-methanol-containing buffers. The lowest detectable dehydroascorbate concentration using this assay is estimated to be below 0.1 mumol/liter. Total analysis time is less than 10 min and allows the simultaneous measurement of numerous samples. The calibration curve is linear (r > 0.995) over the range 0-200 mumol/liter. The dehydroascorbic acid concentrations measured in supplemented samples agree with known concentrations. Interference of ascorbic acid and 2,3-diketogulonic acid with this assay was excluded. The correlation with a highly specific chromatographic procedure gave comparable results over the range of physiologically relevant concentrations. The procedure avoids the most commonly applied method of measuring the native ascorbic acid, then reducing the dehydroascorbic acid, and finally measuring the total ascorbic acid and determining dehydroascorbic acid by the difference. Stabilization of ascorbic acid during assay was achieved by addition of desferrioxamine.

[Video-feedback therapy with the flexible nasopharyngoscope. The potentials for modifying velopharyngeal closure and phonation deficiencies in cleft patients]. / Video-Feedback-Therapie mit dem flexiblen Nasopharyngoskop. Einflussmöglichkeiten auf den velopharyngealen Verschluss und Lautbildungsfehler bei Spaltpatienten.

Psychological interviews with cleft palate patients have revealed why a number of these patients do not profit, or do so only on a limited basis, from conventional speech therapy. They don't control articulation by means of the auditory canal. To treat these patients the video feedback therapy with the nasopharyngoscopy (Witzel et al.) was employed as the initial step. The next step was to expand on this method by establishing indication criteria, necessary diagnostic techniques, and an efficient therapy plan. In this paper a single case study is employed to discuss this method and show the results attained by its use.

Efficient but aberrant cleavage of mitochondrial precursor proteins by the chloroplast stromal processing peptidase.

Cytosol-synthesized chloroplast and mitochondrial precursor proteins are proteolytically processed after import by highly specific, metal-dependent soluble enzymes: the stromal processing peptidase (SPP) and the matrix processing peptidase (MPP), respectively. We have used in vitro processing assays to compare the reaction specificities of highly purified preparations of pea SPP and Neurospora crassa MPP, both of which are unable to cleave a variety of 'foreign' proteins. We show that SPP can cleave all five mitochondrial precursor proteins tested, namely cyclophilin, the beta subunit of the F1-ATPase complex, the Rieske FeS protein, the alpha-MPP subunit and cytochrome b2. In contrast, MPP is unable to cleave any chloroplast precursor proteins tested. Several of the mitochondrial precursor proteins are cleaved more efficiently by SPP than are many authentic chloroplast precursor proteins but, in each case, cleavage takes place at a site or sites which are N-terminal to the authentic MPP site; pre-cyclophilin is cleaved 5 residues upstream of the MPP site and the precursor of the beta subunit of the F1-ATPase complex is cleaved at sites 5 and 12 residues upstream. We discuss the implications of these data for the SPP reaction mechanism.