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Byline: O. Uludag (1), P. Rieu (1), M. Niessen (2), A. Voss (2) Keywords: Key words Surgical site infection; Surveillance; Pediatric; Postoperative wound infection Abstract: During a 3-month period 259 pediatric surgical procedures in 236 patients were followed for the development of surgical site infections (SSI): 17 sites became infected, an overall infection rate of 6.6%. The incidence in our study was therefore higher than expected. As expected, the infection rate increased according to wound contamination: dirty sites had a SSI rate of 30%. Emergency procedures, operation duration over 1h, and inpatients showed a statistically significant higher risk of developing SSI. Although there were differences between males and females, individual surgeons, and the use of antibiotic prophylaxis, these differences were not statistically significant. Author Affiliation: (1) Department of Pediatric Surgery, University Hospital St Radboud P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, NL (2) Department of Medical Microbiology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, NL Article note: Accepted: 8 November 1999

Purpose of Review: Amyloid A (AA) amyloidosis is an organ- or life-threatening complication of chronic inflammatory disorders. Here, we review the epidemiology, causes, pathogenesis, clinical features, and diagnostic and therapeutic strategies of AA amyloidosis., Recent Findings: The incidence of AA amyloidosis has declined due to better treatment of the underlying diseases. Histopathological examination is the gold standard of diagnosis, but magnetic resonance imaging can be used to detect cardiac involvement. There is yet no treatment option for the clearance of amyloid fibril deposits; therefore, the management strategy primarily aims to reduce serum amyloid A protein. Anti-inflammatory biologic agents have drastically expanded our therapeutic armamentarium. Kidney transplantation is preferred in patients with kidney failure, and the recurrence of amyloidosis in the allograft has become rare as transplant recipients have started to benefit from the new agents. The management of AA amyloidosis has been considerably changed over the recent years due to the novel therapeutic options aiming to control inflammatory activity. New agents capable of clearing amyloid deposits from the tissues are still needed., (© 2024. The Author(s).)

Background: Alzheimer's Disease (AD) represents a neurodegenerative disorder characterized by cognitive and behavioral impairments significantly hindering social and occupational functioning. Melatonin, a hormone pivotal in regulating the body's intrinsic circadian rhythm, also acts as a catalyst in the breakdown of beta-amyloid deposits, offering a promising therapeutic approach for AD. The upregulation of Brain and Muscle ARNT-Like 1 (Bmal1) gene expression, stimulated by melatonin, emerges as a potential contributor to AD intervention. Current pharmacological interventions, such as FDA-approved cholinesterase inhibitors and the recently authorized monoclonal antibody, Lecanemab, are utilized in AD management. However, the connection between these medications and Bmal1 remains insufficiently explored., Objective: This study aims to investigate the molecular effects of FDA-endorsed drugs on the CLOCK: Bmal1 dimer. Furthermore, considering the interactions between melatonin and Bmal1, this research explores the potential synergistic efficacy of combining these pharmaceutical agents with melatonin for AD treatment., Methods: Using molecular docking and MM/PBSA methodologies, this research determines the binding affinities of drugs within the Bmal1 binding site, constructing interaction profiles., Results: The findings reveal that, among FDA-approved drugs, galanthamine and donepezil demonstrate notably similar binding energy values to melatonin, interacting within the Bmal1 binding site through analogous amino acid residues and functional groups., Conclusion: A novel therapeutic approach emerges, suggesting the combination of melatonin with Lecanemab as a monoclonal antibody therapy. Importantly, prior research has not explored the effects of FDA-approved drugs on Bmal1 expression or their potential for synergistic effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background/aim: Epidural fibrosis is one of the problems that can be seen after spinal surgery. The aim of this study was to investigate the possible preventive role of medical ozone (O) treatment on epidural fibrosis., Materials and Methods: Twenty-four Sprague Dawley rats were randomly split into four groups: control (C), O, laminectomy (L), and L+O groups. Animals in the C group were sacrificed at the beginning of the experiment. The L and L+O groups had L procedure, while O treatment was supplied for the O and O+L groups. After 42 days of follow-up, for histological evaluation and biochemical measurements, the ratio of epidural fibrosis and catalase (CAT) with malondialdehyde (MDA) levels in serum, respectively, were analyzed in terms of statistical differences., Results: Histologically, a distinct difference was o bserved in the epidural space after O treatment. A significant difference in epidural fibrosis areas is found to be between the O, L, and O+L groups (P < 0,0001). There was no statistically significant difference between CAT and MDA levels that were obtained by spectrophotometric analysis., Conclusion: Histological results suggest that medical O treatment after L can be used as an alternative method to prevent epidural fibrosis. Further studies with wide cohorts and interval measures are required to detail the effects of doses., Competing Interests: None

Objectives: Prophylactic acid suppression with proton pump inhibitors or H2 receptor antagonists is often administered after kidney transplantation. The Association of proton pump inhibitors or H2 receptor antagonists with acute rejection, hypomagnesemia, and graft loss in kidney transplant recipients is not well established., Material and Methods: We performed a retrospective cohort study of 302 kidney transplant recipients at one center (57% male; mean age 35.5±11.2 years) with more than 6 months post-transplant follow-up. Recipients were grouped according to gastric acid prophylaxis: only proton pump inhibitors (n=179), only H2 receptor antagonists (n=42), proton pump inhibitors and H2 receptor antagonists (n=55), and nonusers (n=26). The primary outcome was biopsy-proven acute rejection. Graft loss and hypomagnesemia were defined as secondary outcomes., Results: Nonusers were younger and mostly under steroid-free immunosuppression compared to other study groups (p=0.030 and p=0.009, respectively). The primary outcome was similar across study groups (p=0.266). Kaplan-Meier analyses also demonstrated similar 10-year graft survival rates: 95.5% for proton pump inhibitors, 97.6% for H2 receptor antagonists, 100% for proton pump inhibitors/H2 receptor antagonists, and 96.2% for nonusers (p=0.275)., Conclusions: The use of proton pump inhibitors is not associated with acute rejection or graft loss but may cause mild hypomagnesemia in kidney transplant recipients.

Objective: To evaluate whether the perfusion index (PI) can be used to predict and provide a cut-off value for ultrasound-guided axillary nerve block success., Study Design: Quasi-experimental study., Place and Duration of Study: Department of Anaesthesiology and Reanimation, Adiyaman University Training and Research Hospital, Adiyaman, Turkey, from July to August 2020., Methodology: Fifty patients between the ages of 18 and 65 years, who were in the ASA 1-2 group, undergoing hand, wrist and forearm surgery, were included in the study. PI value was measured from the extremity to the block and the healthy extremity before and after the procedure. Sensory block was evaluated with the pin-prick test, Motor block was evaluated with the Modified Bromage Scale. The minutes when sensory and motor blocks occurred were recorded, and the PI value at these moments were recorded., Results: Pin-prick test was positive in patients at average 8.4±2.4 minutes. The average PI value for which the pin-prick test was positive was 7.41±2.54, and the cut-off value of the sensory block PI ratio was determined as 1.7 times. The modified Bromage scale reached a score of 2 in 7.6±2.3 minutes on average. The average PI value is 7.27±2.69 for which the modified Bromage Scale score is 2. At modified Bromage Scale-2, PI ratio cut-off value was determined as 1.7 times. The modified Bromage Scale reached a score of 3 in an average of 12.6±4.2 minutes. The mean PI value for the modified Bromage Scale score of 3 is 9.56±6.97. The motor block PI ratio cut-off value was determined as 1.9 times., Conclusion: Pulse oximetry perfusion index is a sensitive and simple method that can be used to evaluate the success of axillary block. The cut-off value, indicating successful block for the rate of sensory block and modified Bromage scale PI, was determined as 1.7 times and the motor block PI ratio as 1.9 times., Key Words: Axillary block, Perfusion index, Oximetry, Ultrasonography, Modified bromage scale.

Purpose: The objective of this study was to optimize the Flurbiprofen (FB) nanosuspension (NS) based gel and to investigate the in vitro release, ex vivo permeation, the plasma concentration-time profile and pharmacokinetic parameters., Methods: FB-NSs were developed using the wet milling process with the Design of Experiment (DoE) approach. The optimum FB-NS was characterized on the basis of SEM, DSC, XRPD, solubility and permeation studies. The dermal gel was prepared by incorporating FB-NS into HPMC gel. Then the in-vitro release, ex vivo permeation studies were performed, and pharmacokinetic studies were evaluated on rats., Results: The particle size, polydispersity index and zeta potential values of optimum NS were determined as 237.7 ± 6.8 nm, 0.133 ± 0.030 and - 30.4 ± 0.7 mV, respectively. By means of the surfactant content and nanosized particles of the nanosuspension, the solubility of FB was increased about 7-fold. The percentage permeated amount of FB from FB-NS gel (8.40%) was also found to be higher than the physical mixture (5.25%) and coarse suspension (reference) (2.08%) gels. The pharmacokinetic studies showed that the C max of FB-NS gel was 2.5 times higher than the reference gel, while AUC 0-24 was 2.96 times higher., Conclusion: FB-NSs were successfully prepared with a wet milling method and optimized with the DoE approach. The optimized FB nanosuspension gel provided better permeation and pharmacokinetic performance compared to FB coarse suspension gel.

Flurbiprofen (FB) is an analgesic and anti-inflammatory drug, but its low water solubility (BCS Class II) limits its dermal bioavailability. The aim of this study is to develop a FB nanosuspension (NS) based gel and to evaluate its analgesic and anti-inflammatory activities in rats. FB-NS was produced by the wet milling method with Plantacare 2000 Ⓡ , as stabilizer. The FB-NS was then incorporated in different carrier gels such as hydroxypropyl methyl cellulose (HPMC), polycarbophil, oleogel, and chitosan. To select the optimum gel type, visual examinations, pH and rheological property measurements, texture profile analysis, in vitro release and ex vivo permeation studies were performed. Following these tests, the analgesic and anti-inflammatory activities of the optimum NS based gel were evaluated using the tail flick and carrageenan-induced paw edema methods consecutively. The NS was successfully prepared with the wet milling method, and the PS, PDI and ZP values were found to be 237.7 ± 6.8 nm, 0.133±0.030, and -30.4 ± 0.7 mV; respectively. Among the NS-based gels, HPMC gel showed more suitable rheological and mechanical properties, also the percentage of permeated FB and the flux value observed for HPMC gel were higher for HPMC than for the other gels. Thus, HPMC gel was selected as a carrier gel for in vivo pharmacodynamics studies. The anti-inflammatory activity of FB-NS HPMC gel was higher than that of the physical mixture gel and that of the coarse suspension gel. Results of our analgesic activity studies showed that, in the 180th min of FB nanosuspension treatment, the latency time was significantly prolonged compared to that of the control group (p<0.05). As a conclusion, while nanosuspensions increased the in vivo pharmacodynamics effect of FB by means of nanosized particles and a large surface area, the HPMC gel as a carrier prolonged the contact time of NSs with skin and eased the dermal application., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Endoplasmic reticulum stress (ERS) has been shown to play a crucial role in the pathogenesis of hypertension. However, the role and mechanisms of ERS on hypertension-induced cardiac functional and morphological changes remain unclear. In this study, the effect of ERS inhibition with tauroursodeoxycholic acid (TUDCA) on hypertension-induced cardiac remodelling was examined., Methods: Hypertension was induced by deoxycorticosterone-acetate (DOCA) and salt administration in uni-nephrectomized rats for 12 weeks. TUDCA was administered for the last four weeks. Rhythmic activity and contractions of the right atrium and left papillary muscle (LPM) were recorded. In the left ventricle, the expression of various proteins was examined and histopathological evaluation was performed., Key Findings: Hypertension-induced increments in systolic blood pressure and ventricular contractions were reversed by TUDCA. In the hypertensive heart, while expressions of glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated protein kinase-like ER kinase (p-PERK), sarcoplasmic reticulum Ca-ATPase-2 (SERCA2), matrix metalloproteinase-2 (MMP-2) and nuclear NF-κB p65 increased; Bcl-2 (B-cell lymphoma-2) expression decreased and the altered levels of all these markers were restored by TUDCA. In the microscopic examination, TUDCA treatment attenuated hypertension-stimulated cardiac inflammation and fibrosis., Conclusions: These results suggest that ERS inhibition may ameliorate cardiac contractility through improving ERS-associated calcium mishandling, apoptosis, inflammation and fibrosis, thereby offering therapeutic potential in hypertension-induced cardiac dysfunction., (© 2019 Royal Pharmaceutical Society.)

In this study, the effect of liver X receptor (LXR) activation on hypertension-induced cardiac structural and functional alterations was investigated. Hypertension was induced by deoxycorticosterone acetate (DOCA)-salt administration in uninephrectomized rats for 6 weeks. LXR agonist GW3965 (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid was given for the past week. Rhythmic activity and contractions of the isolated heart tissues were recorded. Biochemical parameters were assessed in ventricular tissue and plasma samples. Cardiac expressions of various proteins were examined, and histopathological evaluation was performed in the left ventricle and liver. GW3965 reduced systolic blood pressure and enhanced noradrenaline-stimulated papillary muscle contraction induced by DOCA-salt + uninephrectomy. Plasma and tissue total antioxidant capacity (TAC) increased and tissue 4-hydroxynonenal (4-HNE) levels decreased in the DOCA-salt group. GW3965 elevated plasma and tissue TAC levels in both of groups. Glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated-protein kinase-like ER kinase (p-PERK), matrix metalloproteinase-2 (MMP-2), and nuclear factor-κB p65 (NF-κB p65) expression was augmented, and inhibitor-κB-α (IκB-α) expression was reduced in hypertensive hearts. The altered levels of all these markers were reversed by GW3965. Also, GW3965 ameliorated DOCA-salt + uninephrectomy-induced cardiac and hepatic inflammation and fibrosis. However, GW3965 unchanged the plasma lipid levels and hepatic balloon degeneration score. These results demonstrated that LXR activation may improve hypertension-induced cardiac changes without undesired effects.

Background and Objectives: Patient self-rating based scales such as Numerical Rating Scale, Visual Analog Scale that is used for postoperative pain assessment may be problematic in geriatric or critically ill patients with communication problems. A method capable of the assessment of pain in objective manner has been searched for years. Analgesia nociception index, which is based on electrocardiographic data reflecting parasympathetic activity, has been proposed for this. In this study we aimed to investigate the effectiveness of analgesia nociception index as a tool for acute postoperative pain assessment. Our hypothesis was that analgesia nociception index may have good correlation with Numerical Rating Scale values., Methods: A total of 120 patients of American Society of Anesthesiologists (ASA) physical status I and II undergoing any surgical procedure under halogenated-based anesthesia with fentanyl or remifentanil were enrolled for the study. At the 15 th minute of arrival to the Postoperative Care Unit the patients' pain was rated on a 0-10 point Numerical Rating Scale. The patients' heart rate, blood pressure, and analgesia nociception index scores were simultaneously measured at that time. The correlation between analgesia nociception index, heart rate, blood pressure and Numerical Rating Scale was examined., Results: The study was completed with 107 patients, of which 46 were males (43%). Mean (SD) analgesia nociception index values were significantly higher in patients with initial Numerical Rating Scale ≤ 3, compared with Numerical Rating Scale> 3 (69.1 [13.4] vs. 58.1 [12.9] respectively, p <0.001). A significant negative linear relationship (r2=-0.312, p=0.001) was observed between analgesia nociception index and Numerical Rating Scale., Conclusion: Analgesia nociception index measurements at postoperative period after volatile agent and opioid-based anesthesia correlate well with subjective Numerical Rating Scale scores., (Copyright © 2019 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.)

Objectives:   To evaluate and compare the performances of new types of supraglottic airway devices (SADs) with endotracheal intubation regarding their ease of insertions, perioperative complications, and effects on hemodynamic parameters and peak airway pressures in laparascopic cholecystectomy (LC).  Methods: One hundred and fourteen patients with ASA 1-2 physical status scheduled for elective LC were recruited for this prospective randomized controlled trial. The study was completed between January  2016 and January 2017 in Adiyaman University Research and Educational Hospital, Adiyaman, Turkey. The patients were divided into AuraGain(Ambu, Ballerup, Denmark) (n=38), i-Gel® (Intersurgical Ltd, UK) (n=35), and endotracheal tube (ETT)(n=32) groups. Ease of insertion, airway pressures, complications, and hemodynamic variables were compared. Results: The trial was completed with 105 patients. Ease of insertion for SADs which was evaluated with insertion procedure duration, attempts, first insertion success rates, and oropharyngeal leak pressures were similar between the groups. Heart rate, systolic and diastolic arterial pressures, and peak airway pressures were significantly lower in the AuraGain and i-Gel® groups, compared with the ETT, p less than 0.017. Conclusion: Both AuraGain and i-Gel® SADs are comparable with ETT used for airway control in general anesthesia for LC, regarding application ease and perioperative complications. Favorable hemodynamic responses to AuraGain and i-Gel® SADs may put them in a better place than ETT.

The present study was designed to determine the possible hepatoprotective effects of Salvia cryptantha (black weed) plant extract against carbon tetrachloride (CCl4)-induced hepatic injury in rats. Animals were grouped as follows: control group (Group I), CCl4 group (Group II), olive oil group (Group III), CCl4 + S. cryphantha 200 mg/kg group (Group IV), and CCl4 + S. cryptantha 400mg/kg group (Group V). Rats were injected intraperitoneally with CCl4 diluted in olive oil (50% v/v) at a dose of 1ml/kg body weight.  Bax and Caspase3 were determined by immunohistochemical staining, while apoptotic index was evaluated using TUNEL assay. Total mRNA was isolated from liver tissues, and the levels of BCL2, Caspase3, SOD, CAT, and glutathione peroxidase (GPx) were determined by using PCR, while MDA level were determined using a colorimetric assay. The antioxidant and anti-apoptotic gene transcripts were decreased in all of the control and treatment groups, while Caspase3 levels were not statistically different. The S. cryptantha plant extract treatment was also found to improve SOD, GPx, and catalase levels, while reducing the serum levels of MDA. The extract of S. cryptantha supplementation had a protective effect against CCl4-induced liver damage. S. cryptantha extract as a supplement may be useful as a hepato-protective agent to combat the toxic effects caused by CCl4 and other chemicals.

The recent reports on the treatment of azoospermia patients, in which spermatozoa could not be traced in their testes, are focused more on the potential use of adult stem cells, like mesenchymal stem cells (MSCs). The aim of this study was to demonstrate the potential use of MSCs derived from adipose tissue in the treatment of azoospermia using rat disease models. After busulfan application, the rats (n = 20) were injected with the GFP(+) MSCs into left rete testes. After 12 weeks, the testes with cell injection (right testes) were compared to control (left testes) after dimensional and immunohistochemical analyses. Testes treated with MSCs appeared morphologically normal, but they were atrophic in rats without stem cell treatment, in which the seminiferous tubules were empty. Spermatogenesis was detected, not in every but in some tubules of cell-treated testes. GFP(+)/VASA(+) and GFP(+)/SCP1(+) cells in testes indicated the transdifferentiation of MSCs into spermatogenetic cells in the appropriate microenvironment. Rats with cell treatment were mated to show the full recovery of spermatogenesis, and continuous generations were obtained. The expression of GFP was detected in the mesenchymal stem cells derived from adipose tissue and bone marrow and also in the sperms of offspring. In conclusion, MSCs might be studied for the same purpose in humans in future.

Objective: Sacral nerve modulation (SNM) for the treatment of faecal incontinence was originally performed in patients with an intact anal sphincter or after repair of a sphincter defect. There is evidence that SNM can be performed in patients with faecal incontinence and an anal sphincter defect., Method: Two groups of patients were analysed retrospectively to determine whether SNM is as effective in patients with faecal incontinence associated with an anal sphincter defect as in those with a morphologically intact anal sphincter following anal repair (AR). Patients in group A had had an AR resulting in an intact anal sphincter ring. Group B included patients with a sphincter defect which was not primarily repaired. Both groups underwent SNM. All patients had undergone a test stimulation percutaneous nerve evaluation (PNE) followed by a subchronic test over 3 weeks. If the PNE was successful, a permanent SNM electrode was implanted. Follow-up visits for the successfully permanent implanted patients were scheduled at 1, 3, 6 and 12 months and annually thereafter., Results: Group A consisted of 20 (19 women) patients. Eighteen (90%) had a positive subchronic test stimulation. Twelve patients had a successful SNM implant during middle-term follow-up. Group B consisted of 20 women. The size of the defect in the anal sphincter varied between 17% and 33% of the anal circumference. Fourteen (70%) had a positive subchronic test stimulation. Twelve patients had a successful SNM implant during middle-term follow-up. In both groups, the mean number of incontinence episodes decreased significantly with SNM (test vs baseline: P = 0.0001, P = 0.0002). There was no significant difference in resting and squeeze pressures during SNM in group A, but in group B squeeze pressure had increased significantly at 24 months. Comparison of patient characteristics and outcome between groups A and B revealed no statistical differences., Conclusion: A morphologically intact anal sphincter is not a prerequisite for success in the treatment of faecal incontinence with SNM. An anal sphincter defect of <33% of the circumference can be effectively treated primarily with SNM without repair.

Objective: Faecal incontinence (FI) is a socially devastating problem. Sacral nerve modulation (SNM) has proven its place in the treatment of patients with FI. In this study, the first 100 definitive SNM implants in a single centre have been evaluated prospectively., Method: Patients treated between March 2000 and May 2005 were included. Faecal incontinence was defined as at least one episode of involuntary faecal loss per week confirmed by a 3-week bowel habit diary. Patients were eligible for implantation of a permanent SNM when showing at least a 50% reduction in incontinence episodes or days during ambulatory test stimulation. Preoperative workup consisted of an X-defaecography, pudendal nerve terminal motor latency measurement, endo-anal ultrasound and anal manometry. The follow-up visits for the permanent implanted patients were scheduled at 1, 3, 6 and 12 months and annually thereafter. The bowel habit diary and anal manometry were repeated postoperatively during the follow-up visits., Results: A total of 134 patients were included and received a subchronic test stimulation. One hundred patients (74.6%) had a positive test stimulation and received a definitive SNM implantation. The permanent implantation group consisted of 89 women and 11 men. The mean age was 55 years (range 26-75). The mean follow-up was 25.5 months (range 2.5-63.2). The mean number of incontinence episodes decreased significantly during the test stimulation (baseline, 31.3; test, 4.4; P < 0.0001) and at follow-up (36 months postoperatively, 4.8; P < 0.0001). There was no significant change in the mean anal resting pressure. The squeeze pressures were significantly higher at 6 months (109.8 mmHg; P = 0.03), 12 months (114.1 mmHg; P = 0.02) and 24 months postoperatively (113.5 mmHg; P = 0.007). The first sensation, urge and maximum tolerable volume did not change significantly. Twenty-one patients were considered late failures and received further treatment., Conclusion: Sacral neuromodulation is an effective treatment for FI. The medium-term results were satisfying.

The L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is known to be involved in central and peripheral nociceptive processes. This study evaluated the rhythmic pattern of the L-arginine/NO/cGMP pathway using the mouse visceral pain model. Experiments were performed at six different times (1, 5, 9, 13, 17, and 21 h after light on) per day in male mice synchronized to a 12 h:12 h light-dark cycle. Animals were injected s.c. with saline, 2 mg/kg L-arginine (a NO precursor), 75 mg/kg L-N(G)-nitroarginine methyl ester (L-NAME, a NOS inhibitor), 40 mg/kg methylene blue (a soluble guanylyl cyclase and/or NOS inhibitor), or 0.1 mg/kg sodium nitroprusside (a nonenzymatic NO donor) 15 min before counting 2.5 mg/kg (i.p.) p-benzoquinone (PBQ)-induced abdominal constrictions for 15 min. Blood samples were collected after the test, and the nitrite concentration was determined in serum samples. L-arginine or L-NAME caused both antinociception and nociception, depending on the circadian time of their injection. The analgesic effect of methylene blue or sodium nitroprusside exhibited significant biological time-dependent differences in PBQ-induced abdominal constrictions. Serum nitrite levels also displayed a significant 24 h variation in mice injected with PBQ, L-NAME, methylene blue, or sodium nitroprusside, but not saline or L-arginine. These results suggest that components of L-arginine/NO/cGMP pathway exhibit biological time-dependent effects on visceral nociceptive process.

Objective: Sacral neuromodulation (SNM) has been a successful treatment in urinary voiding disorders for years. A concomitant effect on bowel function was observed leading to the treatment of faecal incontinence with SNM. In this study we describe the effect of SNM on bowel frequency and (segmental) colonic transit time., Patients and Methods: Fourteen patients with faecal incontinence who qualified for permanent SNM underwent a colon transit study before and one month after permanent implant. Patients completed a three-week bowel habits diary before and during stimulation., Results: Median incontinence episodes and days per week before SNM were, 8.7 and 4.2, respectively, and both decreased significantly to 0.67 (P = 0001) and 0.5 (P = 0001) during trial screening and to 0.33 (P = 0001) and 0.33 (P = 0001) after permanent implant. The median number of bowel movements per week decreased from 14.7 (6.7-41.7) to 10.0 (3.7-22.7)(P = 0005) during trial screening and to 10.0 (6.0-24.3)(P = 0008) during permanent stimulation. Resting and squeeze pressures did not change significantly during stimulation. Segmental colonic transit time before and during stimulation for right colon, left colon and recto sigmoid were, respectively, 6 (0-25) vs 5 (0-16) hours, 2 (0-29) vs 4 (0-45) hours and 7 (28) vs 8 (0-23) hours. No significant changes were found in both segmental and total colonic transit time; 17 (1-65) vs 25 (0-67) hours., Conclusion: SNM in patients with fecal incontinence led to a significant decrease of bowel movements however (segmental) colonic transit time was not influenced.

We previously demonstrated the rhythmic pattern of L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in nociceptive processes. The coupled production of excess NO and superoxide leads to the formation of an unstable intermediate peroxynitrite, which is primarily responsible for NO-mediated toxicity. In the present study, we evaluated the biological time-dependent effects of exogenously administered peroxynitrite on nociceptive processes and peroxynitrite-induced changes in the analgesic effect of morphine using the mouse hot-plate pain model. Experiments were performed at four different times of day (1, 7, 13, and 19 hours after lights on, i.e., HALO) in mice of both sexes synchronized to a 12 h:12 h light-dark cycle. Animals were injected intraperitoneally (i.p.) with saline or 10 mg/kg morphine 30 min before and 0.001 mg/kg peroxynitrite 30 sec before hot-plate testing, respectively. The analgesic effect of morphine exhibited significant biological time-dependent differences in the thermally-induced algesia; whereas, administration of peroxynitrite alone exhibited either significant algesic or analgesic effect, depending on the circadian time of its injection. Concomitant administration of peroxynitrite and morphine reduced morphine-induced analgesia at three of the four different study time points. In conclusion, peroxynitrite displayed nociceptive and antinociceptive when administered alone according to the circadian time of treatment, while it diminished analgesic activity when administered in combination with morphine at certain biological times.

Background: Sacral neuromodulation (SNM) is a new treatment for faecal incontinence. At present the exact underlying mechanism is still unclear. Modulation of the sacral reflex arcs might have an effect on rectal sensitivity, wall tension and compliance., Methods: Fifteen consecutive patients with faecal incontinence who qualified for SNM underwent barostat measurements before and during neuromodulation. An 'infinitely' compliant plastic bag with a volume of 600 ml was placed in the rectum and connected to a computer-controlled barostat system. An isobaric phasic distension protocol was used. Patients were asked to report rectal filling sensations: first sensation (FS), earliest urge to defaecate (EUD) and an irresistible, painful urge to defaecate (maximum tolerated volume; MTV). Rectal wall tension and compliance were calculated., Results: During isobaric phasic distension each patient experienced all rectal filling sensations at the time of stimulation. Median volume thresholds decreased significantly during stimulation, from 98.1 to 44.2 ml for FS (P = 0.003), from 132.3 to 82.8 ml for EUD (P = 0.001) and from 205.8 to 162.8 ml for MTV (P = 0.002). Pressure thresholds tended to be lower for all filling sensations, but only that to evoke MTV was reduced significantly by stimulation (37.3 versus 30.3 mmHg; P = 0.005). Median rectal wall tension for all filling sensations decreased significantly with stimulation. There was no significant difference between compliance before and during stimulation., Conclusion: SNM affects rectal sensory perception, but further research is required to clarify the mechanism.

The effects of selective ((5,5-dimethyl-3-(3-florophenyl)-4-(4-methylsulphonyl-2(5H)-furanon); DFU) and (N-(2-cyclohexyloxy-4-nitrophenyl)-methansulphonamide; NS 398)) or non-selective (diclophenac and proquazon) inducible cyclooxygenase (COX-2) inhibitors on the survival, nitrite (stable product of nitric oxide (NO) as an index for inducible NO synthase (iNOS) activity) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha), stable product of prostacyclin as an index for COX-2 activity) production in serum, lungs, brain and/or kidney were investigated in endotoxin-induced sepsis model in mice. Endotoxin (10 mg x kg(-1), i.p.)-induced mortality was prevented by DFU, NS 398 and proquazon (0.1, 10 and 1 mg x kg(-1), respectively) and enhanced 2.6-fold with 0.1mg x kg(-1) diclophenac. Endotoxin-induced increase in the serum levels of nitrite was only inhibited by 10 mg x kg(-1) diclophenac. Endotoxin caused a significant decrease only in the brain levels of nitrite without affecting 6-keto-PGF(1alpha) levels in all tissues. The decreased levels of nitrite induced by endotoxin is further reduced by 0.1mg x kg(-1) DFU and 1 and 10mg x kg(-1) diclophenac while 10 mg x kg(-1) DFU and 1mg x kg(-1) proquazon increased it. On the other hand, 1mg x kg(-1) diclophenac and proquazon, and 10 mg x kg(-1) NS 398 increased the endotoxin-induced lung levels of 6-keto-PGF(1alpha). The results suggest that the COX inhibitors may have different effects on the survival and NO production depending on tissue and dose.

Purpose: Graciloplasty has been used as a treatment for end-stage fecal incontinence since 1946. Electric stimulation with an implantable pulse generator has existed for 15 years. The gracilis muscle is wrapped around the anal canal and stimulated by intramuscular electrodes connected with an implantable pulse generator. Initial reports have been promising, but long-term results have not been presented to date., Methods: Data of 200 consecutive patients with a follow-up of at least two years were analyzed in a prospective manner from 1986 until 1999., Results: The overall success rate was 72 percent. In patients with fecal incontinence caused by trauma, the rate was 82 percent. Once continent, patients remained continent after a median follow-up of 261 (standard deviation, 132) weeks. Median survival of the implantable pulse generator until battery expiration was 405 weeks. Disturbed evacuation remained a problem in 16 percent of all patients. Complications were frequent but treatable., Conclusion: Dynamic graciloplasty is a good, cost-effective treatment for fecal incontinence with results lasting for a median of more than five years.

Background: In the treatment of faecal incontinence, more than 30% of patients experience continuation of their problem. We discuss new therapeutic procedures for dealing with faecal incontinence., Methods: Discussion of authors' own work in relation to the literature., Results: First-line care includes diets, constipating drugs, biofeedback therapy, anal repair and operations for prolapse and fistulas. For the failures of these first-line treatments there is hope with second-line therapies. Creation of a neosphincter is possible with a dynamic graciloplasty (DGP) or an artificial bowel sphincter (ABS). A DGP is a conventional graciloplasty with the addition of implanted electrodes and a stimulator that transforms the muscle into an automatic contracting sphincter. ABS comprises an inflatable cuff around the anus that is filled from a pressure-regulating balloon. The cuff can be emptied with an implanted pump., Conclusions: DGP and ABS give good results in 56%-88% of cases. For patients with an anatomical intact but nonfunctioning sphincter there is a new treatment: sacral nerve stimulation. This gives continence in a high percentage of cases, but experience is rather limited. Second-line treatment for faecal incontinence is successful and should be considered in cases where initial therapies fail.

Fecal incontinence is a socially incapacitating condition with associated high treatment costs. The most common cause of fecal incontinence is trauma during childbirth followed by surgical interventions. After unsuccessful conventional treatment, muscle transposition is the next treatment option. Two local muscles are used for this purpose: the gluteus and the gracilis muscles. With both muscles, long-term muscle contractions are difficult to maintain due to muscle fatigue. The gracilis muscle, however, is technically much easier to transfer and most activities of daily living and even sports are still possible. Experimental studies have shown that electrical stimulation of skeletal muscles can transform fatigue-prone muscles into fatigue-resistant muscles. In 1986, we started to perform graciloplasty procedures with intramuscular electrodes connected to an electrical stimulator. To date, 200 patients have been treated in our institution using dynamic graciloplasty. All patients had severe incontinence without control of liquid or solid feces, most of them had previously received unsuccessful treatment using other techniques. The mean age was 48 years, the average time that patients had been incontinent was 12.4 years, and the cause of incontinence were trauma (n = 99), congenital (n = 28), pudendopathy (n = 58), and low motor neurological lesions (n = 15). Of these patients, 76% were considered to have successful outcomes. Patients whose cause of incontinence was trauma or pudendopathy tended to respond better to this treatment than patients with anal atresia., (Copyright 2001 Wiley-Liss, Inc.)

In the present study, we have investigated the effects of nitric oxide (NO) synthase inhibition on mortality in lipopolysaccharide (LPS)-induced sepsis in mice. Serum nitrite levels peaked at 15 h after an injection of LPS (10 mg kg-1, i.p.). Aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, at a dose of 100 mg kg-1 significantly reduced the LPS-induced increase in nitrite levels and improved mortality. Econazole, iNOS inhibitor, calmodulin antagonist, 5-lipoxygenase and a specific thromboxane synthase inhibitor, at a 1 mg kg-1 dose significantly decreased the LPS-induced increase in nitrite levels, but increased mortality 4. 9-fold when compared to the LPS group (control). Indomethacin, a putative iNOS and non-selective cyclo-oxygenase (COX) inhibitor, of 1, 10 and 100 mg kg-1, dose dependently decreased the LPS-induced increase in nitrite levels. This decrease was significantly different from the control at 10 and 100 mg kg-1 dose levels. When indomethacin (100 mg kg-1) was combined with aminoguanidine (100 mg kg-1), LPS-induced nitrite levels were significantly attenuated. NO precursor, L-arginine, was added to this combination in order to test the inhibition of iNOS activity which resulted in no change in nitrite levels. An indomethacin and aminoguanidine combination increased mortality twofold when compared to the control. The addition of L-arginine to the combination enhanced the mortality rate to 1.5-fold. These results suggest that NO appears to play a role in the LPS-induced septic shock model in mice. The improvement in sepsis-induced mortality enhanced by aminoguanidine by the inhibition of iNOS but not with the other agents or combinations should be re-evaluated in order to make an appropriate choice of the therapeutic target. In addition, it may also suggest that other mediators, such as arachidonic acid products and cytokines play a role in septic shock pathogenesis as well. (c) 1998 The Italian Pharmacological Society.