Randomized clinical trial comparing collagen plug and advancement flap for trans-sphincteric anal fistula.

BACKGROUND: The role of a collagen plug for treating anal fistula is not well established. A randomized prospective multicentre non-inferiority study of surgical treatment of trans-sphincteric cryptogenic fistulas was undertaken, comparing the anal fistula plug with the mucosal advancement flap with regard to fistula recurrence rate and functional outcome. METHODS: Patients with an anal fistula were evaluated for eligibility in three centres, and randomized to either mucosal advancement flap surgery or collagen plug, with clinical follow-up at 3 and 12 months. The primary outcome was the fistula recurrence rate. Anal pain (visual analogue scale), anal incontinence (St Mark's score) and quality of life (Short Form 36 questionnaire) were also reported. RESULTS: Ninety-four patients were included; 48 were allocated to the plug procedure and 46 to advancement flap surgery. The median follow-up was 12 (range 9-24) months. The recurrence rate at 12 months was 66 per cent (27 of 41 patients) in the plug group and 38 per cent (15 of 40) in the flap group (P = 0·006). Anal pain was reduced after operation in both groups. Anal incontinence did not change in the follow-up period. Patients reported an increased quality of life after 3 months. There were no differences between the groups with regard to pain, incontinence or quality of life. CONCLUSION: There was a considerably higher recurrence rate after the anal fistula plug procedure than following advancement flap repair. Registration number: NCT01021774 (http://www.clinicaltrials.gov).

Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome.

BACKGROUND/AIMS: Deregulation of cell cycle control is a hallmark of cancer. The primary cyclins (A, B1, D1, D3, and E) are crucial for cell cycle progression. Secondary cyclins (C and H) have putative indirect effects on cell cycle progression and have not previously been evaluated in colon cancer. This study examined cyclin protein expression and gene amplification in colon adenocarcinoma and the correlation with patient outcome. METHODS: Immunohistochemistry and real time quantitative polymerase chain reaction were used to determine cyclin expression and gene amplification in 219 tumours. The results were compared with clinical variables and patient outcomes. RESULTS: Cyclin H was overexpressed in all tumours, cyclin C in 88%, cyclin B1 in 58%, cyclin A in 83%, cyclin D3 in 36%, cyclin E in 25%, and cyclin D1 in 11% of the tumours. Extra gene copies of cyclin A were seen in 6.2% of the tumours, cyclin B1 in 9%, cyclin C in 26.9%, cyclin D1 in 55%, cyclin D3 in 20.5%, cyclin E in 19.1%, and cyclin H in 5.1%. A significant correlation between protein overexpression and gene amplification was seen for cyclin C only. High expression of cyclin A was independently associated with improved survival. Amplification of cyclin C was independently associated with an unfavourable prognosis. CONCLUSIONS: Amplification of the cyclin C gene was related to an unfavourable prognosis and high protein expression of cyclin A was associated with a better outcome in colon adenocarcinoma.

Cholesterol metabolism in patients with resection of ileum and proximal colon.

Compartmental analysis of the disappearance curve of serum cholesterol specific activity after an intravenous administration of a tracer does of cholesterol-4-14C was carried out in five patients with resection of the distal small intestine, cecum, and proximal colon. The data fit best a two compartment model in all five cases with the rapidly exchangeable pool of 16.6+/-3.2 g (mean +/- SD, 60% of the mean of 15 normal subjects) and the slowly exchangeable pool of 31.5 +/- 10.9 g (65%). The reduction of the pool sizes was associated with a shorter mean transit time of cholesterol, 22.15 +/- 8.07 days (40%) and increased turnover rate, 2.42 +/- 0.72g/ day (172%). Direct fecal analysis for the neutral sterols and bile acids derived from the exchangeable pool confirmed the turnover rate obtained from the compartmental analysis. The increased fecal excretion was mainly in the bile acid fraction. The study suggests that the ileal and proximal colon resection results in bile acid malabsorption which, in turn, increases hepatic cholesterol and bile acid synthesis. The synthetic rates, however, could not compensate totally for the excretory rate. Therefore, the pool size decreased to a new low steady state of equilibrium.

Antiparkinsonian efficacy of a novel transdermal delivery system for (+)-PHNO in MPTP-treated squirrel monkeys.

We examined the ability of the antiparkinsonian agent (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) to enter the systemic circulation in therapeutic concentrations after continuous transdermal absorption in squirrel monkeys rendered parkinsonian by MPTP. Direct subcutaneous administration of (+)-PHNO in the dose range of 2.5 to 20 micrograms/kg restored locomotor activity to levels seen in normal monkeys for approximately 1 hour. Application of transdermal patches capable of delivering, into an infinite sink, an estimated 2.6 micrograms/cm2/h of (+)-PHNO over a skin surface area of 4.78 to 19.12 cm2 also restored locomotor activity to the normal range during a 24-hour period. We suggest the use of transdermal application of PHNO as a novel drug delivery system for the improved management of Parkinson's disease.

Low-dose intravenous erythromycin: effects on postprandial and fasting motility of the small bowel.

BACKGROUND: Erythromycin is a motilin agonist and its effects on gastrointestinal motility are dependent on both dose and whether it is administered during the postprandial or fasting state. AIM: To study the motility response of the small bowel to a low dose of intravenous erythromycin after meal intake and during fasting. METHODS: Eighteen healthy subjects with mean age of 25 years were studied by small bowel manometry. Erythromycin was administered intravenously (0.75 mg per kg body weight) during 20 min in the postprandial (n=9) and the fasting state (n=9), and the motility response was recorded. RESULTS: Erythromycin significantly reduced the frequency of propagated contractions (P < 0.001) and the amplitude of contractions (P < 0.02) in the small bowel during established postprandial motility. During the fasting state, erythromycin invariably initiated a phase III-like activity, which was similar to the spontaneous nocturnal phase III and migrated significantly more slowly than the diurnal phase III (P < 0.01). CONCLUSIONS: A low dose of erythromycin administered intravenously during the postprandial state significantly inhibits small bowel motility, whereas administration during the fasting state initiates a phase III resembling the nocturnal rather than the diurnal phase III. These effects of erythromycin may indicate interference with vagal pathways. Due to its inhibitory effects, the clinical use of erythromycin in patients with hypomotility should be reconsidered, and the potential usefulness of these effects in patients with exaggerated intestinal motility deserves further attention.

2'-Nor-2'-deoxyguanosine is an effective therapeutic agent for treatment of experimental herpes keratitis.

2'-Nor-2'-deoxyguanosine (2'NDG), previously reported by us to effectively treat acute herpes simplex infections in mice, was used therapeutically to significantly enhance healing of established herpetic corneal lesions and prevent stromal disease in rabbits. Treatment using 0.06% 2'NDG drops (5 times daily) starting 3 days after infection resulted in more rapid healing of corneal epithelial lesions, rapid resolution of conjunctival inflammation, and prevention of stromal clouding compared to placebo-treated animals. In comparative dose-response titrations, the relative potency of 2'NDG to acyclovir was 6.4, which was significant. In addition, soluble ophthalmic inserts were developed for delivery of 2'NDG. Once a day treatment using ophthalmic inserts which released 100 micrograms 2'NDG significantly enhanced corneal and conjunctival healing and prevented stromal disease; 2'NDG eye drops (100 micrograms) delivered once a day were also effective in inhibiting the progression of corneal lesions. These results indicate that 2'NDG may be therapeutically effective in treatment of herpes keratitis, and further suggest that for use as eye drops or in an ophthalmic insert, 2'NDG may be effective even if applied once per day.

Duplex scanning versus conventional arteriography for the evaluation of carotid artery plaque morphology.

Examinations that are performed for the evaluation of the extracranial cerebrovascular system need to supply accurate information regarding the luminal surface of the carotid artery as well as the morphologic characteristics of the plaque. To compare conventional carotid artery angiography and Duplex scanning, 32 consecutive patients underwent both evaluations, the results of which were compared, in a blinded manner, to the plaque characteristics noted on direct examination by the attending surgeon and pathologist. The following observations were made: angiographic and Duplex scanning evaluations concurred with direct-specimen examination for luminal narrowing in 31 of 32 patients (97%) and 30 of 32 patients (94%), respectively, whereas Duplex scanning was more accurate for diagnosing ulcerative lesions, 13 of 14 patients (93%), than angiography, five of 14 patients (36%) (p less than 0.0001). Luminal surface irregularity was accurately described by Duplex scanning in 20 of 23 patients (87%) and by angiography in 11 of 23 patients (48%) (p less than 0.005), whereas plaque morphology or consistency was not commented on with angiography but was accurately described with Duplex scanning in 12 of 12 patients (100%). This series clearly demonstrates that both angiography and Duplex scanning are extremely accurate for determining the reduction in the diameter of the carotid artery, whereas Duplex scanning is more accurate for detecting important plaque characteristics such as irregularity, ulceration, and composition.

Presence of isolated tumour cells in mesenteric lymph nodes predicts poor prognosis in patients with stage II colon cancer.

AIM: Most patients with stage I and stage II colon adenocarcinomas do not have disseminated disease, and the group is not offered adjuvant therapy. However, more than 30% of stage II colon adenocarcinoma patients get metastases to remote organs. Thus, it is important to identify patients in this group at risk of disease relapse. PATIENTS AND METHODS: We have examined the prognostic value of isolated tumour cells (ITC) in mesenteric lymph nodes in a consecutive series of 156 colon carcinoma patients with stage II disease. Immunohistochemistry, using antibodies to cytokeratins, and morphology were used to identify presence of ITC. RESULTS: ITC were detected in 59 (37.8%) patients. Presence of ITC in mesenteric lymph nodes was independently associated with reduced relative survival both in univariate (p=0.0199) and in a multivariate analysis (p=0.041). CONCLUSION: The results strongly suggest that presence of ITC in mesenteric lymph nodes is associated with reduced relative survival in colon carcinoma patients stage II, and that detection of ITC may be important in treatment of these patients.

Dissolution rate studies of compression-molded units made from hydroxypropyl cellulose films.

Hydroxypropyl cellulose films were prepared by compression molding of three different lots of hydroxypropyl cellulose powder at 149 degrees C, 188 degrees C, and 232 degrees C. Rectangular pieces were cut from these films and viscosity average molecular weight (Mv), degree of orientation, and rate of dissolution were measured. The viscosity average molecular weight (Mv) decreased with increasing processing temperature, while, as expected, the dissolution rate increased. Orientation in the thermoformed units was also evaluated. Correlation of these data with the Mv values suggests that orientation has some controlling influence on the dissolution rate. Because the samples possessing the least orientation were molded at the highest temperature, they also had the lowest Mv due to thermal degradation. Therefore, the effects of molecular weight were not fully separated from orientation effects with regard to control over the dissolution rate.

Bioavailability assessment under quasi- and nonsteady-state conditions. I: theoretical considerations.

A strategy was devised to permit bioavailability estimations at quasi- and nonsteady states. The proposed method retains most attributes of a steady-state comparison without being burdened by its protractiveness. The only necessary requirements are that drug disposition obeys linear kinetics and that succeeding doses are administered during the log-linear phase free from the influence of continuing absorption.

Bioavailability assessment under quasi- and nonsteady-state conditions III: Application.

The applicability of bioavailability assessment at quasi- and nonsteady state is illustrated with data from a study comparing two formulations of amitriptyline hydrochloride in humans. Relative bioavailability as a function of the observed mean plasma concentrations may be expressed in closed form, provided the affected intervals begin and end in the log-linear region. Alternatively, numerical, graphical and/or electronic computational techniques may be used to stimulate the appropriate [Cp(i)]sim, the proximity of which to [Cp(i)]obs is a function of relative bioavailability and omega. If a model can be found to fit the data adequately, it would be sufficient that only one sampled interval end in the log-linear phase.

Intraoperative manometry to assess the esophagogastric junction during laparoscopic fundoplication and myotomy.

SUMMARY: Surgery for gastroesophageal reflux disease and achalasia is performed to alleviate symptoms by improving esophagogastric junction (EGJ) function. Intraoperative manometry was used to evaluate the pressure-length characteristics of the reconstructed EGJ during laparoscopic Nissen fundoplication and laparoscopic Heller myotomy. Intraoperative manometry was performed in 37 consecutive patients undergoing laparoscopic Nissen fundoplication (n = 22) or laparoscopic Heller myotomy (n = 15). Measurements were taken before surgery, after creation of the pneumoperitoneum, after completion of the myotomy in achalasia, and after creation of the fundoplication. Tracings were analyzed for pressure, length, and the integrated pressure-length relation (area under the curve [AUC]). Statistical comparison was made using paired t tests; intraoperative EGJ measurements did not correlate well with preoperative values for either pressure or length. Laparoscopic Nissen fundoplication significantly increased pressure, length, and AUC of the EGJ compared with prefundoplication values. Laparoscopic Heller myotomy significantly decreased EGJ pressure, length, and AUC. Creation of a Toupet fundoplication after myotomy did not significantly increase pressure, length, and AUC of the EGJ compared with postmyotomy values. Intraoperative manometry identified 2 of 15 achalasia patients (13%) with persistent areas of high pressure after initial myotomy that were corrected by extending the myotomy. Intraoperative manometry identifies mechanical changes created during EGJ surgery and may be a useful adjunct to improve outcomes of laparoscopic Nissen fundoplication and laparoscopic Heller myotomy.

A new approach for three-dimensional reconstruction of arterial ultrasonography.

This report describes a computerized approach that allows the creation of realistic three-dimensional arterial images from two-dimensional contiguous slices derived from a conventional ultrasound scan. Furthermore, the study assesses the method's feasibility and accuracy by performing in vitro cadaver artery three-dimensional reconstructions. Images are digitized into a computer, with a resolution of 512 x 480 pixels, and a dynamic range of 8 bits/pixel (256 gray scale). After edge enhancement with convolution filters through the original binary data, the intraluminal and outer edges are traced and converted to a polygon vector within a defined three-dimensional space. Serial cuts, 2 mm apart, are then "stacked" into a three-dimensional model, with interpolation of polyhedra between slices. Sixteen normal and arteriosclerotic distal aortic and common iliac arteries were obtained from fresh cadavers. Three-dimensional reconstruction models were compared with gross examination of the original artery. Anatomically accurate reconstructions were obtained, all with detailed surface information. Data analyzed included diameter, area, residual lumen, and percent stenosis. Pearson's coefficients determined for the pairs of data indicated excellent correlation (greater than or equal to 0.90) between separate measurements. With use of the described technology it is feasible to perform arterial three-dimensional reconstructions on a personal computer, with detailed and accurate surface information. The three-dimensional reconstruction method used can reliably and consistently reproduce the anatomic specimens.