A review of basic principles of fractals and their application to pharmacokinetics.

Pharmacokinetic models play a crucial role in analyzing and assessing the results of in vitro and in vivo studies. In this review, comparative analysis of pharmacokinetic models under homogeneous and heterogeneous conditions is performed, placing special focus on the role of fractal theory. The concept of fractals provides a new perspective from which processes occurring in heterogeneous, confined, or poorly mixed environments can be modeled. Following a brief theoretical overview, the applicability of fractals in characterizing anatomical structures and physiological processes as well as the transport and reaction of drugs within the body is discussed. There is significant evidence that drug absorption, distribution, metabolism, and excretion are often anomalous, that is to say their behavior deviates from classical theory, and possible reasons and appropriate models are considered.

Application of a random network with a variable geometry of links to the kinetics of drug elimination in healthy and diseased livers.

This paper discusses an application of a random network with a variable number of links and traps to the elimination of drug molecules from the body by the liver. The nodes and links represent the transport vessels, and the traps represent liver cells with metabolic enzymes that eliminate drug molecules. By varying the number and configuration of links and nodes, different disease states of the liver related to vascular damage have been simulated, and the effects on the rate of elimination of a drug have been investigated. Results of numerical simulations show the prevalence of exponential decay curves with rates that depend on the concentration of links. In the case of fractal lattices at the percolation threshold, we find that the decay of the concentration is described by exponential functions for high trap concentrations but transitions to stretched exponential behavior at low trap concentrations.

Asymptotic time dependence in the fractal pharmacokinetics of a two-compartment model.

We further investigate, both analytically and numerically, the properties of the fractal two-compartment model introduced by Fuite [J. Fuite, R. Marsh, and J. Tuszynski, Phys. Rev. E 66, 021904 (2002)]. Specifically, we look at the effects of the fractal exponent of the elimination rate coefficient on the long-time behavior of the pharmacokinetic clearance tail. For small exponent values, the tail exhibits exponential behavior, while for larger values, there is a transition to a power law. The theory is applied to seven data sets simulating drugs taken from the pharmacological literature.

Endoscopic SIS injection into the lower oesophageal sphincter in dogs.

AIM: To determine the usefulness of endoscopically-delivered small intestinal submucosa (SIS) as a scaffold in enhancing the lower oesophageal sphincter (LOS) pressures. METHODS: Six dogs were endoscopically injected--four with the SIS and two with its glycerin carrier. Manometry was performed prior to injection and every four weeks post-op. RESULTS: Adequate and site correct injections were made in four dogs. In one dog, significant augmentation of pressures were obtained at four weeks. None had significant changes in pressure at eight weeks, differences in length at either four or eight weeks or significant differences in the thickness of the examined layers. Four of the six had capillary cushions on pathological examination. The dog injected with the carrier had a loose and disorganise collection, while the others were well organised. CONCLUSION: SIS is a biologically compatible material. Lack of an animal model for gastro-oesophageal reflux disease (GORD) makes determining the ability of injections of SIS to combat reflux problematic.

Use of software to search for higher symmetry: space group C2.

From a search of the October 2000 release of the Cambridge Structural Database we find coordinate data for approximately 1500 entries under space group No. 5: C2 or, occasionally, A2, I2 or B112. Software designed to detect cases of missed higher symmetry identified 144 entries for detailed inspection. Of these, 50 should, we believe, be revised to space groups of higher symmetry. The most common revision is to space group C2/m, which entails adding a center of inversion and usually results in important changes in bond lengths and angles.

Space-group changes: a revision to a revision.

The space group for the entry under the reference codes FEBMUU and FEBMUU01 in the Cambridge Structural Database (1992) should be further corrected to space group C2/c rather than P1 (FEBMUU) or C2 (FEBMUU01).

The preoperative predictability of the short esophagus in patients with stricture or paraesophageal hernia.

BACKGROUND: Esophageal shortening is a known complication of advanced gastroesophageal reflux disease that may preclude a tension-free antireflux procedure. A retrospective analysis was performed to test the accuracy of preoperative testing. METHODS: From September 1993 to December 1998, 39 patients underwent esophageal mobilization with intraoperative length assessment. Patients were selected on the basis of irreducible hiatal hernia, stricture formation, or both. Patients in the upright position with a fixed hiatal hernia larger than 5 cm on an esophagram were considered to have a short esophagus. Manometric length two standard deviations below the mean for height was considered abnormally short. RESULTS: In 31 patients, intraoperative mobilization was sufficient to allow the gastroesophageal junction to lie 2 cm below the diaphragmatic crus, so no esophageal-lengthening procedure was required. Eight patients with a short esophagus required an esophageal-lengthening procedure after complete mobilization. Two patients subsequently underwent intrathoracic migration of the gastroesophageal junction (GEJ), with recurrence of symptoms and required gastroplasty during the second surgery. An esophagram had a sensitivity of 66% and a positive predictive value of 37%, whereas manometric length had a sensitivity of 43% and a positive predictive value of 25% for the diagnosis of short esophagus. The preoperative endoscopic finding of either a stricture or Barrett's esophagus was the most sensitive test for predicting the need for a lengthening procedure. CONCLUSIONS: Manometry and esophagraphy are not reliable predictors of the short esophagus. Additional tests and/or tests combined with other parameters are needed.

Left side thoracoscopically assisted gastroplasty: a new technique for managing the shortened esophagus.

Laparoscopic antireflux surgery is the procedure of choice for gastroesophageal reflux disease (GERD). However, many clinicians have reservations about its application in patients with complicated GERD, notably those with esophageal shortening. In this report, we present our experience with the laparoscopic management of the shortened esophagus. A total of 235 patients with primary GERD underwent laparoscopic antireflux procedures, 38 of whom were suspected preoperatively to have a shortened esophagus. Of the 235 patients, 8 (3.4%) needed a left thoracoscopically assisted gastroplasty in addition to laparoscopic Toupet repair (n = 4) or Nissen fundoplication (n = 4). Complications included pleural effusion (n = 1), pneumothorax (n = 2), and minor atelectasis (n = 1). The average hospital stay was 3 days. Results were satisfactory in 7 of 8 patients, with a mean follow-up of 20.2 months (range, 9-34 months). The surgical management of the shortened esophagus is difficult. However, the role of minimally invasive techniques is justified. Early results are appealing, with less morbidity, satisfactory control of GERD related symptoms, and a shortened hospital stay.

Persistent dysphagia after laparoscopic vagotomy.

BACKGROUND: Laparoscopic vagotomy represents a new and less invasive treatment for peptic ulcer disease, but the problem of postvagotomy dysphagia has not been solved. The aim of this study was to determine the etiologic factors related to long-term laparoscopic postvagotomy dysphagia. METHODS: Two female and 11 male patients with a mean age of 48.5 years who underwent laparoscopic vagotomy were investigated retrospectively. Preoperative diagnosis included duodenal ulcer resistant to medical treatment, gastric hypersecretion, gastric outlet obstruction, cholelithiasis, and gastroesophageal reflux disease (GERD). Ten patients underwent laparoscopic highly selective vagotomy, and three patients had laparoscopic truncal vagotomy with gastrojejunostomy or pyloroplasty. Nine of these patients had a Nissen fundoplication in conjunction with the vagotomy. RESULTS: The median long-term follow-up period was 47 months. Two patients complained of severe dysphagia, one of moderate dysphagia, and two of mild dysphagia. Neither type of vagotomy nor an additional fundoplication was correlated with the severity of postoperative long-term dysphagia. Severity of postoperative dysphagia was associated with severity of preoperative dysphagia (r = 0.752, p = 0.003) but not with heartburn (r = 0.358, p = 0.531) or regurgitation (r = 0.024, p = 0.938). The cause of preoperative dysphagia varied; however, all of these patients had GERD and consequent esophageal lesions. CONCLUSION: Preexisting dysphagia appears to play an integral role in persistent postoperative dysphagia. Care must be taken to construct a loose fundoplication in patients with dysphagia.

Does the duration of gastroesophageal reflux disease and degree of acid reflux correlate with esophageal function? A retrospective analysis of 768 patients.

To reconfirm that the duration of symptoms is not associated with esophageal motility in patients with gastroesophageal reflux disease (GERD), esophageal manometric data from 768 patients with GERD were retrospectively analyzed with relation to the duration of symptoms. GERD was defined by positive acid reflux test results monitored by ambulatory 24-hour pH monitoring. Correlation of the duration of symptoms with esophageal body pressures, the presence of dysmotility determined by simultaneous waves, average resting pressure of the lower esophageal sphincter (LES), and abdominal and overall lengths of the LES were statistically analyzed. The median duration of the symptoms was 60 months (range, 1-600). Duration of symptoms was not associated with contraction pressures of the esophageal body at 3 and 8 cm above the LES (r = -0.070 and -0.063, respectively). There was no correlation between LES pressures, LES lengths, or the percentage of simultaneous waves and duration of symptoms. Stricture formation is related to decreased distal esophageal function in GERD patients. In conclusion, the duration of GERD has little influence on esophageal body and LES function.

Laparoscopic repair of a Morgagni hernia.

Morgagni hernias are unusual diaphragmatic hernias which usually present in adulthood. They have traditionally been repaired through transabdominal or transthoracic approaches. The authors present a case of a laparoscopic repair of a Morgagni hernia in a 52-year-old female. A tension free repair of the defect was accomplished utilizing Goretex (W.L. Gore & Associates, Inc., North Elkton, MD) mesh. The patient had an uneventful recovery and is asymptomatic at 6 months follow-up. The etiology, diagnosis and traditional surgical approaches to this problem are discussed. A technique for laparoscopic repair of a Morgagni hernia is described. The literature on the laparoscopic repair of a Morgagni hernia is reviewed and different operative techniques are discussed.

Surgery for achalasia: 1998.

Technical controversies abound regarding the surgical treatment of achalasia. To determine the value of a concomitant antireflux procedure, the best antireflux procedure, the correct length for gastric myotomy, the optimal surgical approach (thoracic or abdominal), and the equivalency of minimally invasive surgery, a literature review was carried out. The review is based on 23 articles on open transabdominal or transthoracic myotomy, 14 articles on laparoscopic myotomy, and four articles on thoracoscopic myotomy. Postoperative results of traditional open thoracic or transabdominal myotomy as determined by symptomatology were better with fundoplication than without fundoplication. The incidence of postoperative reflux as proved by pH monitoring was high in patients who had an open transabdominal myotomy without fundoplication. The type of antireflux procedure used and the length of gastric myotomy had little effect on results. The results of transthoracic Heller myotomy do not require a concomitant fundoplication. Laparoscopic and thoracoscopic myotomy had excellent results at short-term follow-up. A fundoplication must be added if the myotomy is performed transabdominally. A randomized prospective study is required to determine the best fundoplication and the extent of gastric myotomy. Although minimally invasive surgery for achalasia has excellent initial results, longer follow-up in a larger population of patients is needed.

Correlations between esophageal diseases and manometric length: a study of 617 patients.

The purpose of this study was to measure the length of the esophagus and assess its relationship to sex, weight, age, height, and various esophageal disorders. A retrospective analysis was undertaken of 617 esophageal manometric studies, which included 51 normal control subjects (27 males and 24 females) and 566 patients (297 males and 269 females) with esophageal disorders (50 with achalasia, 6 with diffuse esophageal spasm, 64 with strictures, 38 with nutcracker esophagus, 398 with gastroesophageal reflux disease [GERD] with positive 24-hour pH monitoring, and 66 with possible GERD but negative 24-hour pH monitoring). Manometry was performed in all of them by the station pull-through technique. The length of the esophagus was defined as the distance between the proximal end of the upper esophageal sphincter and the distal end of the lower esophageal sphincter. In the control group the mean (+/- standard deviation) length of the esophagus was 28.3 +/- 2.41 cm. In patients with esophageal disorders the mean length of the esophagus was 28.0 +/- 2.87 cm. Length of the esophagus is related to height but not to weight, sex, age, diffuse esophageal spasm, or nutcracker esophagus. Achalasia is associated with a longer esophagus, and GERD is associated with a shorter esophagus. Stricture is associated with a shorter esophagus, but this is in part due to the association between stricture and GERD. Patients with possible GERD but negative 24-hour pH monitoring have an esophageal length similar to that of GERD patients with positive 24-hour pH monitoring. Patients with GERD and stricture formation showed esophageal shortening in shorter patients. Achalasia, GERD, and GERD with stricture formation influence esophageal length. GERD-related strictures shorten the esophagus more significantly in short patients.

Manometric and radiographic verification of esophageal body decompensation for patients with achalasia.

BACKGROUND: Although morphologic, radiographic, and manometric features of achalasia have been well defined, it has not been established by careful retrospective analysis whether achalasia is a progressive disorder resulting in complete decompensation. STUDY DESIGN: To verify the hypothesis that achalasia is a progressive disease, we retrospectively investigated manometric, radiographic, and symptomatic data in patients with achalasia. Sixty-three patients (36 women and 27 men) with a median age of 44 years (range 11 to 79 years) were evaluated. The duration of symptoms ranged from 1 to 442 months, with a median of 48 months. Patients were divided into four groups according to the duration of symptoms: 36 patients with less than 5 years, 11 with 5 to 10 years, 9 with 10 to 15 years, and 7 with 15 years or more. RESULTS: Contraction pressures of the esophageal body decreased significantly at every level when the duration of symptoms increased (p < 0.04). The percentage of simultaneous waves in the esophageal body rose as the duration of symptoms increased. All waves were synchronous in every patient who had had symptoms for more than 15 years. The maximal width of the esophageal body measured on esophagram became greater with an increase in the duration of symptoms, but this measurement did not reach statistical significance (p = 0.063). The tortuosity of the esophagus, measured by the maximal angle of the esophageal axis, was significantly greater in patients with a longer duration of symptoms (p < 0.02). The type of symptoms was not associated with the duration of symptoms. CONCLUSIONS: Achalasia is a progressive disease, as verified by manometric and radiographic findings. The classification of esophageal motor function expressed by amplitude of contraction pressure and angle of tortuosity is objective and useful. Classification of achalasia by duration of symptoms may be important in treatment selection and effectiveness.

A new form of access for endo-organ surgery. The initial experience with percutaneous endoscopic gastrostomy.

BACKGROUND: Intraluminal gastric surgery provides a new treatment option for various disease processes. This study assesses the safety of a new large-diameter percutaneous endoscopic gastrostomy (PEG) for intraluminal surgery. METHODS: Investigators at six institutions were asked to complete a standard questionnaire to assess the difficulties associated with the assembly and introduction of the PEG, plus intraoperative and postoperative problems related to placement of the device. RESULTS: In terms of assembly; 1.9% of respondents reported difficulty obtaining complete vacuum of the balloon tip, and 3.8% had difficulty fitting the graduated dilator to the balloon-tipped cannula. Difficulties associated with introduction of the PEG included disengagement of the dilator from the balloon-tipped cannula (0%), extraction of the dilator-port assembly (0%), difficult PEG pullout (1.9%), abdominal wall bleeding (0%), and difficult PEG dilator separation (7.5%). Intraoperatively, 7.5% of respondents reported inadequate skin bolster fitting, 1.9% had CO(2) leakage into the peritoneal cavity, 0% had inadvertent PEG extraction, and 0% reported injury to the esophagus, colon, or small intestine. Postoperatively, there was a 9.4% rate of wound infection, a 1.9% rate of gastrocutaneous fistula, and a 1.9% rate of esophageal, colon, or small intestine injury. CONCLUSIONS: The large-diameter PEG is safe and effective for endo-organ surgery. Additional preventive measures for PEG site infection should be investigated.

A combined laparoscopic-endoscopic method of assessment to prevent the complications of short esophagus.

As antireflux surgery has been used increasingly for gastroesophageal reflux disease (GERD), a need has arisen for an accurate method to assess esophageal length. There are a number of preoperative tests that can help surgeons to establish the presence of a short esophagus, but intraoperative assessment after esophageal mobilization is the standard method. In this era of laparoscopic surgery, the surgeon mobilizes the esophagus extensively from the abdomen and then determines if mobilization is sufficient. We report an intraoperative technique that combines laparoscopic with endoscopic methods to determine the position of the gastroesophageal junction. Because two physicians are required, there is additional operating room time, resulting in increased costs. However, these costs are offset by the assurance that the complications of the short esophagus can be avoided. With experience, modifications were made, resulting in the technique described herein.

Endo-organ full-thickness excision for gastric cancer: report of a case.

We performed endo-organ full thickness gastric excision to treat a high-risk patient with T2 gastric cancer. The patient, a 75-year-old white man with a gastric adenocarcinoma located just below the gastroesophageal junction, had a history of chronic obstructive pulmonary disease and cor pulmonale, and developed markedly elevated pulmonary artery pressures under general anesthesia. The less invasive endo-organ approach was utilized because of these severe morbidities. The carcinoma was staged laparoscopically, then removed utilizing the full-thickness endo-organ excision technique. This case report serves to demonstrate that full thickness endo-organ gastric excision may be indicated not only for certain early gastric cancers, but also for high-risk patients who cannot tolerate open surgery due to advanced age or serious illness.

X-ray diffraction study of the crystal structure of the pi-molecular compound pyrene ... pyromellitic dianhydride at 19 K.

The crystal structure of the pyrene ... pyromellitic dianhydride (PMDA) pi-molecular compound [(C16H10:C10H2O6); PYRPMA] has been refined from intensities measured at 19 K using the low-temperature accessory designed by Samson, Goldish & Dick [J. Appl. Cryst. (1980), 13, 425-432] for a four-circle diffractometer. Earlier results for the ordered structure [Herbstein & Snyman (1969). Philos. Trans. R. Soc. London Ser. A, 264, 635-666] are confirmed and extended; at 19 K, a = 13.664 (3), b = 9.281 (2), c = 14.420 (3) A, beta = 91.80 (2) degrees, space group P2(1)/n, Z = 4, with two sets of pyrenes at independent centres of symmetry and the four PMDAs at general positions. The geometrical structures of the two components are in good agreement with quantum mechanical calculations. Analyses of thermal motion and packing show that one set of pyrenes is more tightly packed than the other; the principal interactions in the crystal are pi-pi* plane-to-plane interactions between pyrene and PMDA and > CH ... O = C <, between pyrene and PMDA, and between PMDAs.

A chiral N-crotonyloxazolidinone Diels-Alder adduct.

(4S)-4-Benzyl-3-[(4S,5S)-(1-methoxy-5-methylcyclohexen-4- yl)carbonyl]-2-oxazolidinone, C19H23NO4, M(r) = 329.40, monoclinic, P2(1), a = 11.453 (3), b = 7.163 (4), c = 11.929 (2) A, beta = 111.86 (2) degree, V = 908.3 (5) A3, Z = 2, D chi = 1.20 g cm-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.79 cm-1, F(000) = 352, T = 297 K, R = 0.034 for 885 reflections with Fo2 greater than 0. The molecule is extended in the crystal; there is a small twist, -13.1 (2) degree, about the amide-like C--N bond joining the oxazolidinone ring to the carbonyl group. The configurations at the two optical centers in the cyclohexene ring confirm the anticipated stereospecificity of the Diels-Alder cycloaddition synthesis.