Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial.

Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12-week, double-blind controlled trial. The primary end-point was the percentage of subjects with clinical remission [Crohn's Disease Activity Index (CDAI) < 150] or clinical response (100-point CDAI reduction). Twenty-six (56·5%) and 13 (54·2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR-6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62(+) expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug-induced leucopenia in the DR-6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.

The metabolic regulator PGC-1α links anti-cancer cytotoxic chemotherapy to reactivation of hepatitis B virus.

Patients with chronic hepatitis B virus (HBV) infection are at an increased risk for a severe and a potentially fatal viral reactivation following anti-cancer therapy. The molecular mechanism for this induction of HBV expression is still unclear. Here, we show that treating hepatoma cell line expressing HBV with various anti-cancer cytotoxic agents results in a significant up-regulation of HBV expression. This HBV induction is at the transcriptional level and is time dependent. Interestingly, treating hepatoma cells with anti-cancer cytotoxic agents results in a robust induction of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a metabolic and energy regulator that is normally induced in the liver under starvation conditions and that has been previously shown to strongly coactivate HBV transcription. Most importantly, HBV up-regulation following anti-cancer therapy depends on PGC-1α induction, because PGC-1α knock-down abolishes HBV induction. Finally, pretreatment of HBV-expressing cells with the antioxidant agent N-acetylcysteine attenuates the induction of both PGC-1α and HBV in response to anti-cancer treatment, suggesting that chemotherapy-associated PGC-1α induction is mediated by cellular oxidative stress that ultimately leads to HBV up-regulation. We conclude that cytotoxic anti-cancer chemotherapy has a direct and an immune system-independent effect on HBV gene expression, which is mediated by PGC-1α. Our results attribute to this metabolic regulator an unexpected role in linking anti-cancer treatment to HBV reactivation and make PGC-1α a potential target for future anti-HBV therapy, especially under conditions in which it is robustly induced, such as following anti-cancer treatment.

Cutaneous melanoma arising from a cesarean delivery skin scar.

A 41-year-old pregnant African-American woman noticed rapid growth of her cesarean delivery skin scar beginning at 14-week gestation. Skin biopsy, which was performed at 31 weeks, revealed poorly differentiated cutaneous melanoma. At 34 weeks, she underwent repeat cesarean delivery with tumor excision, pelvic lymphadenectomy and abdominal wall reconstruction. Locally advanced disease and anatomical limitations prevented attainment of negative surgical margins. Despite adjuvant chemotherapy and radiation, she died 1 year after diagnosis. Deferring biopsy of a suspicious skin lesion during pregnancy may have delayed the diagnosis of melanoma in this case and possibly affected the long-term outcome.

Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging findings in 6 patients.

CLOVES syndrome is a complex disorder of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal anomalies. We report the occurrence of spinal-paraspinal fast-flow lesions within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6 patients with CLOVES syndrome.

Klippel-Trenaunay syndrome and spinal arteriovenous malformations: an erroneous association.

BACKGROUND AND PURPOSE: KTS is a rare limb overgrowth disorder with slow-flow vascular anomalies. This study examines the presumed association between KTS and spinal AVMs. MATERIALS AND METHODS: We performed a MEDLINE search of articles and reviewed textbooks of spinal diseases to study the association between KTS and spinal AVM. Our goal was to ascertain the basis on which the diagnosis of KTS was established and to evaluate the evidence of its association with spinal AVMs. In addition, the data base of the Vascular Anomalies Center at Children's Hospital Boston was queried for patients with KTS, and the association with spinal AVM was investigated. RESULTS: Twenty-four published reports on spinal AVMs in 31 patients with KTS were reviewed. None of these references provided solid evidence of the diagnosis of KTS in any patient. Clinical data were either incompatible with the diagnosis of KTS or were inadequate to establish the diagnosis. Alternative possible diagnoses (CLOVES syndrome and CM-AVM) were suggested by the first author for 9 of the patients reported in these articles. The medical records of 208 patients with the diagnosis of KTS were analyzed; not a single patient had clinical or radiologic evidence of a spinal AVM. CONCLUSIONS: An association between KTS and spinal AVM, as posited in numerous references, is most likely erroneous. The association has neither been reliably proved in the limited published literature nor encountered in a large cohort.

Profiling multiple provider prescribing of opioids, benzodiazepines, stimulants, and anorectics.

BACKGROUND: The main objective of this study was to determine the prevalence of multiple providers for different controlled substances using the largest electronic prescription monitoring program (PMP) in the United States. A secondary objective was to explore patient and medication variables associated with prescriptions involving multiple providers. PMPs monitor the final allocation of controlled substances from pharmacist to patient. The primary purpose of this scrutiny is to diminish the utilization of multiple providers for controlled substances. METHODS: This is a secondary data analysis of the California PMP, the Controlled Substance Utilization Review and Evaluation System (CURES). The prevalence of multiple provider episodes was determined using data collected during 2007. A series of binomial logistic regressions was used to predict the odds ratio (OR) of multiple prescriber episodes for each generic type of controlled substance (i.e., opioid, benzodiazepine, stimulant, or diet pill (anorectic) using demographic and prescription variables. RESULTS: Opioid prescriptions (12.8%) were most frequently involved in multiple provider episodes followed by benzodiazepines (4.2%), stimulants (1.4%), and anorectics (0.9%), respectively. The greatest associations with multiple provider episodes were simultaneously receiving prescriptions for different controlled substances. CONCLUSIONS: Opioids were involved in multiple provider prescribing more frequently than other controlled substances. The likelihood of using multiple providers to obtain one class of medications was substantially elevated as patients received additional categories of controlled substances from the same provider or from multiple practitioners. Polypharmacy represents a signal that requires additional vigilance to detect the potential presence of doctor shopping.

Double-humped states in the nonlinear Schrödinger equation with a random potential.

The role of double-humped states in spreading of wave packets for the nonlinear Schrödinger equation (NLSE) with a random potential is explored and the spreading mechanism is unraveled. Comparison to an NLSE with a double-well potential is made. There are two independent effects of the nonlinearity on the double-humped states for the NLSE: coupling to other states and destruction. The interplay between these effects is discussed.

Infantile hemangiomas involving the neuraxis: clinical and imaging findings.

BACKGROUND AND PURPOSE: The neuroradiology and neurosurgery literature is replete with references to "hemangioma" involving the central nervous system (CNS). However, the number of cases of true infantile hemangiomas in the CNS reported to date is 15. Our purpose was to delineate the definition of infantile hemangiomas, determine their prevalence in the neuraxis, and describe their imaging characteristics and associations in this location. MATERIALS AND METHODS: We reviewed our Vascular Anomalies Center data base from 1999 through May 2008 to assess the prevalence of intracranial or intraspinal involvement within the total cohort of infantile hemangiomas. Fifteen patients were identified with infantile hemangiomas that involved the neuraxis. Two board-certified neuroradiologists reviewed the available imaging of these 15 patients, and a board-certified pathologist reviewed the available histopathology. Clinical records of all 15 patients were reviewed to identify the type of treatment and the treatment response. RESULTS: Of the 1454 patients listed with infantile hemangioma, 15 (approximately 1.0%) had involvement of the CNS. Eight patients had intracranial infantile hemangioma, 6 had intraspinal hemangioma, and 1 had both. In most instances, there was continuous extension into the neuraxis from an extracranial or extraspinal lesion. There were no cases of a CNS hemangioma without an accompanying extra-CNS tumor. Two patients had findings consistent with posterior fossa anomalies, cervicofacial hemangioma, arterial anomalies, cardiac defects, ocular abnormalities, and associated sternal or ventral defect. Of note, there were no brain or spinal parenchymal signal-intensity abnormalities, and there was no evidence of parenchymal invasion. CONCLUSIONS: CNS involvement by infantile hemangiomas is an unusual occurrence, which, when recognized, can help optimize patient management.

Fractional variant Planck's over 2pi scaling for quantum kicked rotors without Cantori.

Previous studies of quantum delta-kicked rotors have found momentum probability distributions with a typical width (localization length L) characterized by fractional variant Planck's over 2pi scaling; i.e., L approximately variant Planck's over 2pi;{2/3} in regimes and phase-space regions close to "golden-ratio" cantori. In contrast, in typical chaotic regimes, the scaling is integer, L approximately variant Planck's over 2pi;{-1}. Here we consider a generic variant of the kicked rotor, the random-pair-kicked particle, obtained by randomizing the phases every second kick; it has no Kol'mogorov-Arnol'd-Moser mixed-phase-space structures, such as golden-ratio cantori, at all. Our unexpected finding is that, over comparable phase-space regions, it also has fractional scaling, but L approximately variant Planck's over 2pi;{-2/3}. A semiclassical analysis indicates that the variant Planck's over 2pi;{2/3} scaling here is of quantum origin and is not a signature of classical cantori.

Theory of 2 delta-kicked quantum rotors.

We examine the quantum dynamics of cold atoms subjected to pairs of closely spaced delta kicks from standing waves of light and find behavior quite unlike the well-studied quantum kicked rotor (QKR). We show that the quantum phase space has a periodic, cellular structure arising from a unitary matrix with oscillating bandwidth. The corresponding eigenstates are exponentially localized, but scale with a fractional power L is less similar to h(-0.75), in contrast to the QKR for which L is less similar to h(-1). The effect of intercell (and intracell) transport is investigated by studying the spectral fluctuations with both periodic as well as "open" boundary conditions.

Quantum accelerator modes from the Farey tree.

We show that mode locking finds a purely quantum nondissipative counterpart in atom-optical quantum accelerator modes. These modes are formed by exposing cold atoms to periodic kicks in the direction of the gravitational field. They are anchored to generalized Arnol'd tongues, parameter regions where driven nonlinear classical systems exhibit mode locking. A hierarchy for the rational numbers known as the Farey tree provides an ordering of the Arnol'd tongues and hence of experimentally observed accelerator modes.

Non-invasive computerised detection of acute coronary occlusion.

The goal of this study was to evaluate the role of a computerised, non-invasive ECG method for detecting acute coronary occlusion (ACO). Ninety-five standard ECG leads were recorded, before and during ACO, from 18 patients undergoing balloon angioplasty. ECG amplitude and derivative parameters were calculated for the ORS, ST and T components of the ECG signal, before and during ACO. Results were obtained for each lead. Sensitivity of the standard visual ECG analysis for detecting ACO was 48%, whereas the percentage of conventional ECG changes during baseline was 14%. For the best ECG parameter, the amplitude parameter of the ORS component, sensitivity was 82%, and the percentage of parameter changes during baseline was 20%. The sensitivity for detecting ACO with five of the six ECG parameters studied was greater than that of the standard visual analysis. Ischaemic changes were detected in 4.3 +/- 1.6 leads per patient using the amplitude parameter of the ORS component, whereas, with the standard visual analysis, 2.5 +/- 2.1 leads demonstrated such changes (p<0.001). Results were then summarized per patient. The standard visual ECG analysis detected ACO in 15 of 18 patients (83%), if at least one lead showed ischaemic changes. The computerised analysis detected ACO in all 18 patients using the same criterion. The sensitivity of the computerised method for detecting ACO in the clinical setting of angioplasty was greater than that of the standard visual analysis. It is suggested that the computerised method may be useful for detecting myocardial ischaemia in other clinical settings of acute myocardial ischaemia.

Semiclassical quantization of separatrix maps.

Quantization of energy balance equations, which describe a separatrixlike motion is presented. The method is based on an exact canonical transformation of the energy-time pair to the action-angle canonical pair, (E,t)-->(I,theta). Quantum mechanical dynamics can be studied in the framework of the new Hamiltonian. This transformation also establishes a relation between a wide class of the energy balance equations and dynamical localization of classical diffusion by quantum interference, that was studied in the field of quantum chaos. An exact solution for a simple system is presented as well.

Exercise stress testing, myocardial perfusion imaging and stress echocardiography for detecting restenosis after successful percutaneous transluminal coronary angioplasty: a review of performance.

When chest symptoms recur in a patient who underwent percutaneous transluminal coronary angioplasty (PTCA), it is necessary to rule out restenosis (R). Three main noninvasive tests suggest the presence of R: exercise stress test (XT), myocardial perfusion imaging (MPI) and stress echocardiography (s-echo). The objectives of this review were: (1) to estimate the pretest probability of R as a function of time after PTCA in symptomatic patients and (2) to obtain an approximation of the diagnostic parameters of the XT, MPI and s-echo for detecting R. A MEDLINE search (English-language, years: 1980-2001) was conducted to identify studies examining post-PTCA functional testing for diagnosing R. Data from the studies were pooled. Comparing studies was often difficult due to varying methodology in the studies. Pretest probability of R in symptomatic patients increases in a nonlinear fashion from 20% or less at 1 month, to nearly 90% at 1-year postangioplasty. The approximated accuracy of the XT, MPI, and s-echo for detecting R was 62, 82 and 84%, respectively. During the first month after PTCA, none of the noninvasive modalities is able to accurately detect R. Late (7-9 months) after PTCA, the pretest probability of R is high and therefore the noninvasive measure may be spared. Our analysis suggests that MPI and s-echo should be preferred over the XT for diagnosing R.

Quantum localization for a kicked rotor with accelerator mode islands.

Dynamical localization of classical superdiffusion for the quantum kicked rotor is studied in the semiclassical limit. Both classical and quantum dynamics of the system become more complicated under the conditions of mixed phase space with accelerator mode islands. Recently, long time quantum flights due to the accelerator mode islands have been found. By exploration of their dynamics, it is shown here that the classical-quantum duality of the flights leads to their localization. The classical mechanism of superdiffusion is due to accelerator mode dynamics, while quantum tunneling suppresses the superdiffusion and leads to localization of the wave function. Coupling of the regular type dynamics inside the accelerator mode island structures to dynamics in the chaotic sea proves increasing the localization length. A numerical procedure and an analytical method are developed to obtain an estimate of the localization length which, as it is shown, has exponentially large scaling with the dimensionless Planck's constant (tilde)h<<1 in the semiclassical limit. Conditions for the validity of the developed method are specified.

The effect of Losartan on insulin resistance and beta cell function in chronic hemodialysis patients.

Insulin resistance (IR) is prevalent in hemodialysis patients. IR and hyperinsulinemia have an important role in the development of atherosclerosis, which is the most common cause of morbidity and mortality in hemodialysis patients. Thus, antihypertensive drugs that lower IR, may have an additional beneficial effect in the treatment of cardiovascular diseases in these patients. In this preliminary study we examined the effect of Losartan (an angiotensin II receptor antagonist) treatment on IR and beta cell function in five hypertensive non-diabetic chronic hemodialysis patients. All other known causes of IR in end stage renal failure were excluded. After a washout period of two weeks, Losartan 50 mg, was administered for 6 weeks. Fasting blood glucose (FBG) and insulin levels were measured before and after the treatment IR and beta cell function were calculated using the "homeostasis model assessment"-HOMA. Systolic and diastolic blood pressure (BP) have not changed significantly throughout the study. FBG increased significantly from 76 mg/dL +/- 1 to 89 mg/dL +/- 4 (p < 0.01), however, insulin levels have not changed significantly. Calculated IR values did not show a difference, but calculated beta cell function decreased significantly after Losartan treatment from 291% +/- 50 to 146% +/- 10, (p < 0.016). These preliminary results suggest that in chronic hemodialysis hypertensive non-diabetic patients short treatment with Losartan has deleterious effect on glucose homeostasis mediated via a decrease in beta cell function.

Theoretical analysis of systematic errors introduced by a pedicel-girdling technique used to estimate separately the xylem and phloem flows.

The water budget of fruits was analysed by means of a biophysical model of fruit growth, built and calibrated recently for peaches [Prunus persica (L.) Batsch]. This analysis was applied to the evaluation of systematic errors introduced by a pedicel-girdling method (with the observations being treated by means of a subtractive technique) used to separate the contributions of xylem and phloem flow to the total water inflow to the fruit. The flows were considered as solution transport through composite membranes and were calculated by means of equations drawn from non-equilibrium thermodynamics. The total inflow of water was simulated as dependent on the water status in the tree. The hourly time step was used for the simulation. The flows obtained by simulation of the pedicel-girdled fruit were compared with those found by simulation of the intact-pedicel fruit. The error introduced by the pedicel-girdling technique was evaluated theoretically and was shown to vary during the day, ranging from very small (relative error of 3-7%) at the period when the rate of fruit growth is maximal to 100% when the fruit volume does not change. The vascular flows obtained from the "girdling experiments" are discussed in relation to the possible theoretically estimated errors.

Laparoscopic and thoracoscopic esophagomyotomy for children with achalasia.

BACKGROUND: Minimally invasive esophagomyotomy, consisting of a laparoscopic or thoracoscopic approach, has become a preferred surgical treatment for adults with achalasia. This multicenter study reports on the clinical status of children who have undergone minimally invasive esophagomyotomy for achalasia. METHODS: Symptomatology for achalasia was assessed in 22 pediatric patients who underwent minimally invasive esophagomyotomy for achalasia between 1995 and 2000. All patients were evaluated for duration of hospitalization, postoperative resumption of feeds, postoperative complications, and symptomatic relief. Participants were assigned pre-and postoperative symptom severity scores ranging from 0 (no symptoms) to 3 (severe). RESULTS: The median age of the 10 females and 12 males at time of surgery was 11.3 years +/- 3.4 (standard deviation). Transabdominal laparoscopic esophagomyotomy with fundoplication was performed in 18 patients, and thoracoscopic esophagomyotomy without fundoplication was performed in 4. Two patients required conversion from transabdominal laparoscopic esophagomyotomy to open esophagomyotomy because of intraoperative esophageal perforation. The mean duration of postsurgical follow-up was 17 +/- 16 (standard deviation) months (range, 1-54 months). Mean duration of hospitalization (days +/- standard error or mean) was less for transabdominal laparoscopic esophagomyotomy than for converted open esophagomyotomy (2.7 +/- 0.3 vs. 9.0 +/- 3.0 days; P < 0.05) or for thoracoscopic esophagomyotomy (4.8 +/- 1.7 days; P = not significant). Mean time to resumption of soft feedings (days +/- standard error or mean) occurred sooner after transabdominal laparoscopic esophagomyotomy than after converted open esophagomyotomy (2.0 +/- 0.2 vs. 5.5 +/- 0.5 days; P < 0.001) or after thoracoscopic esophagomyotomy (4.0 +/- 1.3 days; P = not significant). Patients experienced significant pre-to postoperative improvement in mean severity score with regard to dysphagia (2.6 vs. 0.4; P < 0.001) and regurgitation (1.7 vs. 0.2; P < 0.001). CONCLUSIONS: Minimally invasive esophagomyotomy can provide excellent symptomatic relief from dysphagia and regurgitation for children with achalasia.

Visceral vascular anomalies.

Gastrointestinal endoscopy is an essential modality often used for initial diagnostic assessment and staging of visceral vascular anomalies, especially when bleeding is the presenting symptom. Some lesions have a pathognomonic appearance on endoscopy. Others are less clearly identifiable and require a multidisciplinary assessment, including histopathology, for a correct diagnosis. Proper application of nomenclature is crucial to prevent the institution of improper therapies. Advanced endoscopic methods, including endosonography and various hemostatic techniques, are useful to evaluate the depth and character of gastrointestinal wall involvement and to provide minimally invasive treatment when appropriate.

[Diagnosis of idiopathic autonomic neuropathy].

This is a case report of a 51 years old woman admitted to the hospital due to abdominal pain and intractable diarrhea of two months duration. Her history and her physical examination revealed signs and symptoms leading to the diagnosis of the rare syndrome of idiopathic autonomic neuropathy. In this case report we briefly describe the characteristics of the syndrome and its natural history and treatment. We also raise the important issue of common error patterns in diagnostic reasoning such as "omission" and "anchoring" and how these patterns are reflected in the present case.