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.

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.

The expression of MDP-1, a component of Drosophila embryonic basement membranes, is modulated by apoptotic cell death.

Using a novel monoclonal antibody we have studied the expression of a large proteoglycan-type molecule in Drosophila embryos. This molecule is secreted exclusively by migratory, embryonic hemocytes/macrophages and was therefore named MDP-1 for Macrophage-Derived Proteoglycan-1. Expression of MDP-1 begins late during hemocyte differentiation, after these cells have left their birthplace in the head mesoderm. At this time, macrophages are engaged in extracellular matrix deposition and the phagocytosis of cell debris generated by apoptotic events in various parts of the embryo, in particular from the developing central nervous system. Embryos deficient for programmed cell death display a greatly reduced amount of MDP-1 deposition in tissues that normally undergo morphogenetic cell death. This suggests a regulatory role for apoptosis in the terminal differentiation of Drosophila hemocytes. MDP-1 is initially deposited around the developing central nervous system and is later found in basement membrane structures surrounding various other organs, such as the gut, Malpighian tubules and part of the tracheal system. The temporal and localized deposition of MDP-1 suggests that it may play a role in delineating the central nervous system structure during axonogenesis and may participate in the formation of a functional 'blood-brain barrier' in Drosophila.

Clonazepam blockade of spontaneous and CO2 inhalation-provoked panic in a patient with panic disorder.

A 30-year-old woman with panic disorder and phobic avoidance responded partially to treatment with alprazolam but recovered fully while receiving clonazepam, which blocked her panic attacks and anticipatory anxiety. Before treatment, the patient underwent a carbon dioxide inhalation test as a challenge and sustained a full-featured panic attack. After clonazepam therapy and retesting under identical conditions, no panic attack was reported. This is the first report of provoked panic blocked by clonazepam, a putative, clinically effective antipanic agent.

Thyroid indices in panic disorder.

Eighty-two patients suffering from panic attacks with or without phobias were examined for evidence of thyroid disease. None of the patients had abnormal total T4 or T3 resin uptake measurements, regardless of whether they were nonmedicated or treated with one of three antipanic drugs: alprazolam, phenelzine, or imipramine. A higher than expected incidence of undetectable TSH levels (22% overall) appeared in all groups. The clinical relevance of this finding is currently uncertain.

Lactate infusion in anxiety research: its evolution and practice.

The unpredictability of spontaneous unexpected panic attacks has inhibited the controlled study of this phenomenon. Previous studies demonstrated that an increase in blood lactic acid occurred concomitant with symptoms of anxiety in anxiety-prone patients who underwent standard physical exercise. The question of whether these patients had an excessive sensitivity to lactate led to the development of the lactate infusion model, in which anxiety is induced in a controlled environment. The history and current application of the lactate infusion model in the study of neurochemical correlates of panic are described, and a methodology for lactate infusion procedures is outlined.

Symptoms of patients with silent ischemia as detected by thallium stress testing.

This study was undertaken to determine whether patients with silent ischemia (SI) (a positive thallium stress test without chest pain) have nonchest-pain symptoms that might serve as "anginal equivalents." Two hundred ninety-four individuals on completing a stress test were requested to score ten symptoms on a questionnaire (0 absent; 3 severe). Forty-three with a positive test had pains (chest, back, arm, and/or jaw) (no SI), whereas 93 with a positive test did not (SI). Patients with SI and patients without SI did not differ as to age, gender, or clinical features (including presence of diabetes or a history of myocardial infarction), but patients with SI were less likely to report a history of effort-related chest pains. Patients with SI exercised longer and had a higher peak heart rate. Patients were comparable with respect to myocardial ischemia (ST segment depression, double product, thallium lung uptake, and positive thallium scintigrams) and severity of coronary disease. Patients with SI complained less of weakness (p < 0.02) and tended to have lower overall symptom scores (4.2 +/- 0.3 vs 5.4 +/- 0.6), but breathlessness was comparable for both groups. On multivariate analysis, no nonanginal symptom was associated with SI. Only absence of a history of chest pain with activity and longer exercise time were related to SI. Patients with SI have similar clinical features as those with angina but tend to be less symptomatic with myocardial ischemia even for symptoms other than chest pain.

The effects of Carmeda Bioactive Surface on human blood components during simulated extracorporeal circulation.

Postoperative morbidity after cardiopulmonary bypass most commonly manifests as bleeding diatheses or pulmonary dysfunction. The pathophysiology has been attributed to the activation of cellular and humoral components of blood after contact with an artificial surface. Development of a surface that would be nonthrombogenic and also would constitute a less potent inflammatory stimulus would therefore be beneficial. In the following experiments, we evaluated the heparin-bonded Carmeda Bioactive Surface (Medtronics Cardiopulmonary, Anaheim, Calif.) in an in vitro model of extracorporeal circulation at standard-dose heparin (5 U/ml), to examine the effects of the surface treatment on activation of blood elements, and at reduced-dose heparin (1 U/ml), to determine whether surface-bound heparin would serve as an effective anticoagulant. During the initial recirculation period, platelet counts in the Carmeda (n = 12) circuits were preserved at both doses of heparin and compared with control values (n = 12): At 5 U/ml, control 36% +/- 4% (mean +/- standard error of the mean) versus Carmeda 81% +/- 5%; at 1 U/ml, 43% +/- 3% versus 61% +/- 10%, expressed as a percent of baseline at 30 minutes, p < 0.05. Furthermore, plasma levels of platelet factor 4 and beta-thromboglobulin were significantly reduced in the Carmeda circuits throughout the experiment: At heparin 5 U/ml, 2500 +/- 340 ng/ml versus 604 +/- 191 ng/ml; at 1 U/ml, 2933 +/- 275 ng/ml versus 577 +/- 164 ng/ml of platelet factor 4 at 2 hours (p < 0.05). The pattern of beta-thromboglobulin release was similar, with effects more pronounced at the lower dose of heparin. Surface modification also reduced leukocyte depletion (p < 0.05) and release of elastase at both concentrations of heparin (5 U/ml, 0.72 +/- 0.29 ng/ml versus 0.33 +/- 0.23 ng/ml; 1 U/ml, 0.85 +/- 0.08 ng/ml versus 0.20 +/- 0.05 ng/ml, at 2 hours, p < 0.05). Moreover, as heparin concentration was reduced, Carmeda surface treatment significantly decreased generation of C3a des Arg (1 U/ml, 14,410 +/- 3558 ng/ml versus 3053 +/- 1039 ng/ml at 2 hours, p < 0.05). Although heparin bonding was originally intended to obviate the need for systemic heparinization, Carmeda treatment did not reduce fibrinopeptide A generation at the lower dose of heparin. In summary, Carmeda treatment failed to exhibit anticoagulant efficacy in this model; however, the data suggest that surface modification may have a role in ameliorating the typical inflammatory response initiated by blood contact with an artificial surface.

Relaxation and diffusion for the kicked rotor

The dynamics of the kicked rotor, which is a paradigm for a mixed system, where the motion in some parts of phase space is chaotic and in other parts is regular, is studied statistically. The evolution operator of phase space densities in the chaotic component is calculated in the presence of noise, and the limit of vanishing noise is taken in the end. The relaxation rates to the equilibrium density are calculated analytically within an approximation that improves with increasing stochasticity. The results are tested numerically. A global picture is presented of relaxation to the equilibrium density in the chaotic component when the system is bounded and to diffusive behavior when it is unbounded.

Correlations in the adiabatic response of chaotic systems

Adiabatic variation of the parameters of a chaotic system results in a fluctuating reaction force. The quantum analog of a classical dissipative force, proportional to the time integral of the force-force correlation function, vanishes. We study this quantum-classical crossover for random matrix models. For the Gaussian unitary ensemble the crossover is found to take place on the Heisenberg time scale and the finite time integral practically vanishes for longer times. For the Gaussian orthogonal case, there is no such time scale and the integral falls off inversely proportional to time.

Acute plasticity in the human somatosensory cortex following amputation.

We studied a patient after amputation of an arm and found that in less than 24 h stimuli applied on the ipsilateral face were referred in a precise, topographically organized, modality-specific manner to distinct points on the phantom. Functional magnetic resonance imaging (fMRI) performed one month later showed that brush-evoked activity in the brain demonstrates objective signal changes which correlate with perceptual changes in the phantom hand. This finding in humans corresponds to the observations of immediate plasticity in cortical pathways described in animals, including primates. The results suggest that reorganization of sensory pathways occurs very soon after amputation in humans, potentially due to the unmasking of ordinarily silent inputs rather than sprouting of new axon terminals.

Hypercapneic ventilatory response in patients with panic disorder before and after alprazolam treatment and in pre- and postmenstrual women.

We tested the ventilatory and anxiety response to hypercapneic (CO2) challenge in women with panic disorder as well as in normal women in the premenstrual phase and mid-points of their menstrual cycles. Panic disorder patients were challenged on two occasions, each time while in the premenstrual phase of the menstrual cycle, receiving an open trial of alprazolam through the intervening 8 weeks between tests. This study confirms previous reports indicating increased sensitivity to CO2 in patients with panic disorder and that this sensitivity can be attenuated by treatment. We found a significant decrease in the ventilatory response of panic disorder patients comparing pre- and post-therapy. We also observed that normal females, while in the premenstrual phase of their menstrual cycle, have a heightened anxiety response to CO2 challenge.

Aggressive multimodal treatment of pleuropulmonary blastoma.

Pleuropulmonary blastoma is a rare intrathoracic neoplasm almost solely confined to childhood. Survival is poor. The authors report 2 children with extensive intrathoracic disease who are long term survivors after multimodal therapy. Both children received multiagent neoadjuvant chemotherapy, followed by surgical resection to remove all gross tumor. Postoperative chemotherapy was given to both children; radiotherapy was also given in the second case because of a question of positive tumor margins. Experience supports the use of multimodal therapy, including an aggressive surgical approach in the potentially curative treatment of this tumor.

The opioid contract in the management of chronic pain.

Although the "opioid contract" is widely used in the administration of chronic opioid therapy, its use has not been well defined and there are few guidelines for developing or revising such tools. We reviewed opioid contracts from 39 major academic pain centers and analyzed every statement for its core meaning. These statements were grouped into general categories and then into specific statement groups. Substantial diversity in the content of the 39 contracts was found. Statements could be grouped into 12 general categories, 43 statements groups, and 125 individual statements. Each of the 39 contracts reviewed contained 22.5% +/- 10.9% of the entire list of 125 statements and 32.6% +/- 11.2% of the 43 statement categories. Contract length averaged less than 3 pages (range: 1 to 1 mean 2.2). We describe frequent and infrequent themes that may be well suited for inclusion in any given contract. While there are many significant issues related to the usage of a formal contract in chronic opioid therapy, there was substantial consistency among the contracts in their universal attempts to improve care through dissemination of information, facilitate a mutually agreed-upon course, or enhance compliance. This study serves as an initial step in considering the risk and benefits of an opioid contract as well as its ideal content and presentation.

Adherence monitoring and drug surveillance in chronic opioid therapy.

Monitoring adherence with chronic opioid therapies is a critical yet often difficult task. Because chronic opioid therapy is often fraught with complex pharmacological, psychological, social, and legal issues, its application is often controversial or altogether avoided. Improved drug monitoring and surveillance may help reduce some of the reluctance to use chronic opioid therapy in patients with chronic pain states. We review the literature on patient adherence/compliance with chronic administration of opioids as well as novel methods by which adherence with opioid therapy can be measured.

Naloxone blocks exercise-stimulated water intake in the rat.

To examine whether opiate receptors modulate exercise-induced water intake, we measured water intake during four consecutive hours after a one-hour swim stress in male, Sprague-Dawley rats. Increased cumulative water intake was found four hours following exercise and this response was naloxone-reversible (P = 0.06). Suppression of water intake in the naloxone-treated, exercised group was most marked in the first two hours after exercise (P less than 0.05). Non-exercised rats consumed water at a constant, linear rate (P less than 0.05) whether treated with naloxone or saline. These results indicate an endogenous opioid role in regulating exercise-induced water intake in the rat, but do not delineate whether this role reflects a non-specific stress behavior or specific physiological processes related to thirst.

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.

Vascular anomalies of the mediastinum.

Vascular anomalies, including hemangiomas and vascular malformations, comprise 3% to 6% of mediastinal masses in childhood. These lesions, whether in the mediastinum or elsewhere, often are misdiagnosed and treated inappropriately. Correct diagnosis almost always can be established by history, external physical examination of associated anomalies, bronchoscopy, and/or radiographic studies. Hemangiomas are benign tumors that involute spontaneously but may require antiangiogenic therapy or laser ablation to maintain airway patency prior to involution. Vascular malformations, most commonly lymphatic in origin, will not involute nor respond to drug therapy. Resection and/or sclerotherapy often are indicated.

Determination of estrogens in dosage forms by fluorescence using dansyl chloride.

A sensitive, reproducible, fluorometric procedure for the determination of estrogens in pharmaceutical preparations is presented. The estrogens are determined fluorometrically following their reaction with dansyl chloride. The optimum conditions for the reaction such as pH, reaction solvent composition variations, and speed of reaction are discussed. In addition, a linearity study of the relationship between concentration and fluorescence intensity for estrone, estradiol, and ethinyl estradiol is reported. Solvent extraction procedures based on acid-base behavior or column chromatography are used when necessary to isolate the estrogen prior to reaction with dansyl chloride and fluorometric measurement. The recovery of estrogens from spiked samples indicated that the proposed method is efficient and reproducible. Comparison of the dansyl procedure with the official NF method in the analysis of estrone aqueous suspension showed the proposed method to be accurate and more precise than the NF assay. Estrone aqueous suspension, estradiol in sesame oil, estradiol valerate in castor oil and in sesame oil (in the latter case, in the presence of testosterone), estradiol benzoate in sesame oil, and ethinyl estradiol tablets (0.5 mg/tablet) from commercial sources were satisfactorily analyzed, with average results within compendial limits and no coefficient of variation greater than 2%.