Evaluating the potential of chelation therapy to prevent and treat gadolinium deposition from MRI contrast agents.

Several MRI contrast agent clinical formulations are now known to leave deposits of the heavy metal gadolinium in the brain, bones, and other organs of patients. This persistent biological accumulation of gadolinium has been recently recognized as a deleterious outcome in patients administered Gd-based contrast agents (GBCAs) for MRI, prompting the European Medicines Agency to recommend discontinuing the use of over half of the GBCAs currently approved for clinical applications. To address this problem, we find that the orally-available metal decorporation agent 3,4,3-LI(1,2-HOPO) demonstrates superior efficacy at chelating and removing Gd from the body compared to diethylenetriaminepentaacetic acid, a ligand commonly used in the United States in the GBCA Gadopentetate (Magnevist). Using the radiotracer 153Gd to obtain precise biodistribution data, the results herein, supported by speciation simulations, suggest that the prophylactic or post-hoc therapeutic use of 3,4,3-LI(1,2-HOPO) may provide a means to mitigate Gd retention in patients requiring contrast-enhanced MRI.

Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy.

Allogeneic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin lymphoma (HL). When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB. Ninety-eight patients were included. Median follow-up was 31 months for the whole cohort. All patients in the HAPLO group (N=34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, N=31, 91%) or a RIC (N=3, 9%) followed by post-transplant cyclophosphamide. After adjustment for significant covariates, MMUD and CB were associated with significantly lower GvHD-free relapse-free survival (GRFS; hazard ratio (HR)=2.02, P=0.03 and HR=2.43, P=0.009, respectively) compared with HAPLO donors. In conclusion, higher GRFS was observed in Hodgkin lymphoma patients receiving a RIC or NMA allo-SCT with post-transplant cyclophosphamide from HAPLO donors. Our findings suggest they should be favoured over MMUD and CB in this setting.

Nasal immunization with subunit proteosome influenza vaccines induces serum HAI, mucosal IgA and protection against influenza challenge.

The immunogenicity of a mucosally delivered subunit influenza vaccine was assessed in mice. Split influenza virus vaccine (sFlu) was formulated with proteosomes (Pr-sFlu), administered intranasally, and the induced immunity was compared with the responses elicited by sFlu alone given either intramuscularly or intranasally. Intranasal (i.n.) immunization with Pr-sFlu induced specific serum IgG and hemagglutination inhibition (HAI) titers comparable to or better than those induced by intramuscular (i.m.) sFlu, and in contrast to sFlu alone, i.n. Pr-sFlu also induced high levels of influenza-specific IgA in lung and nasal washes. Mice receiving i.n. Pr-sFlu were completely protected against live virus challenge, as were mice immunized by injection with sFlu alone. The i.n. Pr-sFlu elicited cytokine responses polarized towards a type 1 phenotype whereas those elicited by sFlu alone were of a mixed type 1/type 2 phenotype. The data strongly suggest that i.n. proteosome-formulated influenza antigens are highly effective and are excellent candidates for a non-invasive human vaccine.

[Neovascular glaucoma following proton-beam therapy. Case report]. / Glaucome néovasculaire compliquant la protonthérapie. A propos d'une observation.

A 52-year-old-male patient was treated for a posterior choroid melanoma of the right eye. When it was diagnosed, it measured 6mm in thickness and 11.9mm for the largest diameter and had a typical mushroom shape. General investigations found no metastatic disease. It was treated with proton-beam irradiation. Seven years later, the patient experienced increased intraocular pressure associated with cataract and pain. The patient finally accepted enucleation, as the vision of this eye was completely lost and the eye had become painful. Histologic analysis of the eye showed changes affecting both the anterior and the posterior segments of the eye, mostly related to the tumor and the consequences of treatment. Neovascular glaucoma is a major complication that very often leads to enucleation.

Use of binaural beat tapes for treatment of anxiety: a pilot study of tape preference and outcomes.

CONTEXT: Recent studies and anecdotal reports suggest that binaural auditory beats can affect mood, performance on vigilance tasks, and anxiety. OBJECTIVE: To determine whether mildly anxious people would report decreased anxiety after listening daily for 1 month to tapes imbedded with tones that create binaural beats, and whether they would show a definite tape preference among 3 tapes. DESIGN: A 1-group pre-posttest pilot study. SETTING: Patients' homes. PARTICIPANTS: A volunteer sample of 15 mildly anxious patients seen in the Clinique Psyché, Montreal, Quebec. INTERVENTION: Participants were asked to listen at least 5 times weekly for 4 weeks to 1 or more of 3 music tapes containing tones that produce binaural beats in the electroencephalogram delta/theta frequency range. Participants also were asked to record tape usage, tape preference, and anxiety ratings in a journal before and after listening to the tape or tapes. MAIN OUTCOME MEASURES: Anxiety ratings before and after tape listening, pre- and post-study State-Trait Anxiety Inventory scores, and tape preferences documented in daily journals. RESULTS: Listening to the binaural beat tapes resulted in a significant reduction in the anxiety score reported daily in patients' diaries. The number of times participants listened to the tapes in 4 weeks ranged from 10 to 17 (an average of 1.4 to 2.4 times per week) for approximately 30 minutes per session. End-of-study tape preferences indicated that slightly more participants preferred tape B, with its pronounced and extended patterns of binaural beats, over tapes A and C. Changes in pre- and posttest listening State-Trait Anxiety Inventory scores trended toward a reduction of anxiety, but these differences were not statistically significant. CONCLUSIONS: Listening to binaural beat tapes in the delta/theta electroencephalogram range may be beneficial in reducing mild anxiety. Future studies should account for music preference among participants and include age as a factor in outcomes, incentives to foster tape listening, and a physiologic measure of anxiety reduction. A controlled trial that includes binaural beat tapes as an adjunctive treatment to conventional therapy for mild anxiety may be warranted.

Synthesis, characterization, and activity of metabolites derived from the cyclooxygenase-2 inhibitor rofecoxib (MK-0966, Vioxx).

Metabolites of the COX-2 inhibitor rofecoxib (MK-0966, Vioxx) were prepared by synthetic or biosynthetic methods. Metabolites include products of oxidation, glucuronidation, reduction and hydrolytic ring opening. Based on an in vitro whole blood assay, none of the known human metabolites of rofecoxib inhibits COX-1 nor contributes significantly to the inhibition of COX-2.

Comparative effects of bisoprolol and nitrendipine on exercise capacity in hypertensive patients with regular physical activity.

The aim of this study was to evaluate the long-term effects of administering bisoprolol compared with nitrendipine on the duration of the exercise tolerated by male and female patients, aged 18-65 years, having mild to moderate hypertension and taking regular exercise. In this double-blind, randomized prospective study, 96 patients (85 men and 11 women, 48+/-10 years) formed two groups: 49 in the bisoprolol group, and 47 in the nitrendipine group. After a washout period of 14 days, either 10 mg of bisoprolol or 20 mg of nitrendipine was given daily over a treatment period of 12 weeks. During the treatment period, the stability of the physical training was monitored weekly by using a questionnaire. The results of two maximal triangular exercise tolerance tests (ETTs) on an ergometric bicycle performed at D0 under placebo and at D84 under active treatment were compared. No statistical difference was observed between both groups, concerning age, gender, morphologic characteristics, resting cardiovascular parameters, or physical training. Both groups maintained the same training level throughout the study. No significant differences between the groups were noted for duration of ETT [D0 892+/-284 s, D84, 919+/-267 s (NS) vs. D0 929+/-290 s, D84 904+/-324 s (NS)], or maximal work load [D0 190+/-49 W, D84 197+/-48 W (NS) vs. D0 198+/-49 W, D84 196+/-55 W (NS)]. On the other hand, both groups differed in maximal systolic blood pressure [D0 239+/-24 mm Hg, D84 215+/-22 mm Hg (p<0.001) vs. D0 237+/-24 mm Hg, D84 222+/-27 mm Hg (p<0.05)] (p = 0.05), and maximal pulse rate during exercise [141+/-18 vs. 163+/-17] (p<0.001), albeit not in maximal diastolic blood pressure [D0 113+/-13 mm Hg, D84 106+/-17 mm Hg (p<0.05) vs. D0 112+/-13 mm Hg, D84 104+/-15 mm Hg (p<0.05)]. The patient's own perception of the maximal effort (Borg scale) was not significantly different in either of the groups (placebo vs. treatment). Overall, in a population of hypertensive patients taking regular exercise, long-term treatment with bisoprolol produced no significant changes in the duration of peak effort, maximal workload, or the effort perceived by the patients themselves. The effects of regular exercise were comparable in both groups (bisoprolol or nitrendipine). Because previous studies have shown that dihydropyridines do not modify exercise performance in hypertensive patients, it may be concluded that the antihypertensive therapy with bisoprolol is well tolerated in a population of active hypertensive patients during dynamic exercise.

Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles.

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for the inhibition of COX-1-derived thromboxane B(2) synthesis after blood coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50) values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50) = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a (51)Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.

RFLP mapping of the whole genome of ten viral isolates representative of different biological groups of potato virus Y.

Ten PVY isolates representative of four PVY groups (YN, YNTN, YN-W, YO), differing by their ability to induce reactions of vein necrosis on tobacco and tuber necrosis on potato, were studied in order to research the regions of the viral genome involved in these necrosis phenomena. The whole genome of these isolates was amplified in two fragments (4,063 and 5,670 nucleotides) and was subjected to a restriction fragment length polymorphism (RFLP) study. In the first 4,063 nucleotides of the PVY genome, a phenetic analysis of RFLP data resulted in a clustering of our PVY isolates into three groups: PVYN isolates (group A); PVYNTN and PVYN-W isolates (group B) and PVYO isolates (group C). In the last 5,670 nucleotides, two groups were found: PVYN and PVYNTN isolates (group D) and PVYO and PVYN-W isolates (group E). From this clustering and the necrosing properties known for these isolates, the tobacco necrosis determinants seem more likely located in the 5' than in the 3' half part of the viral RNA, whereas it would be the opposite situation for the determinants of the necrosis on potato tubers. Moreover a recombination event seemed to have occurred in the genome of the PVYN-W isolates.

Development of a protocol for allogeneic marrow transplantation for severe systemic sclerosis: paradigm for autoimmune disease.

Some types of severe autoimmune disease are associated with significant morbidity and a high mortality rate. Many of these cases occur in young adults who, even if they survive, become severely debilitated. Systemic sclerosis (SSc) is a paradigm for other severe autoimmune diseases in which patients with poor prognostic features can be identified early in the course of the disease. Allogeneic marrow transplantation may be effective for the control of autoimmune diseases like SSc because the preparative regimen will significantly suppress the host immune system and the antihost effects of the donor immune system in the engrafted marrow will help maintain the suppression of the host immune system. Considering the morbidity and poor prognosis associated with severe SSc and the favorable outcome now associated with allogeneic marrow transplantation from HLA identical siblings for other nonmalignant diseases, Phase I and II studies are warranted. These will evaluate the safety of allogeneic marrow transplantation and explore its role in the management and control of a severe autoimmune disease. We review issues important in the development of an allogeneic marrow transplant protocol for severe SSc, including patient selection, plan of treatment, prevention of graft versus host disease, supportive care, and evaluation after transplant.

The role of home practice in the thermal biofeedback treatment of migraine headache.

The present study examined the role of home practice of hand warming in the thermal biofeedback treatment of migraine headache. Seventeen female migraine sufferers were randomly assigned to one of the following conditions: thermal biofeedback with regular home practice (HP) or thermal biofeedback without home practice (NHP). Biofeedback treatment consisted of 12 training sessions over a 6-week period, and all subjects completed 5 weeks of headache monitoring before and after treatment. Results indicated that subjects in the HP condition experienced decreases in headache activity and medication intake that were both statistically and clinically significant compared with the NHP condition. None of the outcome measures revealed significant improvement in the NHP condition. Thus, regular home practice appears to enhance the efficacy of biofeedback in the treatment of migraine.

Long-term effects of biofeedback on migraine headache: a prospective follow-up study.

The aim of the present study was two-fold: to assess the long-term effects of biofeedback on migraine, and to determine the extent to which additional treatment after biofeedback treatment is completed can affect follow-up results. Ninety-six women whose migraine had been treated through biofeedback either 2-3 years (shorter follow-up) or 6-7 years (longer follow-up) earlier were divided into four groups according to how long ago they had received their biofeedback treatment and whether or not they had received any additional treatment (whatever the nature) since the posttreatment assessment: shorter follow-up without additional treatment (n = 24), shorter follow-up with additional treatment (n = 22), longer follow-up without additional treatment (n = 24), and longer follow-up with additional treatment (n = 26). Subjects were asked to keep a headache diary for five weeks, as they had done during earlier assessments. Overall, results showed that migraine activity was significantly less at follow-up than at pretreatment. However, whether the observed long-term benefits could be attributed to biofeedback was unclear because medication was found to be as much in use at follow-up as at pretreatment. Results also indicated that 51% of the subjects did seek additional treatment between posttreatment and follow-up. Contrary to expectations, however, additional treatment was not associated with better therapeutic benefits at follow-up. The research and the clinical implications of those findings are discussed.

The differential effects of biofeedback in the treatment of menstrual and nonmenstrual migraine.

The aim of the present study was to investigate the effects of biofeedback training in the treatment of menstrual and nonmenstrual migraine. Accordingly, 39 female patients suffering from both migraine associated, and migraine not associated, with menstrual periods were drawn from a pool of research volunteers enrolled in a biofeedback treatment program for migraine headaches. All patients were required to complete 5 weeks of daily self-monitoring of headache and menstruation activity immediately before and after treatment, and again at 6-month follow-up. Within-subjects comparisons of the effects of biofeedback on menstrual and nonmenstrual migraine, and between-subjects comparisons of the effects of biofeedback on patients suffering predominantly from either menstrual or nonmenstrual migraine showed that biofeedback is just as effective in reducing menstrual migraine as it is in reducing nonmenstrual migraine. Questions as to whether or not these conclusions can apply to patients who experience migraine headaches only during, or shortly before or after, menstruation, are raised.

Odontoblast-like cytodifferentiation of human dental pulp cells in vitro in the presence of a calcium hydroxide-containing cement.

The cement produced microcrystals of calcite by reaction with culture medium supplemented with calf serum. Human dental pulp cells seeded on such a substrate preferentially adhered and aggregated around the microcrystals. Immunofluorescence and immunogold labelling revealed a high affinity of serum fibronectin molecules for the calcite crystals. At 4 weeks in culture, the cells had various features of differentiated odontoblasts, notably nuclear polarization, typical appearance of the Golgi apparatus, synthesis of type I collagen and absence of type III, and apical accumulation of actin and vimentin. These cells also elaborated a collagenous extracellular matrix which did not mineralize.

Biofeedback control of migraine headaches: a comparison of two approaches.

In order to assess the relative effectiveness of finger warming and temporal blood volume pulse reduction biofeedback in the treatment of migraine, 22 female migraine patients were assigned to one of three experimental conditions: temporal artery constriction feedback, finger temperature feedback, or waiting list. Biofeedback training consisted of 12 sessions over a 6-week period. All patients completed 5 weeks of daily self-monitoring of headache activity (frequency, duration, and intensity) and medication before and after treatment. Treatment credibility was assessed at the end of Sessions 1, 6, and 12. Results showed that temporal constriction and finger temperature biofeedback were equally effective in controlling migraine headaches and produced greater benefits than the waiting list condition. Power analyses indicated that very large sample sizes would have been required to detect any significant differences between the two treatment groups. No significant relationships were found between levels of therapeutic gains and levels of thermal or blood volume pulse self-regulation skills. Likewise, treatment outcome was not found to be related to treatment credibility. Further analyses revealed that changes in headache activity and medication were associated with changes in vasomotor variability. Because blood volume pulse variability was not significantly affected by biofeedback training, questions about its role in the therapeutic mechanism are raised.

Blood volume pulse biofeedback in the treatment of migraine headache: a controlled evaluation.

In order to evaluate the specific effects of blood volume pulse (BVP) biofeedback in the treatment of migraine headaches, 21 female migraine patients were randomly assigned to one of three experimental conditions: temporal artery constriction feedback, temporal artery dilation feedback, or waiting list. Biofeedback training consisted of 15 sessions over an 8-week period. All patients completed 5 weeks of daily self-monitoring of headache activity and medication before and after treatment. Results showed that constriction and dilation biofeedback were equally effective in controlling migraines and produced greater benefits than the waiting-list condition. No significant relationships were found between therapeutic gains and BVP self-regulation skills. However, further analyses revealed that changes in headache activity and medication were associated with changes in vasomotor variability. The current rationale for the use of BVP biofeedback in the treatment of migraine is questioned and a new one is proposed.

Evaluation of skin temperature biofeedback training at two different sites for migraine.

All combinations of cooling versus warming and finger versus temporal artery were used in the present study, the aim of which was to identify an optimal biofeedback training site and to assess the specific effects of skin temperature biofeedback upon migraine. After an initial 4-week baseline phase, during which daily records of headache activity and medication were kept, 24 migraine patients were randomly assigned to one of the four experimental conditions. Training sessions for all patients were of 50-min duration and occurred once per week for 8 weeks. The headache charts were completed for another 4 weeks after treatment was terminated and again at 6-month follow-up. The results showed significant reductions in migraine activity and drug usage. However, self-regulation of skin temperature in different directions at different sites did not in fact result in significantly different magnitudes of change in migraine activity across groups. The role of nonspecific factors is discussed and a physiological model is proposed to explain how warming and cooling may produce clinical improvement in migraine.