CiteULike: Author Busse

Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATPase and mu-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone.

V Randriamboavonjy — 2008-08-08T18:37:21-00:00

Circulation, Vol. 117, No. 1. (1 January 2008), pp. 52-60.

BACKGROUND: Platelets from patients with type 2 diabetes mellitus display hyperaggregability and increased thrombogenic potential. METHODS AND RESULTS: In platelets from patients with type 2 diabetes mellitus, we found enhanced tyrosine nitration and inactivation of the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA-2), elevated platelet [Ca2+]i, and activation of mu-calpain. The tyrosine nitration of SERCA-2 and the activation of mu-calpain in vitro in platelets from healthy volunteers could be evoked in vitro by peroxynitrite. Platelet endothelial cell adhesion molecule-1 was identified as a mu-calpain substrate; its in vitro degradation was stimulated by peroxynitrite and prevented by calpain inhibitors. Calpain activation also was linked to hyperresponsiveness to thrombin and the loss of platelet sensitivity to nitric oxide synthase inhibitors. Platelets from patients with type 2 diabetes mellitus (hemoglobin A1c >6.6%) contained little or no intact platelet endothelial cell adhesion molecule-1, whereas degradation products were detectable. The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone increased SERCA-2 expression in megakaryocytes, and treating patients with type 2 diabetes mellitus with rosiglitazone for 12 weeks increased platelet SERCA-2 expression and Ca2+-ATPase activity, decreased SERCA-2 tyrosine nitration, and normalized platelet [Ca2+]i. Rosiglitazone also reduced mu-calpain activity, normalized platelet endothelial cell adhesion molecule-1 levels, and partially restored platelet sensitivity to nitric oxide synthase inhibition. CONCLUSIONS: These data identify megakaryocytes/platelets as additional cellular targets for peroxisome proliferator-activated receptor-gamma agonists and highlight potential benefits of rosiglitazone therapy in cardiovascular diseases.

Characteristics associated with citation rate of the medical literature.

AV Kulkarni — 2008-08-07T16:27:49-00:00

PLoS ONE, Vol. 2, No. 5. (2007)

BACKGROUND: The citation rate for articles is viewed as a measure of their importance and impact; however, little is known about what features of articles are associated with higher citation rate. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cohort study of all original articles, regardless of study methodology, published in the Lancet, JAMA, and New England Journal of Medicine, from October 1, 1999 to March 31, 2000. We identified 328 articles. Two blinded, independent reviewers extracted, in duplicate, nine variables from each article, which were analyzed in both univariable and multivariable linear least-squares regression models for their association with the annual rate of citations received by the article since publication. A two-way interaction between industry funding and an industry-favoring result was tested and found to be significant (p = 0.02). In our adjusted analysis, the presence of industry funding and an industry-favoring result was associated with an increase in annual citation rate of 25.7 (95% confidence interval, 8.5 to 42.8) compared to the absence of both industry funding and industry-favoring results. Higher annual rates of citation were also associated with articles dealing with cardiovascular medicine (13.3 more; 95% confidence interval, 3.9 to 22.3) and oncology (12.6 more; 95% confidence interval, 1.2 to 24.0), articles with group authorship (11.1 more; 95% confidence interval, 2.7 to 19.5), larger sample size and journal of publication. CONCLUSIONS/SIGNIFICANCE: Large trials, with group authorship, industry-funded, with industry-favoring results, in oncology or cardiology were associated with greater subsequent citations.

Financing reforms in the German hospital sector: from full cost cover principle to prospective case fees.

R Busse — 2008-08-05T09:19:25-00:00

Medical care, Vol. 35, No. 10 Suppl. (October 1997)

OBJECTIVES: The authors provide an overview of the hospital sector in Germany with a focus on the impact of recent reform legislation on this sector. METHODS: Data from the Federal Statistics Office, the Ministry of Health, and the Federal Association of Physicians are synthesized with information obtained from a general review of the literature. RESULTS: Before the implementation of recent health-care reforms, the German health-care system has been sharply divided into inpatient and ambulatory care sectors, resulting in a fragmented system of care delivery. All hospital operating costs were fully covered through per diem charges. The 1992 Health Care Structure Act and subsequent pieces of legislation have introduced new mechanisms to improve cost efficiency in the hospital sector and increase coordination between the inpatient and outpatient care. These measures notably include implementing an inpatient prospective payment system and permitting ambulatory surgery and care services to be offered in inpatient settings. CONCLUSIONS: Whereas prospective payments have greatly reduced the length of stay, hospitals were reluctant to offer ambulatory surgery due to budgetary constraints and the high level of ambulatory surgery by office-based physicians. The reforms passed have not yielded substantial cost savings. These reforms offer a natural experiment that could benefit from national and international studies on the impact of hospital sector redesign on management, financing, and patient outcomes.

Euler equations in geophysics and astrophysics

FH Busse — 2008-02-17T11:20:50-00:00

Physica D: Nonlinear Phenomena, Vol. In Press, Accepted Manuscript

Lead poisoning due to adulterated marijuana.

F Busse — 2008-04-15T01:27:15-00:00

The New England journal of medicine, Vol. 358, No. 15. (10 April 2008), pp. 1641-1642.

Weakly interacting graphene on a metal: Dirac cones and minigaps for C/Ir(111)

I Pletikosic — 2008-07-18T07:18:16-00:00

(17 Jul 2008)

Epitaxial graphene on Ir(111) prepared in excellent structural quality is investigated by angle-resolved photoelectron spectroscopy. It is found to interact only weakly with Ir(111) resulting in an intact Dirac cone with a Dirac point shifted only slightly above the Fermi level. The moire resulting from the overlaid incommensurate graphene and Ir(111) surface lattices imposes a superperiodic potential giving rise to Dirac cone replicas and the opening of minigaps in the band structure.

Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study.

ED Bateman — 2008-07-08T19:43:19-00:00

American journal of respiratory and critical care medicine, Vol. 170, No. 8. (15 October 2004), pp. 836-844.

For most patients, asthma is not controlled as defined by guidelines; whether this is achievable has not been prospectively studied. A 1-year, randomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Treatment was stepped-up until total control was achieved (or maximum 500 microg corticosteroid twice a day). Significantly more patients in each stratum (previously corticosteroid-free, low- and moderate-dose corticosteroid users) achieved control with salmeterol/fluticasone than fluticasone. Total control was achieved across all strata: 520 (31%) versus 326 (19%) patients after dose escalation (p < 0.001) and 690 (41%) versus 468 (28%) at 1 year for salmeterol/fluticasone and fluticasone, respectively. Asthma became well controlled in 1,071 (63%) versus 846 (50%) after dose escalation (p < 0.001) and 1,204 (71%) versus 988 (59%) at 1 year. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone. Across all strata, 68% and 76% of the patients receiving salmeterol/fluticasone and fluticasone, respectively, were on the highest dose at the end of treatment. Exacerbation rates (0.07-0.27 per patient per year) and improvement in health status were significantly better with salmeterol/fluticasone. This study confirms that the goal of guideline-derived asthma control was achieved in a majority of the patients.

Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction.

JA Leff — 2008-07-04T02:36:51-00:00

The New England journal of medicine, Vol. 339, No. 3. (16 July 1998), pp. 147-152.

BACKGROUND: Patients with mild asthma frequently have only exercise-induced bronchoconstriction, a symptom of inadequate control of asthma. We evaluated the ability of montelukast, a leukotriene-receptor antagonist, to protect such patients against exercise-induced bronchoconstriction. METHODS: We randomly assigned 110 patients (age, 15 to 45 years) with mild asthma and a decrease in the forced expiratory volume in one second (FEV1) of at least 20 percent after exercise on two occasions during a placebo run-in period to receive 10 mg of montelukast (54 patients) or placebo (56 patients) once daily at bedtime for 12 weeks in a double-blind study. Treatment was followed by a two-week, single-blind washout period during which all patients received placebo. Exercise challenges were performed at base line; 20 to 24 hours after dosing at weeks 4, 8, and 12; and at the end of the washout period. The primary end point was the area under the curve for FEV1 (expressed as the percent change from base-line values) in the first 60 minutes after exercise. This measure summarized the extent and duration of bronchoconstriction after exercise. RESULTS: At 12 weeks, montelukast therapy offered significantly greater protection against exercise-induced bronchoconstriction than placebo therapy (expressed as the percentage of inhibition of the end points), as evidenced by the improvement in the area under the FEV1 curve (degree of inhibition, 47.4 percent; P=0.002). Montelukast therapy was also associated with a significant improvement in the maximal decrease in FEV1 after exercise (P=0.003) and the time from the maximal decrease in FEV1 to the return of lung function to within 5 percent of pre-exercise values (P=0.04). The differences between groups in the various measures of lung function were similar at 4, 8, and 12 weeks; there was no evidence of rebound worsening of lung function in the montelukast group after the washout period. After 12 weeks of treatment, patients in the montelukast group were more likely to rate their asthma control as better and less likely to require rescue therapy with a beta-agonist during or after exercise challenge. The rates of adverse events were similar in the two groups. CONCLUSIONS: As compared with placebo, once-daily treatment with montelukast provided significant protection against exercise-induced asthma over a 12-week period. Tolerance to the medication and rebound worsening of lung function after discontinuation of treatment were not seen.

The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma.

E Israel — 2008-07-04T02:35:39-00:00

Annals of internal medicine, Vol. 119, No. 11. (1 December 1993), pp. 1059-1066.

OBJECTIVE: To evaluate the effectiveness of inhibiting the formation of the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenase inhibitor zileuton in the treatment of mild-to-moderate asthma. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: University hospitals and private allergy and pulmonary practices. PATIENTS: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV1) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. INTERVENTION: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks. MEASUREMENTS: Airway function, beta-agonist use, and symptoms; inhibition of 5-lipoxygenase assessed by measurement of urinary leukotriene E4 (LTE4). RESULTS: Zileuton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 within 1 hour of administration (P < 0.001 compared with placebo), equivalent to a 14.6% increase from baseline. After 4 weeks of zileuton therapy, airway function and symptoms improved, with the greatest improvements occurring in the 2.4 g/d group: This group's FEV1 increased by 0.32 L (CI, 0.16 to 0.48 L), a 13.4% increase, compared with a 0.05-L (CI, -0.10 to 0.20 L) increase in patients taking placebo (P = 0.02). Symptoms and frequency of beta-agonist use also decreased with zileuton, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creatinine (CI, 18.1 to 60.4 pg/mg creatinine) and 26.5 pg/mg creatinine (CI, 6.6 to 46.5 pg/mg creatinine) in the 2.4 g/d and 1.6 g/d groups, respectively, compared with a slight increase in the placebo group (P = 0.007 and P = 0.05). No difference was noted in the number of adverse events among treatment groups. CONCLUSIONS: Inhibition of 5-lipoxygenase can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be useful therapy for asthma. Also, 5-lipoxygenase products may mediate part of the baseline airway obstruction in patients with mild-to-moderate asthma.

Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis.

TB Casale — 2008-07-04T02:27:31-00:00

The Journal of allergy and clinical immunology, Vol. 100, No. 1. (July 1997), pp. 110-121.

BACKGROUND: Increased serum levels of antigen-specific IgE are often associated with allergic respiratory disorders. RhuMAb-E25, a recombinant humanized monoclonal antibody, decreases free serum IgE by forming biologically inactive immune complexes with free IgE. OBJECTIVE: We hypothesized that rhuMAb-E25 would decrease total serum IgE and reduce symptoms. METHODS: Two hundred forty subjects were enrolled into five groups to determine the safety, tolerance, and efficacy of repeated administration of rhuMAb-E25 in adults with ragweed-induced allergic rhinitis and to explore the pharmacodynamic relationship of rhuMAb-E25 and IgE. One hundred eighty-one subjects received an initial intravenous loading dose (day 0, 1 month before ragweed season), followed by administration of rhuMAb-E25 (in mg/kg body weight) of 0.15 mg/kg subcutaneously, 0.15 mg/kg intravenously, or 0.5 mg/kg intravenously on days 7, 14, 28, 42, 56, 70, and 84. A subcutaneous placebo group and an intravenous placebo group were included. The total evaluation time included the 84-day treatment period, followed by a 42-day observation period. RESULTS: Adverse events were mild, and no differences were observed in the rates between the three active and two placebo treatment groups. Ragweed-specific IgE levels correlated with symptom scores. RhuMAb-E25 decreased serum free IgE levels in a dose- and baseline IgE-dependent fashion. However, only 11 subjects had IgE levels that were suppressed to undetectable levels (< or = 24 ng/ml), a sample too small to demonstrate significant differences and clinical efficacy. Thus the case for efficacy was not proven. Nonetheless, the study confirms that it is safe to repeatedly administer rhuMAb-E25 over a period of months. CONCLUSIONS: Because rhuMAb-E25 decreased serum free IgE in a dose-dependent fashion and because symptom scores correlated with antigen-specific IgE levels, the results suggest that if given in adequate doses, rhuMAb-E25 should be an effective therapy for allergic diseases.

The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma.

WW Busse — 2008-07-03T07:10:32-00:00

The Journal of allergy and clinical immunology, Vol. 121, No. 5. (May 2008), pp. 1167-1174.

BACKGROUND: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study enrolled 7241 patients aged 5 to 66 years with recent-onset, mild persistent asthma to assess early intervention with the inhaled corticosteroid budesonide on long-term asthma control. OBJECTIVE: The open-label phase of the START study was included to determine the effect on lung function and asthma control of adding budesonide to the reference group patients who had not initially received inhaled corticosteroids. METHODS: Patients were randomized to double-blind treatment with budesonide, 200 mug (those aged < 11 years) or 400 mug once daily, or placebo plus the usual asthma therapy for 3 years, after which all patients received 2 years of open-label treatment with budesonide once daily. RESULTS: During the full 5-year study period, postbronchodilator FEV(1) percent predicted decreased, irrespective of randomized treatment during the double-blind phase, by an average of 2.22% (SE, 0.15%). However, patients with inhaled budesonide in the double-blind phase had a significantly lower risk (odds ratio, 0.61; P < .001) of a severe asthma-related event during the full 5-year study period than those in the reference group. Moreover, patients in the reference group used more additional asthma medications during both the open-label and double-blind phases. CONCLUSIONS: In mild persistent asthma early intervention with inhaled budesonide was associated with improved asthma control and less additional asthma medication use.

Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast.

HS Nelson — 2008-07-03T02:48:07-00:00

The Journal of allergy and clinical immunology, Vol. 106, No. 6. (December 2000), pp. 1088-1095.

BACKGROUND: Asthma is a disease of chronic inflammation and bronchoconstriction. Inhaled corticosteroids (ICSs) provide important anti-inflammatory treatment but may not provide optimal control of asthma when taken alone. Two therapeutic alternatives for enhanced asthma control are to substitute the combination of fluticasone propionate (FP) and salmeterol (FP/Salm Combo) through the Diskus inhaler or to add montelukast to existing ICS therapy. OBJECTIVE: We compared the efficacy and safety of FP/Salm Combo through the Diskus inhaler versus montelukast added to FP (FP + montelukast) in patients whose symptoms were suboptimally controlled with ICS therapy. METHODS: We performed a multicenter, double-blind, double-dummy, parallel-group, 12-week study in 447 patients with asthma who were symptomatic at baseline while receiving low-dose FP. Patients were treated for 12 weeks with one of the following: (1) combination of FP 100 microg plus salmeterol 50 microg twice daily through the Diskus inhaler, or (2) FP 100 microg twice daily through the Diskus inhaler plus oral montelukast 10 mg once daily. RESULTS: FP/Salm Combo treatment provided better overall asthma control than FP + montelukast with significantly greater improvements in morning peak expiratory flow (+24.9 L/min vs +13.0 L/min, P <.001), evening peak expiratory flow (+18.9 L/min vs +9.6 L/min, P <.001), and forced expiratory volume in 1 second (+0.34 L vs +0.20 L, P <.001), as well as a change in the percentage of days with no albuterol use (+26.3% vs +19.1%, P =.032) and the shortness of breath symptom score (-0.56 vs -0.40, P =.017). The groups had comparable improvements in chest tightness, wheeze, and overall symptom scores. Asthma exacerbation rates were significantly lower (P =.031) in the FP/Salm Combo group (4 patients, 2%) than in the FP + montelukast group (13 patients, 6%). Adverse event profiles were comparable. CONCLUSION: Symptomatic patients on low-dose ICS therapy had significantly greater improvement in asthma control when switched to the FP/Salm Combo than when montelukast was added to ICS therapy.

Efficacy of soluble IL-4 receptor for the treatment of adults with asthma.

LC Borish — 2008-07-03T02:45:25-00:00

The Journal of allergy and clinical immunology, Vol. 107, No. 6. (June 2001), pp. 963-970.

BACKGROUND: IL-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, increased expression of vascular cell adhesion molecule 1 and promotion of eosinophil transmigration across the endothelium, stimulation of mucus production, and T(H)2 lymphocyte differentiation, leading to release of IL-4, IL-5, IL-9, and IL-13. OBJECTIVE: The current study evaluated the therapeutic potential of inhaled recombinant human soluble interleukin-4 receptor (IL-4R) as an IL-4 antagonist. METHODS: This study was a randomized, double-blind, placebo-controlled study in 62 subjects involving 12 once weekly nebulizations of 0.75, 1.5, or 3.0 mg of IL-4R or placebo. During screening, subjects documented dependence on inhaled corticosteroids by an exacerbation in asthma induced by one or two 50% dose reductions at 2-week intervals. After restabilization for 2 weeks on the dose above which their asthma flared, inhaled steroids were discontinued, patients were randomized, and study medication was started on day 0. RESULTS: IL-4R was well tolerated. Efficacy was demonstrated by a decline in FEV(1) observed in the placebo group (-0.4 L and -13% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -2% predicted; P =.05 over the 3-month treatment period). Daily patient-measured morning FEV(1) also demonstrated a significant decline in the placebo group (-0.5 L and -18% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -4% predicted; P =.02 over the 3-month treatment period). The efficacy of IL-4R was further confirmed by the absence of increase in asthma symptom scores in the group receiving 3.0 mg of IL-4R (Delta 0.1) compared with that seen in the placebo group (Delta 1.4 over 1 month; P =.07). Study discontinuation for asthma exacerbation was not significantly different between groups (placebo, 56%; 3.0 mg of IL-4R, 47%; P = not significant). CONCLUSION: These promising data suggest that IL-4R is safe and effective in the treatment of moderate persistent asthma.

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma.

W Busse — 2008-07-03T02:43:03-00:00

The Journal of allergy and clinical immunology, Vol. 108, No. 2. (August 2001), pp. 184-190.

BACKGROUND: A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma. METHODS: In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period. RESULTS: Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [P =.006] and 14.6% vs 23.3% [P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs 32.3% [P =.004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [P <.001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P <.001]). Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo. CONCLUSION: The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.

The road to reform

Josep Figueras — 2008-07-01T09:52:13-00:00

BMJ, Vol. 331, No. 7510. (23 July 2005), pp. 170-171.

10.1136/bmj.331.7510.170

The spread of attention across modalities and space in a multisensory object

Laura Busse — 2007-03-16T23:30:27-00:00

PNAS, Vol. 102, No. 51. (20 December 2005), pp. 18751-18756.

Attending to a stimulus is known to enhance the neural responses to that stimulus. Recent experiments on visual attention have shown that this modulation can have object-based characteristics, such that, when certain parts of a visual object are attended, other parts automatically also receive enhanced processing. Here, we investigated whether visual attention can modulate neural responses to other components of a multisensory object defined by synchronous, but spatially disparate, auditory and visual stimuli. The audiovisual integration of such multisensory stimuli typically leads to mislocalization of the sound toward the visual stimulus (ventriloquism illusion). Using event-related potentials and functional MRI, we found that the brain's response to task-irrelevant sounds occurring synchronously with a visual stimulus from a different location was larger when that accompanying visual stimulus was attended versus unattended. The event-related potential effect consisted of sustained, frontally distributed, brain activity that emerged relatively late in processing, an effect resembling attention-related enhancements seen at earlier latencies during intramodal auditory attention. Moreover, the functional MRI data confirmed that the effect included specific enhancement of activity in auditory cortex. These findings indicate that attention to one sensory modality can spread to encompass simultaneous signals from another modality, even when they are task-irrelevant and from a different location. This cross-modal attentional spread appears to reflect an object-based, late selection process wherein spatially discrepant auditory stimulation is grouped with synchronous attended visual input into a multisensory object, resulting in the auditory information being pulled into the attentional spotlight and bestowed with enhanced processing. 10.1073/pnas.0507704102

The onset of thermal convection in a rotating cylindrical annulus in the presence of a magnetic field

FH Busse — 2008-06-28T18:42:53-00:00

Physics of The Earth and Planetary Interiors, Vol. 80, No. 1-2. (October 1993), pp. 13-23.

The problem of the onset of convection in a cylindrical annulus with conical end boundaries in the presence of an azimuthal and a radial component of a magnetic field is considered. It is shown that the effect of the radial component on the convection rolls can be quite different from that of the azimuthal component. Convection rolls with low azimuthal wavenumbers are preferred in certain regions of the parameter space. Implications of the analysis for planetary applications are briefly discussed.

From Blood Monocytes to Adipose Tissue-Resident Macrophages: Induction of Diapedesis by Human Mature Adipocytes

Cyrile Curat — 2008-06-27T16:17:31-00:00

Diabetes, Vol. 53, No. 5. (1 May 2004), pp. 1285-1292.

Obesity has been suggested to be a low-grade systemic inflammatory state, therefore we studied the interaction between human adipocytes and monocytes via adipose tissue (AT)-derived capillary endothelium. Cells composing the stroma-vascular fraction (SVF) of human ATs were characterized by fluorescence-activated cell sorter (FACS) analysis and two cell subsets (resident macrophages and endothelial cells [ECs]) were isolated using antibody-coupled microbeads. Media conditioned by mature adipocytes maintained in fibrin gels were applied to AT-derived ECs. Thereafter, the expression of endothelial adhesion molecules was analyzed as well as the adhesion and transmigration of human monocytes. FACS analysis showed that 11% of the SVF is composed of CD14+/CD31+ cells, characterized as resident macrophages. A positive correlation was found between the BMI and the percentage of resident macrophages, suggesting that fat tissue growth is associated with a recruitment of blood monocytes. Incubation of AT-derived ECs with adipocyte-conditioned medium resulted in the upregulation of EC adhesion molecules and the increased chemotaxis of blood monocytes, an effect mimicked by recombinant human leptin. These results indicate that adipokines, such as leptin, activate ECs, leading to an enhanced diapedesis of blood monocytes, and suggesting that fat mass growth might be linked to inflammatory processes. 10.2337/diabetes.53.5.1285

Transcription in Mycoplasma pneumoniae: Analysis of the Promoters of the ackA and ldh Genes

Sven Halbedel — 2008-06-23T01:56:11-00:00

Journal of Molecular Biology, Vol. 371, No. 3. (17 August 2007), pp. 596-607.

The nucleotide sequences that control transcription initiation and regulation in Mycoplasma pneumoniae are poorly understood. Moreover, only few regulatory events have been reported for M. pneumoniae. We have studied changes in the global protein synthesis pattern in M. pneumoniae in response to the presence of glycerol. The ackA and ldh genes, encoding acetate kinase and lactate dehydrogenase, respectively, were controlled in a carbon source-dependent manner. While the ackA gene was strongly expressed in the presence of glucose, transcription of ldh was induced by glycerol. The promoters of both genes were mapped by primer extension analysis. Molecular analysis of transcription regulatory mechanisms in M. pneumoniae has so far not been possible due to the lack of appropriate reporter systems that can be used to study the activity of promoter fragments and their mutant derivatives in vivo. Recently, a reporter system has been developed which allows cloning of promoter fragments in front of a promoterless lacZ gene and inserting this construct into the genome of M. pneumoniae. To study the requirements of M. pneumoniae RNA polymerase for promoter recognition, a series of fusions of deletion and mutant variants of the ldh promoter was constructed and analyzed in vivo. While mutations affecting the -10 region strongly interfered with gene expression, the -35 region seems to be of minor importance in M. pneumoniae.

Towards a standardized format for the description of a novel species (of an established genus): Ochrobactrum gallinifaecis sp. nov.

P Kämpfer — 2008-06-12T08:25:40-00:00

International journal of systematic and evolutionary microbiology, Vol. 53, No. Pt 3. (May 2003), pp. 893-896.

A format for the description of single novel species is proposed, which should facilitate the reviewing process by assisting the provision of data in a standardized form. The abstract must be short and concise, highlighting phylogenetic position, morphology and chemotaxonomy for genus affiliation, the genotypic and phenotypic basis for species differentiation, and the name and deposition numbers from two public culture collections in different countries for the type strain: A Gram-negative, rod-shaped, non-spore-forming bacterium (Iso 196(T)) was isolated from chicken faeces. On the basis of 16S rRNA gene sequence similarity, strain Iso 196(T) was shown to belong to the alpha-2 subclass of the Proteobacteria related to Ochrobactrum tritici (95.6%), Ochrobactrum grignonense (95.0%) and Ochrobactrum anthropi (94.6%), and the phylogenetic distance from any validly described species within the genus Brucella was less than 95%. Chemotaxonomic data (major ubiquinone - Q-10; major polyamines - spermidine and putrescine; major polar lipids - phosphatidylethanolamine, phosphatidylglycerol and phosphatidylcholine; major fatty acids - C(18 : 1)omega7c and C(19 : 0) cyclo omega8c) supported the affiliation of strain Iso 196(T) to the genus Ochrobactrum. The results of DNA-DNA hybridization and physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain Iso 196(T) from the four validly published Ochrobactrum species. Iso 196(T) therefore represents a new species, for which the name Ochrobactrum gallinifaecis sp. nov. is proposed, with the type strain Iso 196(T) (= DSM 15295(T) = CIP 107753(T)).

Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials.

M Bhandari — 2008-06-11T08:28:53-00:00

CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, Vol. 170, No. 4. (17 February 2004), pp. 477-480.

BACKGROUND: Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings. In this study, we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials. METHODS: We examined a consecutive series of 332 randomized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals. Each eligible study was independently reviewed for methodological quality using a 21-point index with 5 domains: randomization, outcomes, eligibility criteria, interventions and statistical issues. Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant. For studies that did not explicitly identify a primary outcome, we defined a "positive" study as one with at least 1 statistically significant outcome measure. We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results, while controlling for study quality and sample size. RESULTS: Among the 332 randomized trials, there were 158 drug trials, 87 surgical trials and 87 trials of other therapies. In 122 (37%) of the trials, authors declared industry funding. An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.3-3.5). The association remained significant after adjustment for study quality and sample size (adjusted OR 1.8, 95% CI 1.1-3.0). There was a nonsignificant difference between surgical trials (OR 8.0, 95% CI 1.1-53.2) and drug trials (OR 1.6, 95% CI 1.1-2.8), both of which were likely to have a pro-industry result (relative OR 5.0, 95% CI 0.7-37.5, p = 0.14). INTERPRETATION: Industry-funded trials are more likely to be associated with statistically significant pro-industry findings, both in medical trials and surgical interventions.

Attitudes Towards Fibromyalgia: A Survey of Canadian Chiropractic, Naturopathic, Physical Therapy and Occupational Therapy Students

Jason Busse — 2008-06-01T18:42:23-00:00

BMC Complementary and Alternative Medicine, Vol. 8 (31 May 2008), 24.

Genome structure described by formal languages.

V Brendel — 2008-05-18T10:32:50-00:00

Nucleic acids research, Vol. 12, No. 5. (12 March 1984), pp. 2561-2568.

Nucleic acid sequences may be looked upon as words over the alphabet of nucleotides. Naturally occurring DNAs and RNAs form subsets of the set of all possible words. The use of formal languages is proposed to describe the structure of these subsets. Regular languages defined by finite automata are introduced to demonstrate the application of the concept on RNA-phages of group I. This approach permits a concise characterization of grammatical patterns in genetic information.

The stability of finite amplitude cellular convection and its relation to an extremum principle

FH Busse — 2008-05-13T16:49:46-00:00

Journal of Fluid Mechanics Digital Archive, Vol. 30, No. 04. (2006), pp. 625-649.

Dynamics of convection and dynamos in rotating spherical fluid shells

E Grote — 2008-05-13T11:22:57-00:00

Fluid Dynamics Research, Vol. 28, No. 5. (May 2001), pp. 349-368.

Numerical simulations of thermal convection in rapidly rotating spherical fluid shells have been carried out with and without magnetic fields generated by the dynamo process. Relaxation oscillations and localized convection activity represent coherent phenomena of turbulent convection in the absence of magnetic fields. In the presence of the latter, the coherent structures are destroyed and the heat transport is enhanced. With increasing Rayleigh number the magnetic energy tends to saturate and the magnetic field assumes an increasingly filamentary structure.

Hemispherical dynamos generated by convection in rotating spherical shells

E Grote — 2008-05-13T11:21:39-00:00

Physical Review E, Vol. 62, No. 3. (2000), 4457.

Effects of Hyperdiffusivities on Dynamo Simulations

E Grote — 2008-05-13T11:18:46-00:00

Geophysical Research Letters, Vol. 27, No. 13. (2000), pp. 2001-2004.

The presence of rhinovirus in lower airways of patients with bronchial asthma.

M Wos — 2008-05-13T03:22:16-00:00

American journal of respiratory and critical care medicine, Vol. 177, No. 10. (15 May 2008), pp. 1082-1089.

RATIONALE: The common cold virus, human rhinovirus (HRV), is the most frequent cause of asthma exacerbations. However, a possible contribution of HRV to the pathogenesis of chronic, persistent asthma has not been defined. OBJECTIVES: To determine if patients with stable asthma, who are free of clinical signs of a respiratory infection for at least 3 weeks, harbor HRV in their bronchi more frequently than nonasthmatic control subjects, and whether clinical features of asthma are associated with the presence of HRV. METHODS: Immunohistochemistry and the indirect in situ reverse transcription-polymerase chain reaction method were used to detect the presence of HRV in bronchial mucosal biopsies in patients with asthma and nonasthmatic control subjects. MEASUREMENTS AND MAIN RESULTS: HRV was found by immunohistochemistry in 9 of 14 bronchial biopsies from subjects with asthma (64.3%) and 2 of 6 nonasthmatic control subjects (33.3%) (P = 0.38). With the more sensitive indirect in situ reverse transcription-polymerase chain reaction method, HRV was found in the mucosal biopsies of 73% of patients with asthma and 22% of nonasthmatic control subjects (P < 0.001). Subjects positive for HRV had lower pulmonary function, higher numbers of blood eosinophils and leukocytes, and eosinophilic infiltration in bronchial mucosa. CONCLUSIONS: HRV was detected in the lower airway tissue of patients with asthma significantly more often than in nonasthmatic subjects, and its presence was associated with clinical features of more severe disease.

Homogeneous Dynamos in Planetary Cores and in the Laboratory

FH Busse — 2008-05-10T19:45:57-00:00

Annual Review of Fluid Mechanics, Vol. 32, No. 1. (2000), pp. 383-408.

Abstract New developments have occurred in recent years in the field of dynamo theory. The increase in computer capacity has permitted simulations of convection-driven dynamos in rotating spherical fluid shells in parameter ranges much closer to those of the Earth's core than has been possible before. The progress in handling flows of liquid sodium in large containers, on the other hand, has opened opportunities for realizations of homogeneous dynamos in the laboratory. These developments will lead to a deeper understanding of the origin of magnetic fields in planets and in stars.

Finite-amplitude convection in rotating spherical fluid shells

A Tilgner — 2008-05-02T11:59:26-00:00

Journal of Fluid Mechanics, Vol. 332, No. -1. (1997), pp. 359-376.

Regular and chaotic spherical dynamos

E Grote — 2008-05-02T11:28:02-00:00

Physics of The Earth and Planetary Interiors, Vol. 117, No. 1-4. (January 2000), pp. 259-272.

The generation of magnetic fields by thermal convection in rotating spherical shells has been simulated numerically in the case of Prandtl numbers of the order unity and Taylor numbers of the order 108. Regular and chaotic dipolar dynamos, hemispherical dynamos and quadrupolar dynamos have been found in different regions of the parameter space depending mainly on the magnetic Prandtl number Pm. The important role played by relaxation oscillations of the convection field is emphasized.

Convection-driven quadrupolar dynamos in rotating spherical shells

E Grote — 2008-05-02T11:26:35-00:00

Physical Review E, Vol. 60, No. 5. (1 November 1999), R5025.

On Convection Driven Dynamos in Rotating Spherical Shells

FH Busse — 2008-05-02T10:59:21-00:00

Studia Geophysica et Geodaetica, Vol. 42, No. 3. (21 July 1998), pp. 211-223.

Solutions for chaotic dynamos driven by thermal convection in a rotating spherical shell are obtained numerically for different Prandtl numbers. The influence of this parameter which is usually suppressed in the magnetostrophic approximation is emphasized in the present analysis.

Reynolds stresses and mean fields generated by pure waves: applications to shear flows and convection in a rotating shell

E Plaut — 2008-04-26T15:41:28-00:00

Journal of Fluid Mechanics, Vol. 602, No. -1. (2008), pp. 303-326.

A general reformulation of the Reynolds stresses created by two-dimensional waves breaking a translational or a rotational invariance is described. This reformulation emphasizes the importance of a geometrical factor: the slope of the separatrices of the wave flow. Its physical relevance is illustrated by two model systems: waves destabilizing open shear flows; and thermal Rossby waves in spherical shell convection with rotation. In the case of shear-flow waves, a new expression of the Reynolds–Orr amplification mechanism is obtained, and a good understanding of the form of the mean pressure and velocity fields created by weakly nonlinear waves is gained. In the case of thermal Rossby waves, results of a three-dimensional code using no-slip boundary conditions are presented in the nonlinear regime, and compared with those of a two-dimensional quasi-geostrophic model. A semi-quantitative agreement is obtained on the flow amplitudes, but discrepancies are observed concerning the nonlinear frequency shifts. With the quasi-geostrophic model we also revisit a geometrical formula proposed by Zhang to interpret the form of the zonal flow created by the waves, and explore the very low Ekman-number regime. A change in the nature of the wave bifurcation, from supercritical to subcritical, is found.

Mild cognitive impairment: long-term course of four clinical subtypes.

A Busse — 2008-04-25T13:26:07-00:00

Neurology, Vol. 67, No. 12. (26 December 2006), pp. 2176-2185.

OBJECTIVE: To empirically validate the expanded concept of mild cognitive impairment (MCI), which differentiates between four clinical subtypes-amnestic MCI-single domain, amnestic MCI-multiple domains, nonamnestic MCI-single domain, and nonamnestic MCI-multiple domains-and to examine the prevalence, course, and outcome of these four clinical MCI subtypes. METHODS: We studied a community sample of 980 dementia-free individuals aged 75 years or older who participated in the Leipzig Longitudinal Study of the Aged (LEILA 75+). All participants were examined by neuropsychological testing based on 6 years of observation. The diagnoses of the four clinical MCI subtypes were made according to the original and to slightly modified criteria by Petersen et al. (2001) (both with a cutoff of 1.0 SD and with a cutoff of 1.5 SD). The complete range of outcome types (dementia, death, improvement, stable diagnosis, unstable diagnosis) was described for all subtypes. The relative predictive power of stable MCI for dementia onset was determined. RESULTS: MCI-single domain is more frequent than MCI-multiple domains, and the nonamnestic MCI type is as frequent as the amnestic MCI type. The "MCI modified, 1.0 SD" criteria have the highest relative predictive power for the development of dementia (sensitivity = 74%, specificity = 73%). Alzheimer disease (AD) was the most common type of dementia at follow-up in all but one MCI subtype. Participants with nonamnestic MCI-multiple domains were more likely to progress to a non-AD dementia. CONCLUSIONS: It has been assumed that each MCI subtype is associated with an increased risk for a particular type of dementia. We can only partially agree with this.

Convective flows in rapidly rotating spheres and their dynamo action

FH Busse — 2008-04-11T12:58:31-00:00

Physics of Fluids, Vol. 14, No. 4. (2002), pp. 1301-1314.

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On hydromagnetic instabilities driven by the Hartmann boundary layer in a rapidly rotating sphere

Keke Zhang — 2008-04-11T11:12:45-00:00

Journal of Fluid Mechanics Digital Archive, Vol. 304, No. -1. (2006), pp. 263-283.

CORBA Based Data Integration Framework

Antonis Ramfos — 2008-03-28T18:57:23-00:00

(1998), pp. 176-183.

The evolving developments of the recent decades in information management have resulted in a situation where information is stored and managed by a large variety of systems around the globe. The growing requirement for information support to the globalised social and economic forces makes efficient and effective availability of distributed information and the correlation of relevant data a pressing business need. The most recent CORBA standard of the Object Management Group provides...

Patterns of convection in rotating spherical shells

R Simitev — 2008-03-01T17:09:06-00:00

New Journal of Physics, Vol. 5 (2003), pp. 97-97.

Patterns of convection in internally heated, self-gravitating rotating spherical fluid shells are investigated through numerical simulations. While turbulent states are of primary interest in planetary and stellar applications the present paper emphasizes more regular dynamical features at Rayleigh numbers not far above threshold which are similar to those which might be observed in laboratory or space experiments. Amplitude vacillations and spatial modulations of convection columns are common features at moderate and large Prandtl numbers. In the low Prandtl number regime equatorially attached convection evolves differently with increasing Rayleigh number and exhibits an early transition into a chaotic state. Relationships of the dynamical features to coherent structures in fully turbulent convection states are emphasized.

Dynamos of giant planets

FH Busse — 2008-03-01T16:08:27-00:00

Proceedings of the International Astronomical Union, Vol. 2, No. Symposium S239. (2007), pp. 467-474.

Possibilities and difficulties of applying the theory of magnetic field generation by convection flows in rotating spherical fluid shells to the Giant Planets are outlined. Recent progress in the understanding of the distribution of electrical conductivity in the Giant Planets suggests that the dynamo process occurs predominantly in regions of semiconductivity. In contrast to the geodynamo the magnetic field generation in the Giant Planets is thus characterized by strong radial conductivity variations. The importance of the constraint on the Ohmic dissipation provided by the planetary luminosity is emphasized. Planetary dynamos are likely to be of an oscillatory type, although these oscillations may not be evident from the exterior of the planets.

Generation of coupled global and local magnetic fields by a cellular MHD dynamo

AV Getling — 2008-03-01T16:08:08-00:00

Proceedings of the International Astronomical Union, Vol. 2, No. Symposium S239. (2007), pp. 482-487.

The convection-driven MHD dynamo in a rotating spherical shell is simulated numerically. Convection cells are regarded as a connecting link between the global and local electromagnetic processes. Local (in many cases, bipolar) magnetic structures are regularly produced by convection cells. Dynamo regimes in “thick” and “thin” shells are discussed. In the first case, the “general” magnetic field maintained by the dynamo has a sign-alternating dipolar component, which varies cyclically, although not periodically. The local structures, as they disintegrate, change into background fields, which drift toward the poles. From time to time, reversals of the magnetic fields in the polar regions occur, as “new” background fields expel the “old” fields. In the second case, the system settles down to a nearly stationary regime without polarity reversals.

Parameter dependences of convection-driven dynamos in rotating spherical fluid shells

Friedrich Busse — 2008-03-01T16:07:09-00:00

Geophysical & Astrophysical Fluid Dynamics, Vol. 100, No. 4. (2006), pp. 341-361.

For the understanding of planetary and stellar dynamos, an overview of the major parameter dependences of convection driven dynamos in rotating spherical fluid shells is desirable. Although the computationally accessible parameter space is limited, earlier work is extended with emphasis on higher Prandtl numbers and uniform heat flux condition at the outer boundary. The transition from dynamos dominated by non-axisymmetric components of the magnetic field to those dominated by the axisymmetric components depends on the magnetic Prandtl number as well as on the ordinary Prandtl number for higher values of the rotation parameter &b.tau;. The dependence of the transition on the latter parameter is also discussed. A variety of oscillating dynamos is presented and interpreted in terms of dynamo waves, standing oscillation or modified relaxation oscillations.

Prandtl-number dependence of convection-driven dynamos in rotating spherical fluid shells

R Simitev — 2008-03-01T16:05:33-00:00

Journal of Fluid Mechanics, Vol. 532, No. -1. (2005), pp. 365-388.

Dynamos driven by convection in rotating spherical shells

FH Busse — 2008-03-01T16:03:47-00:00

Astronomische Nachrichten, Vol. 326, No. 3-4. (2005), pp. 231-240.

The problem of the generation of magnetic fields by convection in rotating spherical fluid shells is reviewed with emphasis on possible applications to planets and rapidly rotating stars. Convection-driven dynamos exhibit a strong dependence on the Prandtl number P of the fluid. An overview of results obtained recently in the computationally accessible region of the parameter space is given with emphasis on the low Prandtl number regime. Of particular interest are various types of dynamo oscillations and torsional oscillations. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Cellular dynamo in a rotating spherical shell

AV Getling — 2008-03-01T16:02:05-00:00

Astronomische Nachrichten, Vol. 326, No. 3-4. (2005), pp. 241-244.

Magnetoconvection in a rotating spherical shell is simulated numerically using a code developed by Tilgner and Busse. The thermal stratification is convectively unstable in the outer part and stable in the inner part of the shell. Regimes are found in which the convective flow is weakly affected by rotation and preserves its cellular structure. The dipolar component of the large-scale magnetic field exhibits undamped oscillations. It appears that convection cells slightly modified by rotation can be building blocks of the global dynamo. The generation of the magnetic field is thus due to regular ?macroscopic? flows, and their structure itself may ensure the presence of the ? effect responsible for the action of the dynamo. Such dynamos can be called deterministic, in contrast to those in which the maintenance of the magnetic field is related to the statistical predominance of a certain sign of helicity in the turbulent velocity field. Investigation of conditions under which dynamos of this sort can operate could suggest a more definite answer to the question of the origin of solar and stellar magnetic fields. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Inertial convection in rotating fluid spheres

FH Busse — 2008-03-01T15:59:36-00:00

Journal of Fluid Mechanics, Vol. 498, No. -1. (2004), pp. 23-30.

Can cellular convection in a rotating spherical shell maintain both global and local magnetic fields?

AV Getling — 2008-03-01T15:56:30-00:00

International Journal of Geomagnetism and Aeronomy, Vol. 7 (31 March 2007), GI1004.

Universal intermittent properties of particle trajectories in highly turbulent flows

A Arneodo — 2008-02-27T17:12:56-00:00

(26 Feb 2008)

We present a collection of eight data sets, from state-of-the-art experiments and numerical simulations on turbulent velocity statistics along particle trajectories obtained in different flows with Reynolds numbers in the range $R_λ ∈ [120:740]$. Lagrangian structure functions from all data sets are found to collapse onto each other on a wide range of time lags, revealing a universal statistics, and calling for a unified theoretical description. Parisi-Frisch Multifractal theory, suitable extended to the dissipative scales and to the Lagrangian domain, is found to capture intermittency of velocity statistics over the whole three decades of temporal scales here investigated.

In vivo imaging in experimental preclinical tumor research--a review.

JT Wessels — 2008-01-17T08:31:09-00:00

Cytometry A, Vol. 71, No. 8. (August 2007), pp. 542-549.

The multiparametric molecular cell and tissue analysis in vitro and in vivo is characterized by rapid progress in the field of image generation technologies, sensor biotechnology, and computational modeling. Fascinating new potentials in unraveling the detailed functions of single cells, organs, and whole organisms are presently emerging and permit the close monitoring i.e. tumor development or basic cell development processes with an unprecedented multiplicity of promising investigative possibilities. To answer basic questions of in vivo tumor development and progression fluorescence based imaging techniques provide new insights into molecular pathways and targets. Genetic reporter systems (eGFP, DsRED) are available and high sensitive detection systems are on hand. These techniques could be used for in vitro assays and quantified e.g. by microscopy and CCD based readouts. The introduction of novel fluorescent dyes emitting in the near infrared range (NIR) combined with the development of sensitive detector systems and monochromatic powerful NIR-lasers for the first time permits the quantification and imaging of fluorescence and/or bioluminescence in deeper tissues. Laser based techniques particularly in the NIR-range (like two-photon microscopy) offer superb signal to noise ratios, and thus the potential to detect molecular targets in vivo. In combination with flat panel volumetric computed tomography (fpVCT), questions dealing e.g. with tumor size, tumor growth, and angiogenesis/vascularization could be answered noninvasively using the same animal. The resolution of down to 150 microm/each direction can be achieved using fpVCT. It is demonstrated by many groups that submillimeter resolutions can be achieved in small animal imaging at high sensitivity and molecular specificity. Since the resolution in preclinical small animal imaging is down to approximately 10 microm by the use of microCT and to subcellular resolutions using ( approximately 1 microm) microscope based systems, the advances of different techniques can now be combined to "multimodal" preclinical imaging and the possibilities for in vivo intravital cytometry now become within one's reach.

A Critical Examination of the Results from the Harvard-MIT NCT Program Phase I Clinical Trial of Neutron Capture Therapy for Intracranial Disease

Paul Busse — 2008-01-10T20:21:27-00:00

Journal of Neuro-Oncology, Vol. 62, No. 1. (1 March 2003), pp. 111-121.

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase I trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24–78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15?cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The 10B carrier, L-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250?mg?kg-1 over 1?h (10 subjects), 300?mg?kg-1 over 1.5?h (two subjects), or 350?mg?kg-1 over 1.5–2?h (10 subjects). The pharmacokinetic profile of 10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.