Efficacy and safety of tonabersat, a gap-junction modulator, in the acute treatment of migraine: a double-blind, parallel-group, randomized study

The ability of tonabersat to relieve the symptoms of migraine attacks with or without aura was evaluated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients received 20 or 40 mg of tonabersat, or 50 mg of sumatriptan (positive control), or placebo at the onset of a moderate or severe attack. Headache intensity, relief and recurrence were recorded for 24 h after dosing. On the basis of primary or secondary efficacy measures, tonabersat did not provide a clinically or statistically significant advantage over placebo. Tonabersat generally was well tolerated and had no effect on vital signs, electrocardiogram recordings or laboratory values. The lack of efficacy may be a function of the slow absorption of tonabersat. As a consequence of slow absorption, daily administration of tonabersat as prophylaxis for migraine attacks is under investigation in ongoing studies.     

La cuerda dulce – a tolerability and acceptability study of a novel approach to specimen collection for diagnosis of paediatric pulmonary tuberculosis

Background  

Recent data demonstrate the utility of the string test for the diagnosis of sputum-scarce HIV-associated TB in adults. We hypothesized that, if well-tolerated by children, this simple tool might offer a breakthrough in paediatric TB diagnosis. Thus the objective of this study, undertaken in the paediatric service of the Hospital Nacional Dos de Mayo, Lima, Perú, was to determine the tolerability and acceptability of the string test to paediatric TB suspects, their parents and nursing staff.     

Columnar specificity of microvascular oxygenation and volume responses: implications for functional brain mapping

Cortical neurons with similar properties are grouped in columnar structures and supplied by matching vascular networks. The hemodynamic response to neuronal activation, however, is not well described on a fine spatial scale. We investigated the spatiotemporal characteristics of microvascular responses to neuronal activation in rat barrel cortex using optical intrinsic signal imaging and spectroscopy. Imaging was performed at 570 nm to provide functional maps of cerebral blood volume (CBV) changes and at 610 nm to estimate oxygenation changes. To emphasize parenchymal rather than large vessel contributions to the functional hemodynamic responses, we developed an ANOVA-based statistical analysis technique. Perfusion-based maps were compared with underlying neuroanatomy with cytochrome oxidase staining. Statistically determined CBV responses localized accurately to individually stimulated barrel columns and could resolve neighboring columns with a resolution better than 400 microm. Both CBV and early oxygenation responses extended beyond anatomical boundaries of single columns, but this vascular point spread did not preclude spatial specificity. These results indicate that microvascular flow control structures providing targeted flow increases to metabolically active neuronal columns also produce finely localized changes in CBV. This spatial specificity, along with the high contrast/noise ratio, makes the CBV response an attractive mapping signal. We also found that functional oxygenation changes can achieve submillimeter specificity not only during the transient deoxygenation ("initial dip") but also during the early part of the hyperoxygenation. We, therefore, suggest that to optimize hemodynamic spatial specificity, appropriate response timing (using < or =2-3 sec changes) is more important than etiology (oxygenation or volume).     

Filters for radiation reduction: a comparison

Aluminum, yttrium, copper, and R-filters were evaluated with respect to effective beam energy, entrance radiation exposure to the skin, x-ray tube loading, and the quality of resultant radiographs. Since all filters yielded acceptable radiographs, a figure of merit was developed to determine which filter delivered the lowest entrance radiation exposure for the lowest increase in x-ray tube loading. The figure of merit indicated that the best results were obtained with the 0.1-mm Cu filter with 2 mm Al at 60-105 kVp and with the 0.2-mm Cu filter with 2 mm Al at 105-120 kVp. Cu filters produced radiographs with quality comparable to that of R- or Y filters. Cu filters are inexpensive alternatives to rare-earth filters and yielded a reduction in radiation exposure with less x-ray tube loading.     

New N-terminal modified proctolin analogues

Five proctolin analogues modified in position 1 of the peptide chain by Cit (I), Lys (II), His (III), Phe(p-NH₂) (IV) and γ-Abu (V) were synthesized by conventional liquid phase method. Biological activity of the obtained peptides was investigated by the cardioexcitatory test on two insect species, cockroach, Periplaneta americana L. and yellow mealworm, Tenebrio molitor L.     

Kidney transplantation in recipients with mental retardation: clinical results in a single-center experience

Mental retardation has been a controversial relative contraindication to organ transplantation. Currently, there are few data available in the literature that describe the outcome of kidney transplantation in mentally retarded patients. In a series of 1,271 kidney transplantations performed between January 1968 and March 1996, we identified eight patients (0.6%) with significant mental retardation (IQ < 70). Only cooperative patients supervised by a reliable long-term caregiver, with long life expectancy, and able to take medication under supervision, were accepted as candidates, independent of the IQ level. At a mean follow-up of 7.3 years, seven patients are alive with functioning grafts, and one lost the kidney to chronic rejection 10 years after transplantation and died of sepsis after resuming dialysis. The 1- and 5-year patient and graft survival are thus 100%. Compliance with immunosuppressive treatment and clinical follow-up was excellent in all of the recipients. The patient quality of life and health were judged by the support persons as highly improved after transplantation in comparison to dialysis. We conclude that kidney transplantation in properly selected patients with mental retardation provides excellent patient and graft survival rates and improves quality of life. In such patients, the presence of mental retardation should not be considered a contraindication to kidney transplantation.     

Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium

We previously showed that endothelial cells (EC) from the vasculature of human solid tumors have a decreased expression of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 as compared with normal tissue EC. This effect is explained by EC exposure to angiogenic factors. It is known that upregulation of endothelial adhesion molecules (EAM) is a sign of EC activation in inflammatory responses. We therefore tested the effect of angiogenic factors on upregulation of EAM on tumor EC and human umbilical vein EC (HUVEC) by proinflammatory cytokines. Incubation of tumor-derived EC in tumor necrosis factor alpha (TNF alpha) did result in expression levels of only 20% of the level of similarly treated normal tissue-derived EC. Pretreatment of HUVEC with 10 ng/ml basic fibroblast growth factor (bFGF) for 3 days, before TNF alpha- or interleukin-1 alpha (IL-1 alpha) stimulation, resulted in ICAM-1 levels of only 30% to 60% of cells without pretreatment. Also, the induction of vascular EC adhesion molecule-1 (VCAM-1) and E- selectin by TNF alpha was significantly inhibited by prior exposure to bFGF. Vascular endothelial growth factor had similar but less prominent effects. The effect of transforming growth factor-beta and IL-8 was studied as well. The functional relevance of the finding of a decreased EC inflammatory response was confirmed by adhesion assays. Our results show that tumor angiogenesis induces EC anergy. This may serve as a tumor-protecting mechanism by impairing the development of an efficient leukocyte infiltrate in tumors.     

Abnormal neutrophil phenotype and neutrophil FcRIII deficiency corrected by bone marrow transplantation

BACKGROUND : Neutrophils from a patient in first remission of acute myeloid leukemia were found to lack NA1 and NA2 alloantigens. This NA null phenotype was converted to the normal phenotype of NA1, NB2 by the transplantation of bone marrow from an HLA-identical sibling. To investigate the inherited or acquired nature of this rare phenotype, a combination of conventional neutrophil serology and recently developed restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) assays was used. STUDY DESIGN AND METHODS : Diagnosis, remission, and posttransplant patient peripheral blood samples were used for neutrophil phenotyping by granulocyte agglutination and immunofluorescence tests. The presence and dose of the gene for neutrophil Fc gamma RIIIb (Fc gamma RIIIB) were tested for with RFLP and Southern analysis and PCR-based RFLP tests. Plasma levels of circulating soluble Fc gamma RIII (sFc gamma RIII) were measured with radioimmunoassay. The sibling bone marrow donor and the patient's parents were also studied. RESULTS : RFLP analysis of DNA obtained from the patient at the time of diagnosis showed that she lacked the Fc gamma RIIIB gene for neutrophil Fc gamma RIII (i.e., Fc gamma RIIIb), but that, in DNA prepared from posttransplant samples, the Fc gamma RIIIB gene was present. Quantitation of plasma levels of soluble FcRIII (sFcRIII) demonstrated a complete absence of sFcRIII in the patient's pretransplant plasma. However, 20 units of sFcRIII were detected in the patient's plasma by 160 days after graft. Hair samples from the patient provided sufficient nonhematopoietic, genomic DNA to confirm that her genotype was NA0NA0. DNA prepared from lymphocytes of both parents and the sibling marrow donor was used to quantitate their Fc gamma RIIIB gene dose. The mother and brother had only one Fc gamma RIIIB gene each, while the father apparently had a normal complement of two Fc gamma RIIIB genes. CONCLUSION : In this case, an inherited absence of Fc gamma RIIIB gene in a patient with acute myeloid leukemia was unintentionally corrected by the transplantation of bone marrow from a sibling donor who himself carried only one Fc gamma RIIIB gene.