The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis

OBJECTIVE: To determine whether sulfasalazine is better than placebo in slowing disability progression in MS. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active relapsing-remitting (n = 151) or progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years). MRI studies were performed at 6-month intervals on a subset of 89 patients. RESULTS: Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits). Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial. CONCLUSIONS: Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol. Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.     

Recent developments in the investigation of thyroid regulation and thyroid carcinogenesis

This review covers new mechanistic information spanning the past 10 years relevant to normal and abnormal thyroid growth and function that may assist in the risk assessment of chemicals inducing thyroid follicular cell neoplasia. Recent studies have shown that thyroid regulation occurs via a complex interactive network mediated through several different messenger systems. Increased thyroid-stimulating hormone (TSH) levels activate the signal transduction pathways to stimulate growth and differentiation of the follicular cell. The important role of TSH in growth as well as in function helps to explain how disruptions in the thyroid-pituitary axis may influence thyroid neoplasia in rodents. New investigations that couple mechanistic studies with information from animal cancer bioassays (e. g., sulfamethazine studies) confirm the linkage between prolonged disruption of the thyroid-pituitary axis and thyroid neoplasia. New initiation/promotion studies in rodents also support the concept that chronic stimulation of the thyroid induced by goitrogens can result in thyroid tumors. Some of these studies confirm previous suggestions regarding the importance of chemically induced thyroid peroxidase inhibition and the inhibition of 3,3',5, 5'-tetraiodothyronine (T4, thyroxine) deiodinases on disruption of the thyroid-pituitary axis leading to thyroid neoplasia. Some comparative physiologic and mechanistic data highlight certain differences between rodents and humans that could be expected to confer an increased vulnerability of rodents to chronic hypersecretion of TSH. New data from epidemiologic and molecular genetic studies in humans contribute further to an understanding of thyroid neoplasia. Acute exposure to ionizing radiation, especially in childhood, remains the only verified cause of thyroid carcinogenesis in humans. Iodine deficiency studies as a whole remain inconclusive, even though several new studies in humans examine the role of dietary iodine deficiency in thyroid cancer. Specific alterations in gene expression have been identified in human thyroid neoplasia, linked to tumor phenotype, and thus oncogene activation and tumor-suppressor gene inactivation may also be factors in the development and progression of thyroid cancer in humans. An analysis by the U.S. EPA Risk Assessment Forum, prepared as a draft report in 1988 and completed in 1997, focused on the use of a threshold for risk assessment of thyroid follicular tumors. New studies, involving several chemicals, provide further support that there will be no antithyroid activity until critical intracellular concentrations are reached. Thus, for chemically induced thyroid neoplasia linked to disruptions in the thyroid-pituitary axis, a practical threshold for thyroid cancer would be expected. More information on thyroid autoregulation, the role of oncogene mutations and growth factors, and studies directly linking persistently high TSH levels with the sequential cellular development of thyroid follicular cell neoplasia would provide further confirmation.     

Prenatal diagnosis of trisomy 13 on fetal cells obtained from maternal blood after minor enrichment

In a pilot study to establish fetal nucleated red blood cell (NRBC) detection in maternal blood, trisomy 13 was diagnosed by FISH analysis at 11 weeks' gestation. The NRBCs were detected after a single-step ficoll density gradient enrichment. In blood samples taken both before and after CVS, 52 and 80 NRBCs, respectively, were found to be positive for fetal haemoglobin. In 47 per cent of these cells, FISH analysis for X and Y chromosomes confirmed the fetal sex. Moreover, 48 per cent of these NRBCs showed three fluorescent signals for a chromosome 13 probe, which confirmed the diagnosis of trisomy 13, previously detected at CVS karyotyping. This is the first report of non-invasive prenatal diagnosis of trisomy 13, i.e., pre-CVS, in the first trimester. The high number of fetal NRBCs detected indicates a connection with aneuploidy, probably due to early impairment of the feto-maternal barrier.     

Serotonin and serotonin receptors in the central auditory system

Single channel currents were activated by GABA (0.5 to 5 microM) in cell-attached and inside-out patches from cells in the dentate gyrus of rat hippocampal slices. The currents reversed at the chloride equilibrium potential and were blocked by bicuculline (100 microM). Several different kinds of channel were seen: high conductance and low conductance, rectifying and "nonrectifying." Channels had multiple conductance states. The open probability (Po) of channels was greater at depolarized than at hyperpolarized potentials and the relationship between Po and potential could be fitted with a Boltzmann equation with equivalent valency (z) of 1. The combination of outward rectification and potential-dependent open probability gave very little chloride current at hyperpolarized potentials but steeply increasing current with depolarization, useful properties for a tonic inhibitory mechanism.     

Measurement of thrombus formation on intravascular catheters

War is a complex social situation due to the interplay of multiple factors. Economical and political ones are of utmost importance, but human attitudes and motivations must be also taken into account. Being desirable to modify human transactions in such a way that they do not interfere with the basic right of everyone to a condition of physical and mental well-being, war must be abolished. The author contends that an understanding of behaviour through Psychology can be helpful in that aim. Aggression is considered the principal psychological cause of war. It is worth while to differentiate between aggression as an instrument for attaining a special end, and as pure hostility. Only in the first form, it is held here, does it play an important role in war. Psychogists must deal also with a wide range of states of mind that can be "served" by aggression: feelings of inferiority or insecurity, fear, greed, projections, compensations, rationalizations, etc. Scientific approach is not the only one Physiology brings to war prevention. It is equally important the wide dissemination of its conclusions among the general public. Information on the dynamics that prompt people to decide war would make it easier to control. This applies not only to political or military leaders, but also to civil populations. Concerning those two possible contributions of psychologists, scientific and educative, it is suggested the extensive use of psychodramatic techniques. Their richness lie in the lifelike experiences they convey to the participants, and particular aptitude to promote changes of attitudes. Investigation and information on the psychological processes related to war should be undertaken by international organizations of social scientists, acting simultaneously in several countries. Some of the initial steps they could further: 1) that prevention of war be a current subject matter in psychological courses; 2) that the World Health Organization take interest in this subject; 3) that psychologists participate in international political and economical bodies in order to clarify the psychological factors leading to war.     

Structure and transport properties of nanocarbon films prepared by sublimation on a 6H-SiC surface

The transport properties of nanocarbon layers on a 6H-SiC substrate, grown by vacuum sublimation, are studied. It is found that these layers consist of a graphene layer adjacent to the substrate and a multigraphene layer coated with a polycrystalline carbine-like phase. In this case, the magnetoresistance and Shubnikov-de-Haas oscillation curves exhibit features inherent to single-layer graphene. The resistance at low temperatures is demonstrated to increase with temperature, which also corresponds to the behavior of single-layer graphene (antilocalization). At the same time, the resistance decreased with temperature at higher temperatures, which corresponds to weak localization. We believe that the observed behavior can be explained by the parallel combination of contributions of single-layer graphene and multigraphene to the conductance.     

Cardiac syncope due to transient coronary artery occlusion: the role of percutaneous angioplasty

A case of cardiac syncope is presented, associated with single vessel coronary disease. The mechanism of the syncope would appear to be a ventricular arrhythmia with transmural myocardial ischaemia due to transient occlusion of the diseased coronary artery. The symptoms and electrocardiographic abnormalities were reproduced and subsequently abolished by percutaneous coronary angioplasty.     

The effects of deprenyl on methamphetamine-induced dopamine depletions

The effects of deprenyl on methamphetamine-induced dopamine depletions were studied in mice. Four SC injections of 12.5 mg/kg of methamphetamine at two-hour intervals caused substantial (72-82%) and long-lasting depletions of striatal dopamine. Pretreatment with either 25 or 40 mg/kg of deprenyl did not significantly alter the magnitude of this depletion. These results indicate that, unlike what is observed following MPTP, there is no protection afforded dopaminergic cells by deprenyl pretreatment in the methamphetamine model of parkinsonism.     

Free-electron lasers: reliability, performance, and beam delivery

The Vanderbilt free-electron laser (FEL) is a continuously tunable source of pulsed, mid-infrared radiation. FEL applications research has been underway for a decade. Recent experimental advances in FEL ablation of soft tissue indicate the potential for FEL-based protocols in surgery and medicine. In anticipation of these medical applications, the Vanderbilt FEL is being upgraded to meet the reliability and performance standards for a medical laser. Facilities for laser surgery have been constructed and equipped and medical delivery systems are being developed for pre-clinical and clinical research