Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications

Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks.     

Short-term interventions for morbid jealousy

This paper discusses short-term treatment for morbid jealousy. A brief account of the clinical presentation of morbid jealousy is given. Theoretical approaches to this phenomenon are summarized and commented on. Specific behavioural and cognitive techniques are described, and their rationale explained. Case examples are cited to illustrate the use of these techniques. Some general comments on the application of these techniques are also made.     

-2-Hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats

L-2-Hydroxyglutaric acid (LGA) is the biochemical hallmark of patients affected by the neurometabolic disorder known as L-2-hydroxyglutaric aciduria (LHGA). Although this disorder is predominantly characterized by severe neurological findings and pronounced cerebellum atrophy, the neurotoxic mechanisms of brain injury are virtually unknown. In the present study, we investigated the effect of LGA, at 0.25-5mM concentrations, on total creatine kinase (tCK) activity from cerebellum, cerebral cortex, cardiac muscle and skeletal muscle homogenates of 30-day-old Wistar rats. CK activity was measured also in the cytosolic (Cy-CK) and mitochondrial (Mi-CK) fractions from cerebellum. We verified that tCK activity was significantly inhibited by LGA in the cerebellum, but not in cerebral cortex, cardiac muscle and skeletal muscle. Furthermore, CK activity from the mitochondrial fraction was inhibited by LGA, whereas that from the cytosolic fraction of cerebellum was not affected by the acid. Kinetic studies revealed that the inhibitory effect of LGA on Mi-CK was non-competitive in relation to phosphocreatine. Finally, we verified that the inhibitory effect of LGA on tCK was fully prevented by pre-incubation of the homogenates with reduced glutathione (GSH), suggesting that this inhibition is possibly mediated by oxidation of essential thiol groups of the enzyme. Considering the importance of creatine kinase activity for energy homeostasis, our results suggest that the selective inhibition of this enzyme activity by increased levels of LGA could be possibly related to the cerebellar degeneration characteristically found in patients affected by L-2-hydroxyglutaric aciduria.     

Tamoxifen induces ultrastructural alterations in membranes of Bacillus Stearothermophilus

Tamoxifen (TAM), a non-steroid antiestrogen, is the mostly used drug for chemotherapy and chemoprevention of breast cancer. However, the mechanisms by which TAM inhibits cell proliferation in breast cancer are not fully understood. TAM strongly incorporates in biomembranes and a variety of effects have been assigned to biophysical and biochemical interactions with membranes. Therefore, a better understanding of the physicochemical basis of interaction of TAM with biomembranes is essential to elucidate the molecular mechanisms of action. A strain of Bacillus stearothermophilus has been used as a model to clarify the interaction of TAM with the cell membrane. TAM effects on the ultrastructure of membranes of this bacterium were evaluated by electron microscopy. Important ultrastructural alterations were observed in B. stearothermophilus treated with TAM, namely change in the geometry of the membrane profile from asymmetric to symmetric, disaggregation of ribosomes, coagulation of the cytoplasmic matrix, occurrence of mesossomes, appearance of fractures in membranes and the alteration of the ultrastructure of cell wall. These ultrastructural alterations confirm that TAM is a membrane-active drug and that membrane damage may be involved in molecular mechanisms of cell death induced by this drug.     

Tamoxifen induces ultrastructural alterations in membranes of Bacillus Stearothermophilus.

Tamoxifen (TAM), a non-steroid antiestrogen, is the mostly used drug for chemotherapy and chemoprevention of breast cancer. However, the mechanisms by which TAM inhibits cell proliferation in breast cancer are not fully understood. TAM strongly incorporates in biomembranes and a variety of effects have been assigned to biophysical and biochemical interactions with membranes. Therefore, a better understanding of the physicochemical basis of interaction of TAM with biomembranes is essential to elucidate the molecular mechanisms of action. A strain of Bacillus stearothermophilus has been used as a model to clarify the interaction of TAM with the cell membrane. TAM effects on the ultrastructure of membranes of this bacterium were evaluated by electron microscopy. Important ultrastructural alterations were observed in B. stearothermophilus treated with TAM, namely change in the geometry of the membrane profile from asymmetric to symmetric, disaggregation of ribosomes, coagulation of the cytoplasmic matrix, occurrence of mesossomes, appearance of fractures in membranes and the alteration of the ultrastructure of cell wall. These ultrastructural alterations confirm that TAM is a membrane-active drug and that membrane damage may be involved in molecular mechanisms of cell death induced by this drug.     

Mercury from gold minings in the Pantanal of Pocone (Mato Grosso,Brazil)

The Pocone gold minings are situated in the Bento Gomes River Basin, at the border of the Pantanal of Mato Grosso. Gold-bearing quartz veins are removed from the subsoils, milled with water, centrifuged and the heavier fraction is subsequently mixed with mercury for gold separation. The gold mining activities caused a very intensive landscape change, threatening many environmental processes like sediment control and storage and recycling capacity of mercury. Cold Vapor Atomic Fluorescence System (CVAFS) was used to determinate total mercury in water, suspended material and sediments from Bento Gomes River, sampled monthly for 1 year. Apart from the fact that mercury concentrations are low in water and bottom sediments, they are slightly higher in relation to background levels measured in the area. The concentration in suspended material is also lower than other rivers with gold mining activities, but the floodplains of the Bento Gomes River act as mercury sinks. Therefore, the discharge of mercury into the Pantanal floodplain should be avoided, in spite of actual contamination of the system being very low.     

Functional uncoupling of hemodynamic from neuronal response by inhibition of neuronal nitric oxide synthase.

The cerebrovascular coupling under neuronal nitric oxide synthase (nNOS) inhibition was investigated in alpha-chloralose anesthetized rats. Cerebral blood flow (CBF), cerebral blood volume (CBV), and blood oxygenation level dependent (BOLD) responses to electrical stimulation of the forepaw were measured before and after an intraperitoneal bolus of 7-nitroindazole (7-NI), an in vivo inhibitor of the neuronal isoform of nitric oxide synthase. Neuronal activity was measured by recording somatosensory-evoked potentials (SEPs) via intracranial electrodes. 7-Nitroindazole produced a significant attenuation of the activation-elicited CBF (P<10(-6)), CBV (P<10(-6)), and BOLD responses (P<10(-6)), without affecting the baseline perfusion level. The average DeltaCBF was nulled, while DeltaBOLD and DeltaCBV decreased to approximately 30% of their respective amplitudes before 7-NI administration. The average SEP amplitude decreased (P<10(-5)) to approximately 60% of its pretreatment value. These data describe a pharmacologically induced uncoupling between neuronal and hemodynamic responses to functional activation, and provide further support for the critical role of neuronally produced NO in the cerebrovascular coupling.     

Tibial hemimelia: report on 37 new cases, clinical and genetic considerations

We report on 37 patients belonging to different families, who have the tibial hemimelia-split hand/foot syndrome. Genetic aspects and phenotypic manifestations are compared with previous reports of tibial hemimelia. An attempt to clinical and genetical approach is suggested.