Physiological and pathophysiological implications of lipid sensing in the brain.

Fatty acid (FA)-sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy homeostasis. Through neuronal output, FA may modulate feeding behaviour as well as insulin secretion and action. Subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Molecular effectors of these FA effects probably include chloride or potassium ion channels. While intracellular metabolism and activation of the ATP-sensitive K⁺ channel appear to be necessary for some of the signalling effects of FA, at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, an FA transporter/receptor that does not require intracellular metabolism to activate downstream signalling. Thus, FA or their metabolites can modulate neuronal activity as a means of directly monitoring ongoing fuel availability by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. Recently, the role of lipoprotein lipase in FA sensing has also been shown in animal models not only in hypothalamus, but also in hippocampus and striatum. Finally, FA overload might impair neural control of energy homeostasis through enhanced ceramide synthesis and may contribute to obesity and/or type 2 diabetes pathogenesis in predisposed subjects.

Lipid sensing in the brain and regulation of energy balance.

Nutrient-sensitive neurons [to glucose and fatty acids (FAs)] are present at many sites throughout the brain, including the hypothalamus and brain stem, and play a key role in the neural control of energy and glucose homoeostasis. Through their neuronal output, FAs can modulate feeding behaviour as well as insulin secretion and activity. Central administration of oleate, for example, inhibits food intake and glucose production in rats. This suggests that daily variations in plasma FA concentrations could be detected by the central nervous system as a signal that contributes to regulation of energy balance. At the cellular level, subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FAs. Possible molecular effectors of these FA effects most likely include the chloride and potassium ion channels. While intracellular metabolism and activation of the ATP-sensitive K(+) channels appear to be necessary for some signalling effects of FAs, at least half the FA responses in ventromedial hypothalamic neurons are mediated by interaction with fatty acid translocase (FAT)/CD36, an FA transporter/receptor that does not require intracellular metabolism to activate downstream signalling. Thus, FAs and their metabolites can modulate neuronal activity by directly monitoring the ongoing fuel availability for brain nutrient-sensing neurons involved in the regulation of energy and glucose homoeostasis. Besides these physiological effects, FA overload or metabolic dysfunction may also impair neural control of energy homoeostasis and contribute to obesity and/or type 2 diabetes in predisposed subjects.

Brain lipid sensing and nervous control of energy balance.

Nutrient sensitive neurons (glucose and fatty acids (FA)) are present in many sites throughout the brain, including the hypothalamus and brainstem, and play a key role in the neural control of energy and glucose homeostasis. Through neuronal output, FA may modulate feeding behaviour as well as both insulin secretion and action. For example, central administration of oleate inhibits food intake and glucose production in rats. This suggests that daily variations in plasma FA concentrations might be detected by the central nervous system as a signal which contributes to the regulation of energy balance. At the cellular level, subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Possible molecular effectors of these FA effects likely include chloride or potassium ion channels. While intracellular metabolism and activation of the ATP-sensitive K(+) channel appear to be necessary for some of the signaling effects of FA, at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, a FA transporter/receptor that does not require intracellular metabolism to activate downstream signaling. Thus, FA or their metabolites can modulate neuronal activity as a means of directly monitoring ongoing fuel availability by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. Besides these physiological effects, FA overload or metabolic dysfunction might impair neural control of energy homeostasis and contribute to obesity and/or type 2 diabetes in predisposed subjects.

Association of enhanced expression of gap junctions with in vitro chondrogenic differentiation of rat nasal septal cartilage-released cells following their dedifferentiation and redifferentiation.

The nasal septum is an important centre of endochondral ossification during the development of the facial region. Previous studies have shown that it is possible to recapitulate the differentiation programme of 21-day-old rat nasal chondrocytes in vitro. The purpose now was to investigate, in vitro, the cell condensation phase that represents the earliest morphological event associated with cartilage differentiation in skeletal development. The study focuses on the ability of the cells to form condensations before overt differentiation, with special emphasis on gap-junction expression. The gap-junction protein connexin 43 was localized by indirect immunofluorescence as primarily intracellular and, on day 5, at the condensation stage, as spot-like contacts between cells. Intracellular injection of the permeable dye Lucifer yellow led to the staining of up to 20 neighbouring cells, indicating functional gap junctions and coupling. In contrast, treatment of cultures with the gap-junction blocker glycyrrhetinic acid inhibited dye coupling and reduced cartilage differentiation. Northern blotting of connexin 43 mRNA showed a faint band during the first days of culture, with a striking increase after day 4. In addition, the mRNA of the homeodomain-containing gene Cart-1 began to be expressed in prechondrogenic condensations and corresponded to the expression of type II collagen mRNA. These data indicate that the early stage of in vitro chondrocyte differentiation is the formation of cell condensations and the ability to establish cell-to-cell communication. Connexin 43, together with other molecular mechanisms, mediates the condensation phase of chondrogenesis and sets up the optimal environment in which nasal septal cells may terminally differentiate into chondrocytes.

Application of malariometric data obtained from longitudinal studies on infants in northern Nigeria.

In Northern Nigeria some 11 000 blood films taken from infants were examined for the presence of malaria parasites during the course of WHO field trials of new insecticides. A first film was taken, in most cases, within the first month and the subsequent ones at monthly intervals thereafter. Analyses of the results obtained from these longitudinal studies were made according to the malaria transmission season, and infant parasite incidences were calculated.The incidences thus obtained were found to be valuable in investigating the epidemiological situation in a particular locality, in assessing the effect of congenital immunity and in evaluating the efficacy of insecticidal attack.

The dynamics of malaria.

Previous studies on dynamic systems of transmission of malaria, and of eradication of infection following the interruption of transmission, have now been adapted for advanced techniques using the facilities offered by computers.The computer programmes have been designed for a deterministic model suitable for a large community and also for a stochastic model relevant to small populations in which infections reach very low finite numbers. In this model, new infections and recoveries are assessed by the daily inoculation rate and are subject to laws of chance. Such a representation is closer than previous models to natural happenings in the process of malaria eradication. Further refinements of the new approach include the seasonal transmission and simulation of mass chemotherapy aimed at a cure of P. falciparum infections.These programmes present models on which the actual or expected results of changes due to various factors can be studied by the analysis of specific malaria situations recorded in the field. The value of control methods can also be tested by the study of such hypothetical epidemiological models and by trying out various procedures.Two specific malaria situations (in a pilot project in Northern Nigeria and in an outbreak in Syria) were studied by this method and provided some interesting results of operational value. The attack measures in the pilot project in Northern Nigeria were carried out according to the theoretical model derived from the basic data obtained in the field.

The conditions of malaria transmission in Katsina Province, Northern Nigeria, and a discussion of the effects of dichlorvos application.

A study has been made of the conditions of malaria transmission in the northern part of the Guinea savannah belt of West Central Africa. It was found that, in this holoendemic area, transmission occurs principally from August to December but continues on a much reduced scale throughout the rest of the year, even when anopheline densities are as low as 0.02 per hut. Longitudinal parasitological studies on infants, carried out on an area rather than an individual village basis, provide the most useful epidemiological technique during the minor transmission period. Examination of the spleens of children from areas that had been treated with dichlorvos suggested that the reduced hut anopheline densities resulting from the treatment were subsequently reflected in the reduced number of children showing markedly enlarged spleens.