Response to Comment on "The extent of forest in dryland biomes".

Griffith et al do not question the quality of our analysis, but they question our results with respect to the definition of forest we employed. In our response, we explain why the differences we report result from a difference of technique and not of definition, and how anyone can adapt-as we did-our data set to any forest definition and tree cover threshold of interest.

Response to Comment on "The extent of forest in dryland biomes".

De la Cruz et al question the reliability of our results, claiming that we do not refer to the most appropriate spatial extent of drylands. In our response, we explain why we chose an existing and internationally recognized delineation of drylands among several options, and why our findings are due to a difference of remote sensing technique and not to the definition of drylands we have selected.

Response to Comment on "The extent of forest in dryland biomes".

Schepaschenko et al question our findings, claiming that we did not refer to all existing maps and that we did not account for all sources of uncertainty. In our response, we detail our selection criteria for reference maps, which clarify why the work of Schepaschenko et al was not used, and we explain why our uncertainty assessment is complete and how it was misunderstood by Schepaschenko et al.

Modulation of motor inhibition by subthalamic stimulation in obsessive-compulsive disorder.

High-frequency deep brain stimulation of the subthalamic nucleus can be used to treat severe obsessive-compulsive disorders that are refractory to conventional treatments. The mechanisms of action of this approach possibly rely on the modulation of associative-limbic subcortical-cortical loops, but remain to be fully elucidated. Here in 12 patients, we report the effects of high-frequency stimulation of the subthalamic nucleus on behavior, and on electroencephalographic responses and inferred effective connectivity during motor inhibition processes involved in the stop signal task. First, we found that patients were faster to respond and had slower motor inhibition processes when stimulated. Second, the subthalamic stimulation modulated the amplitude and delayed inhibition-related electroencephalographic responses. The power of reconstructed cortical current densities decreased in the stimulation condition in a parietal-frontal network including cortical regions of the inhibition network such as the superior parts of the inferior frontal gyri and the dorsolateral prefrontal cortex. Finally, dynamic causal modeling revealed that the subthalamic stimulation was more likely to modulate efferent connections from the basal ganglia, modeled as a hidden source, to the cortex. The connection from the basal ganglia to the right inferior frontal gyrus was significantly decreased by subthalamic stimulation. Beyond motor inhibition, our study thus strongly suggests that the mechanisms of action of high-frequency subthalamic stimulation are not restricted to the subthalamic nucleus, but also involve the modulation of distributed subcortical-cortical networks.

Seeing Central African forests through their largest trees.

Large tropical trees and a few dominant species were recently identified as the main structuring elements of tropical forests. However, such result did not translate yet into quantitative approaches which are essential to understand, predict and monitor forest functions and composition over large, often poorly accessible territories. Here we show that the above-ground biomass (AGB) of the whole forest can be predicted from a few large trees and that the relationship is proved strikingly stable in 175 1-ha plots investigated across 8 sites spanning Central Africa. We designed a generic model predicting AGB with an error of 14% when based on only 5% of the stems, which points to universality in forest structural properties. For the first time in Africa, we identified some dominant species that disproportionally contribute to forest AGB with 1.5% of recorded species accounting for over 50% of the stock of AGB. Consequently, focusing on large trees and dominant species provides precise information on the whole forest stand. This offers new perspectives for understanding the functioning of tropical forests and opens new doors for the development of innovative monitoring strategies.

Pyruvate carboxylase deficiency: An underestimated cause of lactic acidosis.

Pyruvate carboxylase (PC) is a biotin-containing mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, thereby being involved in gluconeogenesis and in energy production through replenishment of the tricarboxylic acid (TCA) cycle with oxaloacetate. PC deficiency is a very rare metabolic disorder. We report on a new patient affected by the moderate form (the American type A). Diagnosis was nearly fortuitous, resulting from the revision of an initial diagnosis of mitochondrial complex IV (C IV) defect. The patient presented with severe lactic acidosis and pronounced ketonuria, associated with lethargy at age 23 months. Intellectual disability was noted at this time. Amino acids in plasma and organic acids in urine did not show patterns of interest for the diagnostic work-up. In skin fibroblasts PC showed no detectable activity whereas biotinidase activity was normal. We had previously reported another patient with the severe form of PC deficiency and we show that she also had secondary C IV deficiency in fibroblasts. Different anaplerotic treatments in vivo and in vitro were tested using fibroblasts of both patients with 2 different types of PC deficiency, type A (patient 1) and type B (patient 2). Neither clinical nor biological effects in vivo and in vitro were observed using citrate, aspartate, oxoglutarate and bezafibrate. In conclusion, this case report suggests that the moderate form of PC deficiency may be underdiagnosed and illustrates the challenges raised by energetic disorders in terms of diagnostic work-up and therapeutical strategy even in a moderate form.

Inhibitory control and error monitoring by human subthalamic neurons.

The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2-4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15-35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions.

Long-term follow-up of bezafibrate treatment in patients with the myopathic form of carnitine palmitoyltransferase 2 deficiency.

Carnitine palmitoyltransferase 2 (CPT2) deficiency is a rare mitochondrial fatty acid oxidation (FAO) disorder characterized by myalgia, exercise intolerance, and rhabdomyolysis. We evaluate the efficacy of bezafibrate (BZ), a hypolipidemic drug, as a treatment for this form of CPT2 deficiency. A pilot trial was conducted with BZ in six patients for 6 months. There was a follow-up period of 3 years. The oxidation rates of the long-chain fatty acid derivative palmitoyl-CoA, measured in the mitochondria of the patients' muscles, were markedly lower than normal before treatment and increased significantly (+39 to +206%; P = 0.028) in all patients after BZ treatment. The evaluation of the therapeutic effects by the patients themselves (using the Short Form Health Survey (SF-36)), as well as by the physicians, indicated an improvement in the condition of the patients; there was an increase in physical activity and a decline in muscular pain. The results suggest that BZ has a therapeutic effect in the muscular form of CPT2 deficiency.

Retinotopic coding of extraretinal pursuit signals in early visual cortex.

During smooth pursuit, the image of the target is stabilized on the fovea, implying that speed judgments made during pursuit must rely on an extraretinal signal providing precise eye speed information. To characterize the introduction of such extraretinal signal into the human visual system, we performed a factorial, functional magnetic resonance imaging experiment, in which we manipulated the factor eye movement, with "fixation" and "pursuit" as levels, and the factor task, with "speed" and "form" judgments as levels. We hypothesized that the extraretinal speed signal is reflected as an interaction between speed judgments and pursuit. Random effects analysis yielded an interaction only in dorsal early visual cortex. Retinotopic mapping localized this interaction on the horizontal meridian (HM) between dorsal areas visual 2 and 3 (V2/V3) at 1-2 degrees azimuth. This corresponded to the position the pursuit target would have reached, if moving retinotopically, at the time of the subject's speed judgment. Because the 2 V2/V3 HMs are redundant, both may be involved in speed judgments, the ventral one involving judgments based on retinal motion and the dorsal one judgments requiring an internal signal. These results indicate that an extraretinal speed signal is injected into early visual cortex during pursuit.

PPARs as therapeutic targets for correction of inborn mitochondrial fatty acid oxidation disorders.

Enzyme defects in the mitochondrial fatty acid oxidation (FAO) are a large family of inherited metabolic disease well characterized clinically and genetically, but for which pharmacological strategies remain limited. It is now well established that regulation of genes involved in mitochondrial FAO is under control of the PPAR (peroxisome proliferator activated receptor) signalling pathway, and this led us to test a possible pharmacological correction of FAO disorders by fibrates and other PPAR activators. This review presents the basic data supporting our initial hypothesis, summarizes the results obtained in cells from patients with CPT II (carnitine palmitoyltransferase II) or VLCAD (very long-chain acyl-CoA dehydrogenase) deficiency, and discusses the perspectives and limits of this approach for therapy of these disorders.

Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy.

Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is an inborn mitochondrial fatty-acid beta-oxidation (FAO) defect associated with a broad mutational spectrum, with phenotypes ranging from fatal cardiopathy in infancy to adolescent-onset myopathy, and for which there is no established treatment. Recent data suggest that bezafibrate could improve the FAO capacities in beta-oxidation-deficient cells, by enhancing the residual level of mutant enzyme activity via gene-expression stimulation. Since VLCAD-deficient patients frequently harbor missense mutations with unpredictable effects on enzyme activity, we investigated the response to bezafibrate as a function of genotype in 33 VLCAD-deficient fibroblasts representing 45 different mutations. Treatment with bezafibrate (400 microM for 48 h) resulted in a marked increase in FAO capacities, often leading to restoration of normal values, for 21 genotypes that mainly corresponded to patients with the myopathic phenotype. In contrast, bezafibrate induced no changes in FAO for 11 genotypes corresponding to severe neonatal or infantile phenotypes. This pattern of response was not due to differential inductions of VLCAD messenger RNA, as shown by quantitative real-time polymerase chain reaction, but reflected variable increases in measured VLCAD residual enzyme activity in response to bezafibrate. Genotype cross-analysis allowed the identification of alleles carrying missense mutations, which could account for these different pharmacological profiles and, on this basis, led to the characterization of 9 mild and 11 severe missense mutations. Altogether, the responses to bezafibrate reflected the severity of the metabolic blockage in various genotypes, which appeared to be correlated with the phenotype, thus providing a new approach for analysis of genetic heterogeneity. Finally, this study emphasizes the potential of bezafibrate, a widely prescribed hypolipidemic drug, for the correction of VLCAD deficiency and exemplifies the integration of molecular information in a therapeutic strategy.

Potential of fibrates in the treatment of fatty acid oxidation disorders: revival of classical drugs?

Exposure to fibrates leads to normalization of fatty acid oxidation (FAO) in fibroblasts from patients with myopathic forms of CPT2 deficiency or VLCAD deficiency. Correction of FAO is related to a drug-induced increase of residual enzyme activity, and this could provide a new treatment strategy for these disorders.

Sun protection initiatives in Cornwall.

Recent evidence indicates that there are significant numbers of cases of malignant melanoma in the UK. In order to assess the current position with regard to sun awareness in Cornwall, a questionnaire survey of all state primary school heads (n = 123) and a survey of a random sample of GP practices (n = 9) was carried out. The data obtained were supported by visits to libraries and Tourist Information Centres at urban and rural centres--this enabled the identification of sun awareness literature. Key health professionals who worked within the field of health promotion were also contacted. The findings showed that in Cornwall public campaigns organized around the issue of sun protection took place only sporadically, although GP surgeries usually organize a display at the appropriate time of the year. None of the public places (e.g. Tourist Information Centres, libraries) surveyed had sun protection messages on display. It is concluded that insufficient sun awareness initiatives were being undertaken in Cornwall. Although most primary schools included sun awareness education in their curriculum in a form based on the Sun Awareness Guidelines produced by the Department of Health in 1995, few schools considered further measures to protect pupils on hot and sunny days. In particular the provision of shade, the scheduling of outdoor activities and the use of sunscreen and protective clothing were not standard.

Conversion electron cascades in 254(102)No.

The spectrum of prompt conversion electrons emitted by excited 254No nuclei has been measured, revealing discrete lines arising from transitions within the ground state band. A striking feature is a broad distribution that peaks near 100 keV and comprises high multiplicity electron cascades, probably originating from M1 transitions within rotational bands built on high K states.

[Health behaviors among first degree students at the Free University of Brussels]. / Les comportements de santé des étudiants de première candidature de l'Université Libre de Bruxelles.

For several years, quality of life is used as a measure of health status. As university constitues a specific setting for young adults, the Health Service of the french-speaking Free University of Brussels initiated a survey in order to study health behaviours of students from the first grade. During the academic year 1998-99, 3,185 students were surveyed in the first degree, using an anonymous self-completed questionnaire with the following topics: health perception, weight, social support, emotional well-being, tobacco, alcohol, medicines, cannabis and ecstasy use as well as access to general practitioner. Body Mass Index was computed and emotional well-being was approached using CES-D scale. Results are presented by gender and faculty. Mutivariate analysis was also realised using logistic regression. In general, results confirm the data resulting from other studies in general population as well as at school. Nevertheless, results show that health is a problem for a minority of students and is a "whole" that has to be approached globally. Moreover, data give a basis to define priorities and strategies to improve students' physical and mental well-being at university. Results are also useful to better target these actions to those at needs.

Monoamine oxidase in developing rat renal cortex: effect of dexamethasone treatment.

The expression of the biogenic amine degrading enzyme monoamine oxidases-A and -B depends on several factors including regional distribution, development and hormonal environment. In the present study, we investigated the expression of monoamine oxidases in developing kidney and their regulation by dexamethasone treatment. Immunoblots and enzyme assays, performed using [14C]5-hydroxytriptamine and [14C]beta-phenylethylamine as substrates for monoamine oxidases-A and -B, respectively, showed that monoamine oxidase-A is the isoenzyme largely predominant in 9-day-old rats renal cortex. Experiments performed in 5-week-old rats showed an increase in monoamine oxidase-B activity and a decrease in monoamine oxidase-A activity and substrate affinity. The changes of monoamine oxidase-A activity and affinity were mimicked by dexamethasone treatment (0.60 mg/kg body weight injected subcutaneously three times at intervals of 24 h) of 9-day-old rats. In contrast, dexamethasone administration induced a modification of monoamine oxidase-B activity opposite to that found between 9-day- and 5-week-old rats. Dexamethasone treatment did not modify immunoreactivity and mRNA corresponding to monoamine oxidases-A and -B indicating that changes of enzyme activities were unrelated to regulation of protein synthesis and mRNA turnover. These results show that monoamine oxidases-A and -B are differently expressed in developing renal cortex and are regulated by dexamethasone treatment.

Regulation of fatty acid transport protein and mitochondrial and peroxisomal beta-oxidation gene expression by fatty acids in developing rats.

Regulation of genes involved in fatty acid (FA) utilization in heart and liver of weanling rats was investigated in response to variations in dietary lipid content and to changes in intracellular FA homeostasis induced by etomoxir, a blocker of FA import into mitochondria. Northern-blot analyses were performed using cDNA probes specific for FA transport protein, a cell membrane FA transporter; long-chain- and medium-chain acyl-CoA dehydrogenases, which catalyze the first step of mitochondrial FA beta-oxidation; and acyl-CoA oxidase, a peroxisomal FA beta-oxidation marker. High-fat feeding from postnatal d 21 to 28 resulted in a coordinate increase (58 to 136%) in mRNA abundance of all genes in heart. In liver, diet-induced changes in mitochondrial and peroxisomal beta-oxidation enzyme mRNAs (from 52 to 79%) occurred with no change in FA transport protein gene expression. In both tissues, the increases in mRNA levels went together with parallel increases in enzyme activity. Changes in FA homeostasis resulting from etomoxir administration led to a marked stimulation (76 to 180%) in cardiac expression of all genes together with parallel increases in enzyme activities. In the liver, in contrast, etomoxir stimulated the expression of acyl-CoA oxidase gene only. Feeding rats a low-fat diet containing 0.5% clofibrate, a ligand of peroxisome proliferator-activated receptor alpha, resulted in similar inductions of beta-oxidation enzyme genes in both tissues, whereas up-regulation of FA transport protein gene was restricted to heart. Altogether, these data suggest that changes in FA homeostasis in immature organs resulting either from high-fat diet or beta-oxidation blockade can efficiently be transduced to the level of gene expression, resulting in tissue-specific adaptations in various FA-using enzymes and proteins.

Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis.

Hereditary hemochromatosis (HC) is one of the most common single-gene hereditary diseases. A phenotypic hallmark of HC is low iron in reticuloendothelial cells in spite of body iron overload. Most patients with HC have the same mutation, a change of cysteine at position 282 to tyrosine (C282Y) in the HFE protein. The role of HFE in iron metabolism and the basis for the phenotypic abnormalities of HC are not understood. To clarify the role of HFE in the phenotypic expression of HC, we studied monocytes-macrophages from subjects carrying the C282Y mutation in the HFE protein and clinically expressing HC and transfected them with wild-type HFE by using an attenuated Salmonella typhimurium strain as a gene carrier. The Salmonella system allowed us to deliver genes of interest specifically to monocytes-macrophages with high transduction efficiency. The accumulation of (55)Fe delivered by (55)Fe-Tf was significantly lower in macrophages from patients with HC than from controls expressing wild-type HFE. Transfection of HC macrophages with the HFE gene resulted in a high level of expression of HFE protein at the cell surface. The accumulation of (55)Fe delivered by (55)Fe-Tf was raised by 40% to 60%, and this was reflected by an increase in the (55)Fe-ferritin pool within the HFE-transfected cells. These results suggest that the iron-deficient phenotype of HC macrophages is a direct effect of the HFE mutation, and they demonstrate a role for HFE in the accumulation of iron in these cells.