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Relief mapping through dense tropical forest is a challenge, which can be met by processing P-band radar images. Digital terrain models (DTMs) obtained over three sites in the Amazon region (French Guiana and North Brazil) are evaluated according to two types of quality criteria: on the one hand, the accuracy of elevations and slopes, calculated by comparison with lidar surveys used as reference data; on the other hand, the hydrographic coherence of the DTM, revealed by its compliance to some universal rules like "all rivers flow downhill", or the fact that landforms shaped by water have a fractal behaviour. The results depend on the scale, the effect of which is addressed. Overall, the results confirm the potential of P-band airborne radar for 3D characterisation of hydrography in tropical forested areas. [ABSTRACT FROM AUTHOR]

Our dependence on the continental water cycle (CWC) is such that we clearly need to improve our understanding of its issues from a multidisciplinary perspective. We assess the water resources in an understudied country, Haiti, to estimate the geomorphological (8 variables), hydrological (7), and climatological (7) behaviors of the main (26) watersheds. This generated almost exhaustive knowledge of the surface and sub-surface components of the CWC. In this paper, we intend to integrate these components into a synthetic and coherent view of the environment by looking for relationships between each other. We explore the correlations between several variables (including daily rainfall, river discharge, and river network metrics) of the pre-mentioned water components using robust and rigorous statistical analyses. We found a significant yet weak (spatiotemporal) correlation between the geomorphologic and climatologic components (RV test comparing two datasets with permutations, p-value = 10-3). Some partial, weak, and contingent relationships between specific geomorphologic, hydrologic, and climatologic behaviors were apparent too. The final comparison between atmosphere, hydrosphere, and geosphere in Haiti consists in the definition of four watershed categories showing strongly differentiated water cycle behaviors in the country, thus suggesting developing integrated mechanistic models for a multidisciplinary management of the CWC. [ABSTRACT FROM AUTHOR]

Presents a study which provided a mathematical representation for the turbulent fluid flow and energy transfer in a radio frequency (rf) induction plasma. Categories of the study of turbulence in thermal plasmas; Description of the schematic of the rf induction plasma torch and the system of coordinates; Boundary conditions for equations used; Result of the test for the case of turbulent mixing of isothermal confined jets at room temperature.

Ethnopharmacological Relevance: The Cannabis sativa L. ssp. indica (Lam.) plant has been historically utilized as a natural herbal remedy for the treatment of several ailments. In Lebanon, cannabis extracts have long been traditionally used to treat arthritis, diabetes, and cancer., Aim of the Study: The current study aims to investigate the anti-cancer properties of Lebanese cannabis oil extract (COE) on acute myeloid leukemia using WEHI-3 cells, and a WEHI-3-induced leukemia mouse model., Materials and Methods: WEHI-3 cells were treated with increasing concentrations of COE to determine the IC 50 after 24, 48 and 72-h post treatment. Flow cytometry was utilized to identify the mode of cell death. Western blot assay was performed to assess apoptotic marker proteins. In vivo model was established by inoculating WEHI-3 cells in BALB/c mice, and treatment commencing 10 days post-inoculation and continued for a duration of 3 weeks., Results: COE exhibited significant cytotoxicity with IC 50 of 7.76, 3.82, and 3.34 μg/mL at 24, 48, and 72 h respectively post-treatment. COE treatment caused an induction of apoptosis through an inhibition of the MAPK/ERK pathway and triggering a caspase-dependent apoptosis via the extrinsic and intrinsic modes independent of ROS production. Animals treated with COE exhibited a significantly higher survival rate, reduction in spleen weight as well as white blood cells count., Conclusion: COE exhibited a potent anti-cancer activity against AML cells, both in vitro and in vivo. These findings emphasize the potential application of COE as a chemotherapeutic adjuvant in treatment of acute myeloid leukemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Colorectal cancer (CRC) is a prevalent malignancy and a leading cause of cancer-related mortality. Extensive research into the aetiology of CRC has revealed that somatic mutations in certain genes play a crucial role in CRC development.AIM: In this study, we utilized data from public databases to investigate prevalent mutation patterns in CRC and developed a prognostic predictive model for CRC patients based on mutant genetic characteristics and other relevant clinical features., Methods: We initially gathered mutation information from CRC patients by analysing data from 15 datasets to identify genes with a mutation frequency of ≥10 %. Next, log-rank analyses were used to determine the relationship between prognosis and the mutational status of the most commonly mutated genes; the SIGnaling database was utilized to generate a protein‒protein interaction network. We consolidated and classified the gene mutation patterns of CRC patients in the database based on frequently mutated genes related to prognosis. A predictive nomogram was constructed, including age, sex, TNM stage, and mutation partner, based on available clinical, mutational, and prognostic information for CRC patients at our institution. Finally, the reliability of the model was verified using time-dependent ROC curve analysis., Results: The top 7 genes somatically mutated ≥10 % in 4477 samples from 4255 patients were TP53 (67 %), APC (66 %), KRAS (43 %), PIK3CA (18 %), FBXW7 (14 %), SMAD4 (14 %), and BRAF (10 %). Log-rank analysis demonstrated that the mutation status of 5 genes, namely, TP53 , APC , PIK3CA , SMAD4 , and BRAF , correlated significantly with prognosis. Protein‒protein interaction analysis confirmed functional interactions between these 5 genes, implicating them in tumorigenesis. We exhaustively enumerated the mutation patterns involving these five genes in 4255 patients, resulting in identification of 32 mutational patterns. After consolidation and classification, these patterns were divided into 3 grades based on patient prognosis. Next, a predictive nomogram based on the clinical, mutational, and prognostic information of 107 CRC patients treated at University Medical Center Rostock was constructed. The area under the curve (AUC) values for the model for predicting 1-, 3-, and 5-year overall survival were 0.779, 0.721, and 0.815, respectively., Conclusion: Common mutational patterns based on frequently mutated genes are associated with prognosis in CRC patients. Our study provides a valuable and concise prognostic predictor for determining outcomes in patients with CRC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Ethnopharmacological Relevance: Cannabis sativa L. is an aromatic annual herb belonging to the family Cannabaceae and it is widely distributed worldwide. Cultivation, selling, and consumption of cannabis and cannabis related products, regardless of its use, was prohibited in Lebanon until April 22, 2020. Nevertheless, cannabis oil has been traditionally used unlawfully for many years in Lebanon to treat diseases such as arthritis, diabetes, cancer and few neurological disorders., Aim of the Study: The present study aims to evaluate the phytochemical and anti-inflammatory properties of a cannabis oil preparation that is analogous to the illegally used cannabis oil in Lebanon., Materials and Methods: Dried Cannabis flowers were extracted with ethanol without any purification procedures to simulate the extracts sold by underground dealers in Lebanon. GC/MS was performed to identify chemical components of the cannabis oil extract (COE). In vivo anti-inflammatory effect of COE was evaluated by using carageenan- and formalin-induced paw edema rat models. TNF-α production were determined by using LPS-activated rat monocytes. Anti-inflammatory markers were quantified using Western blot., Results: Chemical analysis of COE revealed that cannabidiol (CBD; 59.1%) and tetrahydrocannabinol (THC; 20.2%) were found to be the most abundant cannabinoids.Various monoterpenes (α-Pinene, Camphene, β-Myrecene and D-Limonene) and sesquiterpenes (β-Caryophyllene, α-Bergamotene, α-Humelene, Humulene epoxide II, and Caryophyllene oxide) were identified in the extract. Results showed that COE markedly suppressed the release of TNF-α in LPS-stimulated rat monocytes. Western blot analysis revealed that COE significantly inhibited LPS-induced COX-2 and i-NOS protein expressions and blocked the phosphorylation of MAPKs, specifically that of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38 MAPK. COE displayed a significant inhibition of paw edema in both rat models. Histopathological examination revealed that COE reduced inflammation and edema in chronic paw edema model., Conclusion: The current findings demonstrate that COE possesses remarkable in vivo and in vitro anti-inflammatory activities which support the traditional use of the Lebanese cannabis oil extract in the treatment of various inflammatory diseases including arthritis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The sinus elevation procedure is a safe and predictable technique that allows the placement of implants in atrophic posterior maxillae. However, some recommendations have to be followed by the patient to ensure reliable healing. It is particularly important to avoid inducing trauma in the region concerned and through the sinuses. This report describes a rare complication that occurred after the grafting of a sinus, which was attributed to a violent sneeze a few hours after the intervention. The diagnosis of emphysema following air entry was confirmed by the suddenness of the swelling and associated crepitation, and by the radiographic observation of a delimited radiolucent zone in the grafted sinus. The immediate diagnosis and subsequent management prevented further adverse events. This case report supports the need for complete comprehensive instruction of patients after oral surgery, swift diagnosis, and management of emphysema., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Marc El Hage et al.)

Adnexal torsion is a cause of severe pelvic pain in reproductive aged women and during pregnancy. Adnexal torsion occurs when there is a complete turn of the ovary, tube, or both resulting in impaired blood flow to the ovary. The diagnosis of adnexal torsion is sometimes challenging due to the enlarged effect of the uterus, the displacement of abdominal and pelvic structures and the nonspecific symptoms in pregnancy. Therefore, prompt diagnosis is essential for better maternal and neonatal outcomes. The gold standard for confirmation and treatment of ovarian torsion is surgery. Laparoscopy and Laparotomy are surgical options with defined risks and benefits. Therefore, choosing the best surgical technique and surgical procedure are of utmost importance to decrease the chances of adverse events intra and postoperatively. Little literature exists regarding the laparoscopic approach of an ovarian torsion during the second trimester. Our case is a 20-week pregnant patient who had a 1080 degree rotation of the left adnexa. She required laparoscopy for adnexal detorsion and had good intraoperative, postoperative, maternal, and neonatal outcomes following management., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Rawad Halimeh et al.)

This article aims to evaluate and compare the 10-year bone anchorage and protrusion of implants into the sinus using cone beam computerized tomography (CBCT) and periapical radiography. Implants (≤ 10 mm) were placed with osteotome sinus floor elevation (OSFE) without grafting in maxillae with bone height ≤ 8 mm. After 10 years, the CBCT analysis showed bone presence at the buccal and palatal implant sides and corroborated the results obtained using periapical radiographs. In the absence of any symptom or complication, the use of two-dimensional radiography is sufficient for routine long-term follow-up of implants after OSFE without grafting.

Purpose: To evaluate the thickness of the sinus membrane in contact with implants inserted 10 years before using an augmentation procedure without grafting material, and to identify adverse events correlated with implant protrusion in the sinus., Materials and Methods: Osteotome sinus floor elevations were performed without grafting material. The implants (Straumann AG, Basel, Switzerland) were placed simultaneously, all protruded into the sinus. After 10 years, implants were considered viable in the absence of mobility, pain, infection, or continued radiolucency. Sinus health was assessed using cone-beam computed tomography and by the way of a questionnaire in which patients reported symptoms of sinusitis they might have had., Results: Controlled implants (21 implants, 13 patients) were osseointegrated. The membrane thickness was <2 mm in 11 patients and 2 to 3 mm with flat thickening in 2 patients. No patients exhibited any clinical or radiographic signs of sinusitis., Conclusions: No sinus complications were observed after 10 years. The initial protrusion of implants into the sinus did not influence long-term sinus health. The maintenance of successful integration is thus the key to avoiding sinus complication.

Objectives: Over 5 years, (i) to evaluate the clinical efficiency of 8-mm implants placed with osteotome sinus floor elevation (OSFE) in extremely atrophic maxillae and (ii) to compare bone levels around implants placed with and without grafting., Material and Methods: TE ® SLActive ® implants (Institut Straumann AG, Basel, Switzerland) were placed in sites with a residual bone height (RBH) of ≤4 mm. Before surgery, sinuses were randomized to receive anorganic bovine bone (control) or no graft (test). After 10 weeks of healing, implants were functionally loaded with single crowns. Bone levels were measured from standardized peri-apical radiographs., Results: Thirty-seven (17 test, 20 control) implants were placed in 12 patients (RBH: 2.4 ± 0.9 mm). Two early and one late failures occurred. The success rate was 91.9% (94.1% test, 90.0% control). All implants gained endo-sinus bone (3.8 ± 1.0 mm test, 4.8 ± 1.2 mm control; P = 0.004). Mean crestal bone loss (CBL) was 0.6 ± 1.1 mm, without a significant difference between the groups (P = 0.527). Mean bone gain and CBL did not change significantly between 1 and 5 years (P = 0.249 and P = 0.293, respectively)., Conclusions: Atrophic posterior maxillae can be predictably rehabilitated using OSFE with a simultaneous implant placement. The new bone formed around implants after 1 year was stable after 5 years, irrespective of the presence or the absence of graft. Grafting was unnecessary to achieve an average bone augmentation of 3.8 mm, but more bone was gained with grafting., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Numerous xenobiotics are toxic to human and animal cells by interacting with their metabolism, but the precise metabolic step affected and the biochemical mechanism behind such a toxicity remain often unknown. In an attempt to reduce the ignorance in this field, we have developed a new approach called cellular metabolomics. This approach, developed in vitro, provides a panoramic view not only of the pathways involved in the metabolism of physiological substrates of any normal or pathological human or animal cell but also of the beneficial and adverse effects of xenobiotics on these metabolic pathways. Unlike many cell lines, precision-cut tissue slices, for which there is a renewed interest, remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations. Cellular metabolomics (or metabolic flux analysis), which combines enzymatic and carbon 13 NMR measurements with mathematical modeling of metabolic pathways, is illustrated in this brief chapter for studying the effect of insulin on glucose metabolism in rat liver precision-cut slices and of valproate on glutamine metabolism in human renal cortical precision-cut slices. The use of very small amounts of test compounds allows to predict their toxic effect and eventually their beneficial effects very early in the research and development processes. Cellular metabolomics is complementary to other omics approaches, but, unlike them, provides functional, mechanistic, and dynamic pieces of information by measuring enzymatic fluxes.

Oroantral communication (OAC) rarely occurs long after implant placement. The present report describes the rare etiology and the difficulty of the diagnosis of an uncommon OAC occurring 10 years after the implant placement in the posterior maxilla. The difficulty of the diagnosis lies in the absence of clinical symptoms of sinusitis and presence of multiunit prosthesis hiding implant failure. This case report supports the need for sinus check-up during a routine implant examination.

Objectives. The purpose of this panoramic radiography study was to assess the impact of image magnification on the accuracy of vertical measurements in the posterior mandible. Methods. Six dental implants, inserted in the posterior segments of a resin model, were used as reference objects. Two observers performed implant length measurements using a proprietary viewer with two preset image magnifications: the low (1.9 : 1) and the medium (3.4 : 1) image magnifications. They also measured the implant lengths in two Digital Imaging Communications in Medicine viewers set at low (1.9 : 1), medium (3.4 : 1), and high (10 : 1) image magnifications. Results. The error between the measured length and the real implant length was close to zero for all three viewers and image magnifications. The percentage of measurements equal to the real implant length was the highest (83.3%) for the high image magnification and below 30% for all viewers with the low image magnification. Conclusions. The high and medium image magnifications used in this study allowed accurate vertical measurements, with all three imaging programs, in the posterior segments of a mandibular model. This study suggests that a low image magnification should not be used for vertical measurements on digital panoramic radiographs when planning an implant in the posterior mandible.

Introduction: This case series describes single implant rehabilitation in the maxillary first molar sites. It aims to show the surgical approaches carried out versus the residual bone height (RBH) and to evaluate implant success rate and bone anchorage height after 1 year., Materials and Methods: Placement of 10-mm-long tapered bone level implants was carried out according to the RBH: when RBH ≥10 mm, standard implant placement; when 6 mm < RBH < 10 mm, osteotome sinus floor elevation procedure (OSFE) without graft; and, when RBH ≤6 mm, OSFE with graft., Results: Fourteen patients received 15 implants in a mean RBH of 5.0 ± 2.4 mm (range, 2.0-11.0 mm). One implant was placed with a standard placement technique, 4 using OSFE without graft, and 10 using OSFE with graft. The 1-year success rate was 100%, and mean bone anchorage height reached at least 9.5 mm., Conclusions: Almost all cases of maxillary single implant rehabilitation might be performed by using OSFE. In the extremely atrophic maxilla, simultaneous grafting ensures implant embedding in bone.

When the posterior maxilla is atrophic, the reference standard of care would be to perform sinus augmentation with an autologous bone graft through the lateral approach and delayed implant placement. However, placement of short implants with the osteotome sinus floor elevation technique and without graft can be proposed for an efficient treatment of clinical cases with a maxillary residual bone height of 4 to 8 mm. The use of grafting material is recommended only when the residual bone height is ≤4 mm. Indications of the lateral sinus floor elevation are limited to cases with a residual bone height ≤ 2 mm and fused corticals, uncompleted healing of the edentulous site, and absence of flat cortical bone crest or when the patient wishes to wear a removable prosthesis during the healing period. The presented case report illustrates osteotome sinus floor elevation with and without grafting and simultaneous implant placement in extreme conditions: atrophic maxilla, short implant placement, reduced healing time, and single crown rehabilitation. After 6 years, all placed implants were functional with an endosinus bone gain.

Objectives/hypothesis: The aim of this study was to evaluate the nature and incidence of long-term maxillary sinus adverse events related to endosseous implant placement with protrusion into the maxillary sinus., Study Design: Retrospective cohort study., Methods: All patients who underwent placement of endosseous dental implants with clinical evidence of implant penetration into the maxillary sinus with membrane perforation were included in this study. Only patients with a minimum follow-up of 5 years after implant placement were included in this study. Maxillary sinus assessment was both clinical and radiological., Results: Eighty-three implants with sinus membrane perforation in 70 patients met the study's inclusion criteria. Mean age was 65.96 years ± 14.23. Twelve patients had more than one implant penetrating the maxillary sinus, and seven of them had bilateral sinus perforation. Estimated implant penetration was ≤ 3 mm in all cases. The average clinical and radiological follow-up was 9.98 years ± 3.74 (range 60-243 months). At the follow-up appointments, there were no clinical or radiological signs of sinusitis in any patient., Conclusion: This long-term study, spreading over a period of up to 20 years, indicates that no sinus complication was observed following implant penetration into the maxillary sinus. Furthermore, absence of occurrence of such complications is related to the maintenance of successful osseointegration. A contrario, and in the presence of an acute or chronic maxillary sinusitis, the differential diagnosis must always consider other potential odontogenic and nonodontogenic etiologies., (Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

1.Unlike cell lines and primary cells in culture, precision-cut tissue slices remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations. 2.In this article, we illustrate the use of such an experimental model to study the nephrotoxic effects of (i) chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, (ii) of cobalt chloride, a potential leakage product of the cobalt-containing nanoparticles, and (iii) of valproate, a widely used antiepileptic drug. 3.Since all the latter test compounds, like many toxic compounds, negatively interact with cellular metabolic pathways, we also illustrate our biochemical toxicology approach in which we used not only enzymatic but also carbon 13 NMR measurements and mathematical modelling of metabolic pathways. 4.This original approach, which can be applied to any tissue, allows to predict the nephrotoxic effects of milligram amounts of test compounds very early during the research and development processes of drugs and chemicals. This approach, combined with the use of cells that retain their in vivo metabolic properties and, therefore, are predictive, reduces the risk, the time and cost of such processes.

Objectives: To evaluate the long-term survival rate of rough-surfaced implants placed in maxillary sinuses augmented with deproteinized bovine bone (Bio-Oss; Geistlich Pharma AG, Wolhusen, Switzerland)., Materials and Methods: Thirteen maxillary sinuses were augmented in 10 patients with Bio-Oss. After an average healing period of 13.8 months, 24 implants were placed. In 4 cases, biopsies were performed and submitted to histological analysis. Clinical and radiographic evaluation was performed 9 years after implant placement and minimum 8 years after functional loading., Results: At the 9-year control, all the 24 implants were still functional. Thus, the implant survival rate was 100%., Conclusions: Bio-Oss is an acceptable substitute to the autogenous bone, and it can be used as a unique material for sinus floor elevation. Rough-surfaced implants placed in 100% Bio-Oss grafts showed a high survival rate (100%) on the long term. Larger clinical trials are necessary to confirm our results.

Objectives: The aims of this study were (1) to evaluate the vertical shrinkage percentage of nanocrystalline hydroxyapatite embedded in silica gel used for maxillary sinus floor elevation (SFE) and (2) to determine the survival rate of the implants 1 year after placement in the healed grafted sinuses., Materials and Methods: Eleven maxillary sinuses were augmented in eight patients with NanoBone. After a healing period averaging 14.42 months, 19 implants were placed and followed up with clinical and radiographic evaluation. Panoramic radiographs were taken immediately after SFE and at 12 months after grafting. Measurements of changes in height were made by a computerized measuring technique using an image editing software., Results: The mean graft height shrinkage percentage at 12 months after surgery was 8.84% (±5.32). One implant was lost before loading. All the 18 remaining osseointegrated implants received the prosthetic rehabilitation and were controlled after 3 months of functional loading. The implant survival rate at the 1-year interval was 94.74%., Conclusions: A 100% NanoBone alloplastic graft used in lateral SFE procedures presented limited height shrinkage. Implants placed in these grafted sinuses showed survival rates similar to those found in published data. These results should be interpreted cautiously considering the study's reduced sample size.

In the brain, glutaminase is considered to have a key role in the provision of glutamate, a major excitatory neurotransmitter. Brain slices obtained from wild-type (control) and glutaminase-deficient (GLS1+/-) mice were incubated without glucose and with 5 or 1 mmol/L [3-(13)C]glutamine as substrate. At the end of the incubation, substrate removal and product formation were measured by both enzymatic and carbon 13 nuclear magnetic resonance ((13)C-NMR) techniques. Slices from GLS1+/- mice consumed less [3-(13)C]glutamine and accumulated less [3-(13)C]glutamate. They also produced less (13)CO(2) but accumulated amounts of (13)C-aspartate and (13)C-gamma-aminobutyric acid (GABA) that were similar to those found with brain slices from control mice. The newly formed glutamine observed in slices from control mice remained unchanged in slices from GLS1+/- mice. As expected, flux through glutaminase in slices from GLS1+/- mice was found diminished. Fluxes through all enzymes of the tricarboxylic acid cycle were also reduced in brain slices from GLS1+/- mice except through malate dehydrogenase with 5 mmol/L [3-(13)C]glutamine. The latter diminutions are consistent with the decreases in the production of (13)CO(2) also observed in the slices from these mice. It is concluded that the genetic approach used in this study confirms the key role of glutaminase for the provision of glutamate.

Sodium valproate is a drug widely used for the treatment of epilepsy and mood disorders. We studied the effect of valproate on cerebral energy metabolism by incubating rat brain slices with 5 mM [3-(13)C]glutamate in the absence and the presence of 1 mM valproate. Substrate removal and product formation were measured by enzymatic and carbon 13 NMR methods. Fluxes through the enzymatic steps involved were calculated with an original mathematical model. We demonstrate that, in the presence of valproate, glutamate consumption and aspartate accumulation and labeling were inhibited, whereas GABA accumulation and labeling were increased. Consistent with these observations, this drug inhibited the unidirectional flux from glutamate to α-ketoglutarate and fluxes through several enzymes (gamma aminobutyric acid aminotransferase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, malic enzyme, pyruvate dehydrogenase, pyruvate carboxylase and citrate synthase). By contrast, glutamic acid decarboxylase flux was increased. With 2 mM glutamate+1 mM valproate and with 5 mM glutamate+2 mM valproate, GABA and aspartate labelings were similarly altered. On the basis of the effects of valproate, it is concluded that our cellular model and our cellular metabolomic approach appear suitable to study the beneficial and adverse interactions of neurotropic compounds with the cerebral metabolic pathways., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Since glucose is the main cerebral substrate, we have characterized the metabolism of various (13)C glucose isotopomers in rat brain slices. For this, we have used our cellular metabolomic approach that combines enzymatic and carbon 13 NMR techniques with mathematical models of metabolic pathways. We identified the fate and the pathways of the conversion of glucose carbons into various products (pyruvate, lactate, alanine, aspartate, glutamate, GABA, glutamine and CO(2)) and determined absolute fluxes through pathways of glucose metabolism. After 60 min of incubation, lactate and CO(2) were the main end-products of the metabolism of glucose which was avidly metabolized by the slices. Lactate was also used at high rates by the slices and mainly converted into CO(2). High values of flux through pyruvate carboxylase, which were similar with glucose and lactate as substrate, were observed. The addition of glutamine, but not of acetate, stimulated pyruvate carboxylation, the conversion of glutamate into succinate and fluxes through succinate dehydrogenase, malic enzyme, glutamine synthetase and aspartate aminotransferase. It is concluded that, unlike brain cells in culture, and consistent with high fluxes through PDH and enzymes of the tricarboxylic acid cycle, rat brain slices oxidized both glucose and lactate at high rates., (Copyright © 2011 Elsevier B.V. All rights reserved.)

This study was performed to analyze the metabolic fate of a high concentration (5 mM) of glutamine and glutamate in rat brain slices and the participation of these amino acids in the glutamine-glutamate cycle. For this, brain slices were incubated for 60 min with [3-¹³C]glutamine or [3-¹³C]glutamate. Tissue plus medium extracts were analyzed by enzymatic and ¹³C NMR measurements and fluxes through pathways of glutamine and glutamate metabolism were calculated. We demonstrate that both substrates were utilized and oxidized at high rates by rat brain slices and served as precursors of neurotransmitters, tricarboxylic acid (TCA) cycle intermediates and alanine. In order to determine the participation of glutamine synthetase in the appearance of new glutamine molecules with glutamine as substrate, brain slices were incubated with [3-¹³C]glutamine in the presence of methionine sulfoximine, a specific inhibitor of glutamine synthetase. Our results indicate that 36.5% of the new glutamine appeared was glutamine synthetase-dependent and 63.5% was formed from endogenous substrates. Flux through glutamic acid decarboxylase was higher with glutamine than with glutamate as substrate whereas fluxes from α-ketoglutarate to glutamate and through glutamine synthetase, malic enzyme, pyruvate dehydrogenase, pyruvate carboxylase and citrate synthase were in the same range with both substrates., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Numerous xenobiotics are toxic to human and animal cells by interacting with their metabolism, but the precise metabolic step affected and the biochemical mechanism behind such a toxicity often remain unknown. In an attempt to reduce the ignorance in this field, we have developed a new approach called cellular metabolomics. This approach, developed in vitro, provides a panoramic view not only of the pathways involved in the metabolism of physiologic substrates of any normal or pathologic human or animal cell but also of the beneficial and adverse effects of xenobiotics on these metabolic pathways. Unlike many cell lines, precision-cut tissue slices, for which there is a renewed interest, remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations. Cellular metabolomics (or cellular metabonomics), which combines enzymatic and carbon 13 NMR measurements with mathematical modeling of metabolic pathways, is illustrated in this brief chapter for studying the effect of insulin on glucose metabolism in rat liver precision-cut slices, and of valproate on glutamine metabolism in human renal cortical precision-cut slices. The use of very small amounts of test compounds allows to predict their toxic effect and eventually their beneficial effects very early in the research and development processes. Cellular metabolomics is complementary to other omics approaches, but, unlike them, provides functional and dynamic pieces of information by measuring enzymatic fluxes.