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The ketogenic diet, which consists of reduced carbohydrate intake and increased fat intake, is a recognized treatment option for children with intractable epilepsy. This diet is now receiving renewed interest from physicians and researchers because of its potential therapeutic effect in other diseases, such as neurodegenerative diseases, metabolic syndrome or cancer. Since cancer is one of the major public health challenges, complementary approaches to improve the efficacy of standard anti-cancer therapies are the subject of much research. This article reviews the place of the ketogenic diet as a complementary therapy in cancer, the scientific evidence and possible practical aspects of such an approach.

Brain metastases (BM) are a common occurrence of systemic cancers. Technical improvements in neuroimaging offer additional tools for an early detection of BM, to target them precisely and differentiate these lesions from other cerebral pathologies. The therapeutic tools have also evolved from neurosurgery and whole brain therapy to include stereotactic radiosurgery, targeted and immune therapies. Given the numerous treatment options available, a multidisciplinary approach is essential to offer the patient a personalized approach to optimize the sequence and combination of treatments to offer the best outcome possible. This article aims to review key elements of diagnosis, risk stratification and modern treatment paradigms in the diagnosis and management of BM.

Six lactating cows (106.3 ± 14.8 DIM; 550.7 ± 21.8 kg BW) were enrolled in a replicated 3 × 3 Latin square to evaluate the supplementation of double salt of calcium ammonium nitrate decahydrate (CAN), composed by 16.5% N, 76.5% of nitrate (NO3 -), and 85.0% DM, on NO3 - and nitrite (NO2 -) residues, fatty acids (FA) proportion, and antioxidant capacity in milk. Each period lasted 21 d, with 14 d for adaptation and 7 d for sampling. Treatments were URE (11.9 g/DM of urea as a control), CAN15: 15 g of CAN (11.5 g of NO3 - on DM), and CAN30: 30 g of CAN (23 g of NO3 - on DM). Milk samples were collected on d 15–16 of each period, frozen at –20°C, and after analyzed for NO3 - and NO2 - residues, fatty acids, and antioxidant capacity. Data were analyzed using PROC MIXED of SAS. Supplemental CAN increased by 26% NO3 - residue in milk (P = 0.02), whereas did not affect (P < 0.05) NO2 - concentration (average of 0.042 mg/L). Total CLA and short-chain FA were not affected (P > 0.05) by CAN. Medium-chain FA decreased linearly (P < 0.05), while long-chain FA (P = 0.06) and monounsaturated FA (P = 0.08) tended to increase linearly. Saturated FA reduced (P < 0.05) linearly; however, the total of polyunsaturated FA was not affected (P > 0.05). There were no effects of CAN (P > 0.05) on n-3, n-6, and n-6/n-3 ratio. Milk reducing power and TBARS concentration were not affected (P > 0.05) by CAN, whereas conjugated dienes increased (P = 0.02) linearly (URE= 47.6 vs. CAN15= 52.7 vs. CAN30= 63.4 mmol/kg of fat). Supplementing CAN at 30 g/DM reduced total saturated FA and increased conjugated dienes, caused possibly by lower rumen biohydrogenation, which might increase lipid oxidation in milk.

The genetic formation of Central and South Asian populations has been unclear because of an absence of ancient DNA. To address this gap, we generated genome-wide data from 362 ancient individuals, including the first from eastern Iran, Turan (Uzbekistan, Turkmenistan, and Tajikistan), Bronze Age Kazakhstan, and South Asia. Our data reveal a complex set of genetic sources that ultimately combined to form the ancestry of South Asians today. We document a southward spread of genetic ancestry from the Eurasian Steppe, correlating with the archaeologically known expansion of pastoralist sites from the Steppe to Turan in the Middle Bronze Age (2300-1500 BCE). These Steppe communities mixed genetically with peoples of the Bactria Margiana Archaeological Complex (BMAC) whom they encountered in Turan (primarily descendants of earlier agriculturalists of Iran), but there is no evidence that the main BMAC population contributed genetically to later South Asians. Instead, Steppe communities integrated farther south throughout the 2nd millennium BCE, and we show that they mixed with a more southern population that we document at multiple sites as outlier individuals exhibiting a distinctive mixture of ancestry related to Iranian agriculturalists and South Asian hunter-gathers. We call this group Indus Periphery because they were found at sites in cultural contact with the Indus Valley Civilization (IVC) and along its northern fringe, and also because they were genetically similar to post-IVC groups in the Swat Valley of Pakistan. By co-analyzing ancient DNA and genomic data from diverse present-day South Asians, we show that Indus Periphery-related people are the single most important source of ancestry in South Asia —} consistent with the idea that the Indus Periphery individuals are providing us with the first direct look at the ancestry of peoples of the IVC {— and we develop a model for the formation of present-day South Asians in terms of the temporally and geographically proximate sources of Indus Periphery-related, Steppe, and local South Asian hunter-gatherer-related ancestry. Our results show how ancestry from the Steppe genetically linked Europe and South Asia in the Bronze Age, and identifies the populations that almost certainly were responsible for spreading Indo-European languages across much of Eurasia.

Objective The objective of this study was to report the methodology and 1-year experience of a regional service model of teleconsultation for planning and treatment of complex thoracoabdominal aortic disease (TAAD). Methods Complex TAADs without a feasible conventional surgical repair were prospectively evaluated by vascular surgeons of the same public health service (National Health System) located in a huge area of 22,994 km 2 with 3.7 million inhabitants and 11 tertiary hospitals. Surgeons evaluated computed tomography scans and clinical details that were placed on a web platform (Google Drive; Google, Mountain View, Calif) and shared by all surgeons. Patients gave informed consent for the teleconsultation. The surgeon who submits a case discusses in detail his or her case and proposes a possible therapeutic strategy. The other surgeons suggest other solutions and options in terms of grafts, techniques, or access to be used. Computed tomography angiography, angiography, and clinical outcomes of cases are then presented at the following telemeetings, and a final agreement of the operative strategy is evaluated. Teleconsultation is performed using a web conference service (WebConference.com; Avaya Inc, Basking Ridge, NJ) every month. An inter-rater agreement statistic was calculated, and the κ value was interpreted according to Altman's criteria for computed tomography angiography measurements. Results The rate of participation was constant (mean number of surgeons, 11; range, 9-15). Twenty-four complex TAAD cases were discussed for planning and operation during the study period. The interobserver reliability recorded was moderate (κ = 0.41-0.60) to good (κ = 0.61-0.80) for measurements of proximal and distal sealing and very good (κ = 0.81-1) for detection of any target vessel angulation >60 degrees, significant calcification (circumferential), and thrombus presence (>50%). The concordance for planning and therapeutic strategy among all participants was complete in 16 cases. In one case, the consultation was decisive for creating an innovative therapeutic strategy; in the remaining seven cases, the strategy proposed by the patient's surgeon was changed completely after the discussion. Technical success was the same (100%) if concordance in planning was present initially or not. Overall 6-month mortality was 4%, 0% for those patients with initial concordance in planning vs 12% for those without initial concordance ( P = .33). Surgery was always performed in a tertiary hospital by local surgeons, and in two cases (8%) external surgeons joined the local surgical team. Conclusions Such a regional service of teleconsultation may be of value in standardizing the treatment and derived costs of complex TAADs in a huge region under the same health provider. The shared decision-making strategy may be of medical-legal value as well.

PURPOSE: To assess incidence, indicators and outcome of satisfaction with antiepileptic drugs in children. METHODS: Multicenter, observational, open, prospective survey of children and adolescents with epilepsy with three-month follow-up. Included were patients aged 3-17 years with newly diagnosed ("new diagnosis") or chronic epilepsy ("old diagnosis") requiring treatment start or change. Satisfaction was assessed with the Hedonic Visual Scale or direct questions, depending on patient's age. Quality of life of adolescents (QOLIE-48) and of caregivers (SF-36) and predictors of (dis)satisfaction were also assessed. RESULTS: 293 patients completed the study. Most had generalized idiopathic epilepsy, and a disease lasting

Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes. Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant-negative effect on the wild-type (WT) subunit. Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R. Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only). Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.Myotonia congenita is an inherited disease caused by loss-of-function mutations of the skeletal muscle ClC-1 chloride channel, characterized by impaired muscle relaxation after contraction and stiffness. In the present study, we provided an in-depth characterization of F484L, a mutation previously identified in dominant myotonia, in order to define the genotype-phenotype correlation, and to elucidate the contribution of this pore residue to the mechanisms of ClC-1 gating. Patch-clamp recordings showed that F484L reduced chloride currents at every tested potential and dramatically right-shifted the voltage dependence of slow gating, thus contributing to the mild clinical phenotype of affected heterozygote carriers. Unlike dominant mutations located at the dimer interface, no dominant-negative effect was observed when F484L mutant subunits were co-expressed with wild type. Molecular dynamics simulations further revealed that F484L affected the slow gate by increasing the frequency and stability of the H-bond formation between the pore residue E232 and the R helix residue Y578. In addition, using patch-clamp electrophysiology, we characterized three other myotonic ClC-1 mutations. We proved that the dominant L198P mutation in the channel pore also right-shifted the voltage dependence of slow gating, recapitulating mild myotonia. The recessive V640G mutant drastically reduced channel function, which probably accounts for myotonia. In contrast, the recessive L628P mutant produced currents very similar to wild type, suggesting that the occurrence of the compound truncating mutation (Q812X) or other muscle-specific mechanisms accounted for the severe symptoms observed in this family. Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.

The objective of this study was to assess the edible biomass and chemical composition of forages grown on pure form, as a grass mix, and in grass-legume consortia. The following species were tested: white oats (Avena sativa), black oats (Avena strigosa), ryegrass (Lolium multiflorum), forage peanut (Arachis pintoi), white clover (Trifolium repens), and red clover (Trifolium pratense). The experiment consisted of sixteen treatments arranged in a completely randomized design. The parameters measured were total dry matter (PMST), neutral detergent fiber (NDF), acid detergent fiber (ADF), and crude protein (CP). No significant differences in PMST were found among the consortia (p > 0.05). Only the pure cultivated white clover (p > 0.05) was comparable to the consortia in terms of biomass production. The three legumes had the lowest average NDF values (p > 0.05), based on their contributions to the total NDF content of the consortia along the cuts. The ADF content increased for all treatments during the cuts. The results indicate that in pasture, legumes increase protein content, and forage consortia increase both the pasture production and the grazing period. Their chemical composition is adequate for boosting livestock production in pastures. RESUMO. Objetivou-se avaliar a produção de biomassa e a composição bromatológica ao longo do ciclo produtivo de forrageiras cultivadas de forma estreme, misturadas ou consorciadas. Foram utilizadas as seguintes espécies: aveia branca (Avena sativa), aveia preta (Avena strigosa), azevém (Lolium multiflorum), amendoim forrageiro (Arachis pintoi), trevo branco (Trifolium repens) e trevo vermelho (Trifolium pratense). As forrageiras foram cultivadas em 16 tratamentos em delineamento inteiramente casualizado, sendo analisados a produção de matéria seca total (PMST) e os teores de fibra em detergente neutro (FDN), fibra em detergente ácido (FDA) e proteína bruta (PB). Quanto à PMST, não foram constatadas diferenças (p > 0,05) entre os consórcios, sendo apenas o cultivo estreme de trevo branco comparável (p < 0,05) aos consórcios em biomassa produzida. Em relação ao FDN, as três leguminosas isoladas apresentaram os menores valores (p > 0,05) na média geral, ficando evidente a sua contribuição no teor de FDN dos consórcios ao longo dos cortes. O teor de FDA aumentou no decorrer dos cortes para todos os tratamentos. Os resultados indicam que a inclusão de leguminosas aumenta os teores proteicos, e os consórcios de forrageiras aumentam a produção de pastagem e o período de pastejo, com composição bromatológica adequada para potencializar a produção animal a pasto.

It was on the valleys S of Bir-kot-ghwandai that Giuseppe Tucci made his seminal, fundamental observations on the ancient history and archaeology of Swat (1958). It is with a feeling of pride and satisfaction that our Mission returns on its own tracks, also because this happens – and we envisage this as a, particularly appropriate coincidence– on the celebration of our 50th year of continuous field activity. We present the first part of the preliminary report of the Archaeological Map of the Swat valley (AMSV) project, led by Luca M. Oliveri (LMO) and Massimo Vidale (MV) in the framework of the IsIAO Archeological Mission (IAM) activities directed by P. Callieri. This preliminary report has the goal to present all data so far collected during our 2000-2005 survey campaigns, concerning an area of about 100 km.