Because scientists are unable to explain the unexplained, screening for cardiovascular abnormalities is a good method to protect against sudden unexpected death in patients with epilepsy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUniversidade Federal de São Paulo (UNIFESP) Departamento de FisiologiaUniversidade de São Paulo Faculdade de Medicina Hospital das ClínicasUNIFESP, EPMUNIFESP, Depto. de FisiologiaSciEL

Regulatory T Cell Suppression of Gag-Specific CD8+ T Cell Polyfunctional Response After Therapeutic Vaccination of HIV-1-Infected Patients on ART

We tested the hypothesis that therapeutic vaccination against HIV-1 can increase the frequency and suppressive function of regulatory, CD4+ T cells (Treg), thereby masking enhancement of HIV-1-specific CD8+ T cell response. HIV-1-infected subjects on antiretroviral therapy (N = 17) enrolled in a phase I therapeutic vaccine trial received 2 doses of autologous dendritic cells (DC) loaded with HIV-1 peptides. The frequency of CD4+CD25hiFOXP3+ Treg in blood was determined prior to and after vaccination in subjects and normal controls. Polyfunctional CD8+ T cell responses were determined pre- and post-vaccine (N = 7) for 5 immune mediators after in vitro stimulation with Gag peptide, staphylococcal enterotoxin B (SEB), or medium alone. Total vaccine response (post-vaccine–pre-vaccine) was compared in the Treg(+) and Treg-depleted (Treg-) sets. After vaccination, 12/17 subjects showed a trend of increased Treg frequency (P = 0.06) from 0.74% to 1.2%. The increased frequency did not correlate with CD8+ T cell vaccine response by enzyme linked immunosorbent assay for interferon γ production. Although there was no significant change in CD8+ T cell polyfunctional response after vaccination, Treg depletion increased the polyfunctionality of the total vaccine response (P = 0.029), with a >2-fold increase in the percentage of CD8+ T cells producing multiple immune mediators. In contrast, depletion of Treg did not enhance polyfunctional T cell response to SEB, implying specificity of suppression to HIV-1 Gag. Therapeutic immunization with a DC-based vaccine against HIV-1 caused a modest increase in Treg frequency and a significant increase in HIV-1-specific, Treg suppressive function. The Treg suppressive effect masked an increase in the vaccine-induced anti-HIV-1-specific polyfunctional response. The role of Treg should be considered in immunotherapeutic trials of HIV-1 infection

Contamination of Mesenchymal Stem-Cells with Fibroblasts Accelerates Neurodegeneration in an Experimental Model of Parkinson’s Disease

Pre-clinical studies have supported the use of mesenchymal stem cells (MSC) to treat highly prevalent neurodegenerative diseases such as Parkinson’s disease (PD) but preliminary trials have reported controversial results. In a rat model of PD induced by MPTP neurotoxin, we first observed a significant bilateral preservation of dopaminergic neurons in the substantia nigra and prevention of motor deficits typically observed in PD such as hypokinesia, catalepsy, and bradykinesia, following intracerebral administration of human umbilical cord-derived MSC (UC-MSC) early after MPTP injury. However, surprisingly, administration of fibroblasts, mesenchymal cells without stem cell properties, as a xenotransplantation control was highly detrimental, causing significant neurodegeneration and motor dysfunction independently of MPTP. This observation prompted us to further investigate the consequences of transplanting a MSC preparation contaminated with fibroblasts, a plausible circumstance in cell therapy since both cell types display similar immunophenotype and can be manipulated in vitro under the same conditions. Here we show for the first time, using the same experimental model and protocol, that transplantation of UC-MSC induced potent neuroprotection in the brain resulting in clinical benefit. However, co-transplantation of UC-MSC with fibroblasts reverted therapeutic efficacy and caused opposite damaging effects, significantly exacerbating neurodegeneration and motor deficits in MPTP-exposed rats. Besides providing a rationale for testing UC-MSC transplantation in early phases of PD aiming at delaying disease progression, our pre-clinical study suggests that fibroblasts may be common cell contaminants affecting purity of MSC preparations and clinical outcome in stem cell therapy protocols, which might also explain discrepant clinical results

Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry

A Design Method for Multiple Tube Gas-Cooled Electrical Leads forthe g-2 Superconducting Magnets

This report presents a method for designing 5300 A gas cooled electrical leads for the g-2 solenoids and 2850 A leads for the g-2 self shielded inflector dipole magnet. Empirical design equations for annular tube gas cooled leads are presented. The leads are bundled tube leads which are cooled by helium flowing in annular cooling passages between tubes. Each tube in the bundle consists of nested circular copper tubes that can be cooled on both sides. Multiple current carrying tubes will increase the lead current capacity and cooling the tubes on both sides will increase lead efficiency for a given helium flow pressure drop. The design method presented here can applied to leads made from a variety of materials

Priming Immunization with DNA Augments Immunogenicity of Recombinant Adenoviral Vectors for Both HIV-1 Specific Antibody and T-Cell Responses

Induction of HIV-1-specific T-cell responses relevant to diverse subtypes is a major goal of HIV vaccine development. Prime-boost regimens using heterologous gene-based vaccine vectors have induced potent, polyfunctional T cell responses in preclinical studies.The first opportunity to evaluate the immunogenicity of DNA priming followed by recombinant adenovirus serotype 5 (rAd5) boosting was as open-label rollover trials in subjects who had been enrolled in prior studies of HIV-1 specific DNA vaccines. All subjects underwent apheresis before and after rAd5 boosting to characterize in depth the T cell and antibody response induced by the heterologous DNA/rAd5 prime-boost combination.rAd5 boosting was well-tolerated with no serious adverse events. Compared to DNA or rAd5 vaccine alone, sequential DNA/rAd5 administration induced 7-fold higher magnitude Env-biased HIV-1-specific CD8(+) T-cell responses and 100-fold greater antibody titers measured by ELISA. There was no significant neutralizing antibody activity against primary isolates. Vaccine-elicited CD4(+) and CD8(+) T-cells expressed multiple functions and were predominantly long-term (CD127(+)) central or effector memory T cells and that persisted in blood for >6 months. Epitopes mapped in Gag and Env demonstrated partial cross-clade recognition.Heterologous prime-boost using vector-based gene delivery of vaccine antigens is a potent immunization strategy for inducing both antibody and T-cell responses.ClinicalTrials.gov NCT00102089, NCT00108654

Tree rings of Scots pine (Pinus sylvestris L.) as a source of information about past climate in northern Poland

Scots pine (Pinus sylvestris) is a very common tree in Polish forests, and therefore was widely used as timber. A relatively large amount of available wood allowed a long-term chronology to be built up and used as a source of information about past climate. The analysis of reconstructed indexed values of mean temperature in 51-year moving intervals allowed the recognition of the coldest periods in the years 1207–1346, 1383–1425, 1455–1482, 1533–1574, 1627–1646, and 1694–1785. The analysis of extreme wide and narrow rings forms a complementary method of examining climatic data within tree rings. The tree ring widths, early wood and late wood widths of 16 samples were assessed during the period 1581–1676. The most apparent effect is noted in the dry summer of 1616. According to previous research and our findings, temperature from February to March seems to be one of the most stable climatic factors which influenced pine growth in Poland. Correlation coefficients in the calibration and validation procedure gave promising results for temperature reconstruction from the pine chronology

Causes and Consequences of Past and Projected Scandinavian Summer Temperatures, 500–2100 AD

Tree rings dominate millennium-long temperature reconstructions and many records originate from Scandinavia, an area for which the relative roles of external forcing and internal variation on climatic changes are, however, not yet fully understood. Here we compile 1,179 series of maximum latewood density measurements from 25 conifer sites in northern Scandinavia, establish a suite of 36 subset chronologies, and analyse their climate signal. A new reconstruction for the 1483–2006 period correlates at 0.80 with June–August temperatures back to 1860. Summer cooling during the early 17th century and peak warming in the 1930s translate into a decadal amplitude of 2.9°C, which agrees with existing Scandinavian tree-ring proxies. Climate model simulations reveal similar amounts of mid to low frequency variability, suggesting that internal ocean-atmosphere feedbacks likely influenced Scandinavian temperatures more than external forcing. Projected 21st century warming under the SRES A2 scenario would, however, exceed the reconstructed temperature envelope of the past 1,500 years

Climate-induced severe water scarcity events as harbinger of global grain price

The severe water scarcity (SWS) concept allows for consistent analysis of the supply and demand for water sourced grain production worldwide. Thus, the primary advantage of using SWS is its ability to simultaneously accommodate the spatial extent and temporal persistence of droughts using climatic data. The SWS concept was extended here to drivers of global grain prices using past SWS events and prices of three dominant grain crops: wheat, rice and maize. A significant relation between the SWS affected area and the prices of wheat was confirmed. The past price–SWS association was then used to project future wheat prices considering likely climate change scenarios until 2050 and expected SWS extent. The projected wheat prices increase with increasing SWS area that is in turn a function of greenhouse gas emissions. The need to act to reduce greenhouse gas emissions is again reinforced assuming the SWS-price relation for wheat is unaltered