Abstract Hematic administration of bone marrow-derived mesenchymal stem cells (MSCs) in acute ischemic stroke may not only be an effective reparative treatment but also a brain protective therapy ...that improves neurological recovery. Our purpose was to study whether either i.v. or intracarotid (i.c.) administration of allogenic MSCs during the acute phase were effective in improving neurological recovery and decreasing brain damage in an experimental rat model. In a model of permanent middle cerebral artery occlusion (pMCAO), we analyzed: neurological evaluation; MSCs migration and implantation; interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels; lesion volume; cell death; cellular proliferation; vascular endothelial growth factor (VEGF) expression and blood vessel number. Regardless of the administration route, treated groups showed better neurological recovery, without significant differences between the two groups. Migration and implantation of MSCs in the lesion area was observed in animals receiving i.c. but not i.v. treatment. The highest cytokine values were observed in the i.v. MSCs and i.c. control groups, and these levels were significantly different from the corresponding i.v. control and i.c. MSCs groups, respectively. In addition, there were significant differences between the i.v. MSCs and i.c. MSCs groups in IL-6 levels. Neither treatment reduced infarction volume. However, cell death, measured as TUNEL+ cells was decreased with significant differences between control groups. BrdU+ cells were also significantly increased in the peri-infarct zone at 14 days. VEGF expression was significantly higher in the i.c. MSCs group than in the i.c. control group and blood vessel number was significantly higher in treated groups than control groups with significant differences in the peri-infarct zone at 14 days. We conclude that allogenic MSCs administration shows therapeutic efficacy in our acute ischemic stroke model. Both routes demonstrably improved neurological recovery and provided brain protection.
Methods to reduce castration-related pain in piglets are still issues of concern and interest for authorities and producers. Our objectives were to estimate the effectiveness of two protocols of ...local anesthesia (lidocaine and the combination of lidocaine+bupivacaine) as well as the use of meloxicam as a postoperative analgesic in alleviating castration-related pain, measured by acute physiological responses. Eight groups (15 piglets/group) were included in the study: (1) castration without anesthesia or analgesia, without meloxicam (TRAD WITHOUT), (2) castration without anesthesia or analgesia, but with meloxicam (TRAD WITH), (3) handling without meloxicam (SHAM WITHOUT), (4) handling with meloxicam (SHAM WITH), (5) castration after local anesthesia with lidocaine but without meloxicam (LIDO WITHOUT), (6) castration after local anesthesia with lidocaine and meloxicam (LIDO WITH), (7) castration after local anesthesia with lidocaine+bupivacaine without meloxicam (LIDO+BUPI WITHOUT), (8) castration after local anesthesia with lidocaine+bupivacaine and meloxicam (LIDO+BUPI WITH). Acute physiological responses measured included skin surface temperature and serum glucose and cortisol concentrations. On days 4 and 11 post-castration BW was recorded and average daily gain was calculated over this period. Furthermore, piglet mortality was recorded over the 11-day post-castration period. Administration of local anesthetic or meloxicam did not prevent the decrease in skin surface temperature associated with castration. Lidocaine reduced the increase in glucose concentration associated with castration. For castrated pigs, the joint use of lidocaine and meloxicam caused a significant decrease in cortisol concentration; the combination of intratesticular lidocaine and bupivacaine did not seem to be more effective than lidocaine alone. No effect of treatments on mortality and growth were detected.
Abstract Frey syndrome is a common complication after parotidectomy. The time from surgery to disease onset may be quite long; therefore, a time-to-event analysis was performed for the occurrence of ...this syndrome post-parotidectomy. Three hundred and thirty-four patients who underwent a parotidectomy between January 2002 and November 2012 were identified (retrospective study). Of these patients, 102 developed Frey syndrome post-surgery and 232 did not. The time-to-onset analysis enabled us to estimate the risk ratio associated with different types of parotid gland tumours, various parotidectomy procedures, and repeat parotidectomy, which is useful for predicting preoperative and surgical risk. The risk of developing Frey syndrome was lower in patients with malignant tumours than in those with benign tumours (risk ratio 0.351, 95% confidence interval (CI) 0.155–0.594). Risk ratios for lumpectomy PA (pre-auricular area), superficial parotidectomy, and total parotidectomy with respect to lumpectomy T (tail) were 4.378 (95% CI 1.168–16.410), 8.040 (95% CI 3.286–19.670), and 8.174 (95% CI 3.076–21.723), respectively. Repeat parotidectomy also increased the risk of developing Frey syndrome (risk ratio 3.214, 95% CI 1.547–6.678). No effect of the use of a superficial muscular aponeurotic system (SMAS) flap on the risk of developing Frey syndrome was detected ( P = 0.888).
Cultivar pedigrees from two sugarcane origins, 9 Argentine (AR) and 7 American (AM) have been reconstructed, and their genetic similarities (based on coefficient of parentage, COP, estimates) show an ...average of 0.206 ± 0.054. CP clones that enter the pedigrees of AM cultivars are parents or grandparents of AR cultivars, demonstrating that these genotypes have a strong genetic lineage in common. On average, AR pedigrees are smaller and contain less number of founding species than AM pedigrees. However, the lower height of the former is not explained by the different participation of founding species in the pedigrees. The presence of founding species in AR and AM pedigrees increases with the year of cultivar selection, indicating that more founding species entered the pedigree in recently selected cultivars than in older ones. The ancestry of the 16 cultivars trace back to 3 founding species:
Saccharum officinarum
,
S
.
barberi
, and
S
.
spontaneum
, with
S
.
officinarum
showing the greatest percentage of participation. As
S. sinensis
participates in 13 pedigrees and
S. robustum
in 3, the 5 founding species are present in 2 out of 16 pedigrees. Interestingly, the genus
Sorghum
enters the pedigree of
LCP 85
-
384
pedigree. Industrial parameters assayed indicate that AR and AM cultivars were preferentially selected for their relatively high sucrose content and sugar yield in accordance with two facts: (i) the genetic background and the sucrose genes of sugarcane hybrids provided by the 68% of participation
S
.
officinarum
clones, and (ii) no clones of high fiber
S
.
spontaneum
have entered the pedigrees in earlier generations.
OBJECTIVETo investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a ...history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.
METHODSA phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.
RESULTSOf the 35 screened patients, 24 were enrolled and randomized12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.
CONCLUSIONSEfgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.
CLASSIFICATION OF EVIDENCEThis study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.
In 2012, a new betacoronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), was identified in humans. Several studies confirmed dromedary camels to be a potential reservoir and a source ...for human infection. Camels located on the Canary Islands were included in those studies and ca 10% of them were positive for MERS-CoV-specific antibodies. However, these findings could not be correctly interpreted because epidemiological information was not provided. Thus, further investigations were necessary to clarify these results. A total of 170 camels were investigated in this survey, of which seven (4.1%) were seropositive by ELISA. Epidemiological information revealed that all seropositive camels had been imported from Africa 20 or more years prior. We conclude that seropositive camels had contact with MERS-CoV in Africa and that there is no shedding of the virus among camels or people around the farms on the Canary Islands. However, the presence of antibodies in the camel herds should be monitored.
In the Canary Islands, water scarcity is one of the constraints for agricultural activity. Non-conventional water resources generally represent more water volume than conventional ones. The ...distribution of these resources frequently permits the possibility of a conjunctive use of desalinated (DW) water and reclaimed municipal wastewater (RW). Field testing with both water qualities and different irrigation systems is necessary for optimal site-specific management. The objective of this work was to evaluate soil salinity and phosphorus distribution, and alfalfa yield in a 20 month field experiment carried out in the island of Gran Canaria, using municipal RW and freshwater (FW) under subsurface drip irrigation (SDI). Phosphorus speciation was performed both in irrigation waters and in soils (Olsen's inorganic, organic, and microbial). RW had large EC values (2.4
dS
m
−1) with a remarkable nutrient load contribution and an average total P around 3
mg
L
−1, predominantly hydrolysable forms, while FW had very low salinity and negligible amounts of P. For the RW treatment a salt gradient was established, causing plant mortality between the irrigation lines. The study of P speciation allows describing P distribution and plant uptake in terms of P forms. Large values of microbial P were produced for the two irrigation waters around the emitters, especially for FW.
A faster P-cycling could have contributed to the significantly larger inorganic P contents observed in FW irrigated soils, in spite no external sources were added by the irrigation water.
Deep semen deposition, avoiding retrograde flow, lesions and stress, has proved to be very important in the success of sheep AI. The objective of the present study was to develop a new, suitable ...anti-retrograde flow device for sheep cervical AI (DARIO) that enables deep deposition of semen into the cervix without any modifications to the procedures currently used, and to compare the fertility, fecundity, and prolificacy rates between DARIO and a traditional catheter. Field tests were performed on 16 farms actively participating in the non-profit National Association of Rasa Aragonesa Breeders´ genetic selection scheme and where sheep management was similar. A total of 242 AI lots were considered, including 1,299 ewes; 126 lots (662 ewes) were inseminated using DARIO, and 116 lots (637 ewes) using a traditional commercially-available catheter (control group). Several factors affecting AI results were included in the model for mean comparison between DARIO and control groups (farm and ram as random factors; catheter, year and photoperiod as fixed effects; catheter × photoperiod interaction). The type of catheter had a significant effect on fertility ( < 0.01) and fecundity rates ( < 0.01) but no significant effect was detected on the prolificacy rate ( = 0.45). For fertility rate (percentage of ewes lambing after AI), means ± SE for DARIO and control groups were 59.44 ± 2.13% and 49.60 ± 2.48%, respectively; for fecundity rates, means ± SE for DARIO and control groups were 0.99 ± 0.04 and 0.82 ± 0.05 lambs/inseminated ewe, respectively, and, for prolificacy rates, means ± SE for DARIO and control groups were 1.68 ± 0.04 and 1.63 ± 0.04 lambs/ewe lambing, respectively. Fertility rate was greater in the decreasing photoperiod ( = 0.01). Significant effects were found for both year ( < 0.05) and farm ( < 0.01) on fertility, fecundity, and prolificacy rates. Neither ram nor catheter × photoperiod showed any significant effects on the variables investigated ( > 0.05). Overall, the use of DARIO instead of the traditional commercially-available catheter increased both fertility and fecundity rates; the marginal mean differences were 9.05 pregnant ewes per 100 inseminated and 0.15 lambs per inseminated ewe, respectively.
Cenarro A, García‐Otín A‐L, Tejedor MT, Solanas M, Jarauta E, Junquera C, Ros E, Mozas P, Puzo J, Pocoví M, Civeira F. A presumptive new locus for autosomal dominant hypercholesterolemia mapping to ...8q24.22.
Molecular testing of patients with autosomal dominant hypercholesterolemia (ADH) fails to detect a causal functional mutation in 15.25% of subjects. We studied an ADH pedigree in which known ADH‐causing genes (LDLR, APOB and PCSK9) were excluded. Genome‐wide analysis on 15 family members detected significant association for ADH and dbSNP RS ID rs965814 (G/A), located in 8q24.22 cytoband. ADH was significantly associated to rs965814 G allele (p < 0.05) in a case–control study based on 200 unrelated ADH subjects without LDLR or APOB gene defects and 198 normolipidemic controls. We chose 24 markers for a detailed analysis of 8q24.22 cytoband, now based on an extended set of family members (21 individuals). One particular 24 marker haplotype was significantly associated to both higher total and low‐density lipoprotein‐cholesterol concentrations. Similar results were found for a shorter haplotype, composed of the distal six markers from the complete haplotype. Therefore, a presumptive new locus for ADH could be located in 8q24.22 cytoband, a region not previously linked or associated to ADH.
The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its ...high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis.
Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated.
SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96.
The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.
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