Hermanmiles3180

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III.The accumulation of DNA and RNA oxidative damage is observed in cortical and hippocampal neurons from Alzheimer's disease (AD) brains at early stages of pathology. We recently reported that Tau is a key nuclear player in the protection of neuronal nucleic acid integrity in vivo under physiological conditions and hyperthermia, a strong inducer of oxidative stress. In a mouse model of tauopathy (THY-Tau22), we demonstrate that hyperthermia selectively induces nucleic acid oxidative damage and nucleic acid strand breaks in the nucleus and cytoplasm of hippocampal neurons that display early Tau phosphorylation but no Tau fibrils. Nucleic acid-damaged neurons were exclusively immunoreactive for prefibrillar Tau oligomers. A similar association between prefibrillar Tau oligomers and nucleic acid oxidative damage was observed in AD brains. Pretreatment with Methylene Blue (MB), a Tau aggregation inhibitor and a redox cycler, reduced hyperthermia-induced Tau oligomerization as well as nucleic acid damage. This study clearly highlights the existence of an early and critical time frame for hyperthermia-induced Tau oligomerization, which most likely occurs through increased oxidative stress, and nucleic acid vulnerability during the progression of Tau pathology. These results suggest that at early stages of AD, Tau oligomerization triggers the loss of the nucleic acid protective function of monomeric Tau. This study highlights the existence of a short therapeutic window in which to prevent the formation of pathological forms of Tau and their harmful consequences on nucleic acid integrity during the progression of Tau pathology.Type 1 diabetes (T1D) is a complex autoimmune disease with strong genetic influence. In this study, we investigated +49A/G SNP (rs 231775) in exon 1 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) by PCR-RFLP and its influence as a risk factor for the disease in the North Indian population. This polymorphism at codon 17 results in an amino acid substitution (Thr/Ala) in the leader peptide of the molecule. The study included 232 patients with T1D (age at onset of disease (AOD) 0.5-37 years) and 305 ethnically matched healthy controls. The DNA obtained from these 537 individuals was amplified using a set of specific primers followed by restriction enzyme digestion with Fnu4HI. The +49G allele as well as its homozygous genotype G/G was observed to be significantly higher in patients as compared to the healthy controls (37.3% vs. 25.6%, P = 4.96E(-05) , OR = 1.73; 95%CI = 1.33-2.25) (15.52% vs. 6.6%, P = 0.001, OR = 2.62; 95% CI = 1.48-4.63) respectively. The frequency of G/G genotype was significantly higher in patients with early age at onset of disease (AOD less then 12 years) as compared to that in the late-onset patients with AOD ≥12 years (21.1% vs. 10.6%, P = 0.042, OR = 2.26; 95% CI = 1.09-4.67) as well as to that in the healthy controls (21.1% vs. 6.6%, P = 0.00004, OR = 3.8; 95% CI = 2.01-7.2). Further analysis revealed that the median AOD significantly reduced (P = 0.049) from 14 years in patients with A/A genotype to 11 and 10 years in those with A/G and G/G genotypes, respectively. These results suggest that CTLA4+49G allele, particularly in homozygous G/G condition, associates with early onset of T1D.Interaction between fungal pathogens and human phagocytes can lead to remarkably variable outcomes, ranging from intracellular killing to prolonged survival and replication of the pathogen in the host cell. Using live cell imaging we observed primary human neutrophils that release phagocytosed Candida glabrata yeast cells after intracellular killing. This process, for which we propose the name "dumping", adds a new outcome to phagocyte-fungus interaction which may be of potential immunological importance as it allows professional antigen presenting cells to take up and process neutrophil-inactivated pathogens that in their viable state are able to evade intracellular degradation in these cells.The cerato-platanin family is a group of small secreted cysteine-rich proteins exclusive for filamentous fungi. They have been shown to be involved in the interactions between fungi and plants. Functional characterization of members from this family has been performed mainly in Ascomycota, except Moniliophthora perniciosa. Our previous phylogenetic analysis revealed that recent gene duplication of cerato-platanins has occurred in Basidiomycota but not in Ascomycota, suggesting higher functional diversification of this protein family in Basidiomycota than in Ascomycota. In this study, we identified three cerato-platanin homologues from the basidiomycete conifer pathogen Heterobasidion annosum sensu stricto. Expression of the homologues under various conditions as well as their roles in the H. annosum s.s.-Pinus sylvestris (Scots pine) pathosystem was investigated. Results showed that HaCPL2 (cerato-platanin-like protein 2) had the highest sequence similarity to cerato-platanin from Ceratocystis platani and hacpl2 was significantly induced during nutrient starvation and necrotrophic growth. The treatment with recombinant HaCPL2 induced cell death, phytoalexin production and defense gene expression in Nicotiana tabacum. Eliciting and cell death-inducing ability accompanied by retardation of apical root growth was also demonstrated in Scots pine seedlings. Our results suggest that HaCPL2 might contribute to the virulence of H. annosum s.s. by promoting plant cell death.

The aim of this observational study was the evaluation of toxicity, local control and overall survival in non-small cell lung cancer (NSCLC) oligometastatic patients who had undergone stereotactic ablative body radiotherapy (SABR) for lung metastatic lesions.

SABR was carried out in oligometastatic patients with controlled primary tumour (adequate pulmonary function). We adopted the following dose prescriptions according to the site and the maximum diameter of the lung lesions 60 Gy in three fractions for peripheral lesions with diameter ≤ 2 cm, 48 Gy in four fractions for peripheral lesions between 2 and 5 cm and 60 Gy in eight fractions for central lesions. Selleckchem Sodium L-ascorbyl-2-phosphate A radiological response was defined according to RECIST criteria. Toxicity was recorded according to the Common Toxicity Criteria version 4.0.

Between October 2010 and December 2014, 60 NSCLC patients with 90 lung lesions in total were treated at our institution. A radiological response was obtained in most patients. No pulmonary toxicity grade 4, chest pain or rib fracture occurred. The median follow-up from diagnosis was 28 months (range 5.4-104.5 months). The local control at 2 years was 88.9%. Overall survival at 1 and 2 years was 94.5 and 74.6%, respectively.

SABR is well tolerated with a good radiological response and toxicity profile. Discussion within a multidisciplinary team is crucial to identify the oligometastatic patients who would probably benefit from ablative local therapy.

SABR is well tolerated with a good radiological response and toxicity profile. Discussion within a multidisciplinary team is crucial to identify the oligometastatic patients who would probably benefit from ablative local therapy.

Post-proton therapy surveillance of uveal melanomas relies on decreased thickness on repeat ultrasound B every 6 months for 2 years and yearly thereafter. Earlier pseudoprogression, a phenomenon described in other tumour types within the first months of irradiation, can also be observed in uveal melanomas and may lead to inappropriate enucleation. The Collaborative Ocular Melanoma Study (COMS) has defined ultrasound criteria to identify tumour progression after brachytherapy. We aimed to determine the reliability of ultrasound as a means to measure tumour height after proton therapy and predict local relapse.

All 1992-2012 consecutive patients with at least three ultrasound B measurements during follow-up were included.

There were 55 local relapses of 886 patients (6.2%). Ultrasound B reliability was highest at 24 months, with specificity higher than 95% starting at 18 months.

Before 18 months post-proton therapy, the risk of falsely concluding in favour of a relapse exceeds 5% and should prompt repeat measurements 3 and 6 months later but should not prompt enucleation without further clinical assessment.

Before 18 months post-proton therapy, the risk of falsely concluding in favour of a relapse exceeds 5% and should prompt repeat measurements 3 and 6 months later but should not prompt enucleation without further clinical assessment.

We aimed to study the changes of serum N-terminal pro-brain natriuretic to peptide (NT-proBNP) levels after asphyxia-induced myocardial injury in children and explore the relationship between serum NT-proBNP levels and neonatal asphyxia.

One hundred and six cases of neonatal asphyxia were randomly selected for the study, including 46 severe cases with myocardial injury and 60 mild cases with no cardiac injury. Sixty-three healthy newborns were selected as the control group. The serum NT-proBNP level was detected using electrochemiluminescence. Creatine kinase MB (CK-MB) and serum sodium and calcium were measured simultaneously.

The serum NT-proBNP level in the myocardial injury group was significantly higher than that of the noncardiac injury and control groups (p < 0.01). Asphyxia serum NT-proBNP and cardiac enzymes were significantly correlated. The median value of neonatal NT-proBNP was 1491 pg/mL at postnatal Day 3 (P3) and 1077 pg/mL at postnatal Day 14 (P14). The cutoff value for children with myocardial injury was 3612.5 pg/mL; the area under the receiver operating characteristic curve was 0.80 (p < 0.001), with a sensitivity of 83.3%, a specificity of 80.5%, a positive predictive value of 82.8%, and a negative predictive value of 79.4%. After treatment, the serum NT-proBNP level in children with myocardial damage showed a significant decrease.

The serum NT-proBNP level can reflect myocardial injury in neonates with asphyxia and can guide its diagnosis.

The serum NT-proBNP level can reflect myocardial injury in neonates with asphyxia and can guide its diagnosis.

Despite different pharmacologic properties, little is known about the comparative safety of sodium ferric gluconate versus iron sucrose in hemodialysis patients.

Retrospective cohort study using the clinical database of a large dialysis provider (2004-2005) merged with administrative data from the US Renal Data System.

66,207 patients with Medicare coverage who received center-based hemodialysis.

Iron formulation use assessed during repeated 1-month exposure periods (n=278,357).

All-cause mortality, infection-related hospitalizations and mortality, and cardiovascular-related hospitalizations and mortality occurring during a 3-month follow-up period.

For all outcomes, we estimated 90-day risk differences between the formulations using propensity score weighting of Kaplan-Meier functions, which controlled for a wide range of demographic, clinical, and laboratory variables. Risk differences were also estimated within various clinically important subgroups.

Ferric gluconate was administered in 11.4%; however, ferric gluconate was associated with a slightly decreased risk for infection-related outcomes compared to iron sucrose among patients with a hemodialysis catheter. These associations should be explored further using other data or study designs.