Blood lactate, pH, base excess and pCO(2) as prognostic indicators in caesarean-born kids from goats with pregnancy toxaemia

Research Areas: Veterinary SciencesArticle in International JournalsABSTRACT - The objective of this study was to identify the prognostic value for survival of blood parameters in the immediate post-caesarean surgery period in kids born from pregnancy toxaemia (PT) goats. This study involved 10 PT goats, in which a caesarean surgery was performed. Twenty-five kids were born after caesarean surgery of which 16 survived. A blood sample was collected from the jugular vein of the 10 goats and from the kids immediately after caesarean surgery (within 15 min). There were differences between the kids that survived and the kids that did not survive concerning the blood levels of pH (7.22 vs 7.00), base excess (- 9 vs - 18 mmol/L), pCO(2) (46 vs 62 mmHg) and L-lactate (5.6 vs 16 mmol/L). Maternal ketoacidosis due to PT has a negative impact on the survival rate of the offspring. This appears to be associated to a metabolic acidosis of the offspring. However, the only blood parameter in which there was a strong association between the maternal and newborn kids was blood urea nitrogen (r = 0.97).Barao & Barao and Faculdade de Medicina Veterinaria -Universidade de Lisboainfo:eu-repo/semantics/publishedVersio

Telomere Length Shows No Association with BRCA1 and BRCA2 Mutation Status

This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrolment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrolment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL

Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis

BACKGROUND: The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. AIMS: This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. METHODS: This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. RESULTS: Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. CONCLUSIONS: This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH

Benznidazole biotransformation and multiple targets in <i>Trypanosoma</i> cruzi revealed by metabolomics

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methodology/Principal findings&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Parasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions/significance&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Our data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi

The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

Perspectives on the Trypanosoma cruzi-host cell receptor interaction

Chagas disease is caused by the parasite Trypanosoma cruzi. The critical initial event is the interaction of the trypomastigote form of the parasite with host receptors. This review highlights recent observations concerning these interactions. Some of the key receptors considered are those for thromboxane, bradykinin, and for the nerve growth factor TrKA. Other important receptors such as galectin-3, thrombospondin, and laminin are also discussed. Investigation into the molecular biology and cell biology of host receptors for T. cruzi may provide novel therapeutic targets

Rapid viral metagenomics using SMART-9N amplification and nanopore sequencing [version 2; peer review: 2 approved]

Emerging and re-emerging viruses are a global health concern. Genome sequencing as an approach for monitoring circulating viruses is currently hampered by complex and expensive methods. Untargeted, metagenomic nanopore sequencing can provide genomic information to identify pathogens, prepare for or even prevent outbreaks. SMART (Switching Mechanism at the 5' end of RNA Template) is a popular approach for RNA-Seq but most current methods rely on oligo-dT priming to target polyadenylated mRNA molecules. We have developed two random primed SMART-Seq approaches, a sequencing agnostic approach 'SMART-9N' and a version compatible rapid adapters  available from Oxford Nanopore Technologies 'Rapid SMART-9N'. The methods were developed using viral isolates, clinical samples, and compared to a gold-standard amplicon-based method. From a Zika virus isolate the SMART-9N approach recovered 10kb of the 10.8kb RNA genome in a single nanopore read. We also obtained full genome coverage at a high depth coverage using the Rapid SMART-9N, which takes only 10 minutes and costs up to 45% less than other methods. We found the limits of detection of these methods to be 6 focus forming units (FFU)/mL with 99.02% and 87.58% genome coverage for SMART-9N and Rapid SMART-9N respectively. Yellow fever virus plasma samples and SARS-CoV-2 nasopharyngeal samples previously confirmed by RT-qPCR with a broad range of Ct-values were selected for validation. Both methods produced greater genome coverage when compared to the multiplex PCR approach and we obtained the longest single read of this study (18.5 kb) with a SARS-CoV-2 clinical sample, 60% of the virus genome using the Rapid SMART-9N method. This work demonstrates that SMART-9N and Rapid SMART-9N are sensitive, low input, and long-read compatible alternatives for RNA virus detection and genome sequencing and Rapid SMART-9N improves the cost, time, and complexity of laboratory work

Acoustic Oddball during NREM Sleep: A Combined EEG/fMRI Study

Background: A condition vital for the consolidation and maintenance of sleep is generally reduced responsiveness to external stimuli. Despite this, the sleeper maintains a level of stimulus processing that allows to respond to potentially dangerous environmental signals. The mechanisms that subserve these contradictory functions are only incompletely understood. Methodology/Principal Findings: Using combined EEG/fMRI we investigated the neural substrate of sleep protection by applying an acoustic oddball paradigm during light NREM sleep. Further, we studied the role of evoked K-complexes (KCs), an electroencephalographic hallmark of NREM sleep with a still unknown role for sleep protection. Our main results were: (1) Other than in wakefulness, rare tones did not induce a blood oxygenation level dependent (BOLD) signal increase in the auditory pathway but a strong negative BOLD response in motor areas and the amygdala. (2) Stratification of rare tones by the presence of evoked KCs detected activation of the auditory cortex, hippocampus, superior and middle frontal gyri and posterior cingulate only for rare tones followed by a KC. (3) The typical high frontocentral EEG deflections of KCs were not paralleled by a BOLD equivalent. Conclusions/Significance: We observed that rare tones lead to transient disengagement of motor and amygdala responses during light NREM sleep. We interpret this as a sleep protective mechanism to delimit motor responses and to reduce the sensitivity of the amygdala towards further incoming stimuli. Evoked KCs are suggested to originate from a brain state wit

Effect of thermal cycling on denture base and autopolymerizing reline resins

OBJECTIVE: This study evaluated the fracture toughness (FT) of denture base and autopolymerizing reline resins, with and without thermocycling (T). MATERIAL AND METHODS: Specimens of each material (denture base acrylic resin - Lucitone 550 - L; autopolymerizing reline resins - Ufi Gel Hard-UH, Tokuyama Rebase II-TR, New Truliner- NT and Kooliner-K), were produced, notched and divided into two groups (n=10): CG (control group of autopolymerizing reline resins and L): FT tests were performed after polymerization; TG (thermocycled group): FT tests were performed after T (5ºC and 55ºC for 5,000 cycles). RESULTS: Results (MPa.m((1/2))) were analyzed by two-way ANOVA and Tukey's test (p=0.05). L exhibited the highest FT mean values in both groups (CG - 2.33; TG - 2.17). For the CG groups, NT showed the highest FT (1.64) among the autopolymerizing reline resins, and K the lowest (1.04). After T, when the autopolymerizing reline resins were compared, a statistically significant difference in FT was found only between the NT (1.46) and TR (1.00). CONCLUSIONS: Thermocycling increased the FT of K and did not influence the FT of L, UH, TR and NT