Neonatal Hypoxia-Ischemia alters Brain-Derived Contactin-2-Positive Extracellular Vesicles in the Mouse Plasma.

Neonatal encephalopathy (NE) impairs white matter development and results in long-term neurodevelopmental deficits. Leveraging prior findings of altered neuronal proteins carried by brain-derived extracellular vesicles (EVs) that are marked by a neural-specific cell surface glycoprotein Contactin-2 (CNTN2) in NE infants, the present study aimed to determine the correlation between brain and circulating CNTN2+-EVs and whether NE alters circulating CNTN2+-EV levels in mice. Brain tissue and plasma were collected from postnatal day (P)7, 10, 11, 15 mice to determine the baseline CNTN2 correlation between these two compartments (n = 4-7/time point/sex). NE was induced in P10 pups. Brain and plasma samples were collected at 1, 3, 6, 24, and 120 h (n = 4-8/time point/sex). CNTN2 from brain tissue and plasma EVs were quantified using ELISA. ANOVA and linear regression analyses were used to evaluate changes and correlations between brain and plasma CNTN2+-EVs. In baseline experiments, CNTN2 in brain tissue and plasma EVs peaked at P10 with no sex-difference. Brain and plasma CNTN2+-EV showed a positive correlation across early postnatal ages. NE pups showed an elevated CNTN2 in brain tissue and EVs at 1 h and only in brain tissue at 24 h. NE also abolished the positive plasma-brain correlation. The findings establish a link for central CNTN2 and its release into circulation during early postnatal life. The immediate elevation and release of CNTN2 following NE highlight a potential molecular response shortly after a brain injurious event. Our findings further support the utility of circulating brain-derived EVs as a possible bioindicator of NE.

From Cullowhee Creek to Conley: genome sequence and annotation of a cluster DJ Gordonia phage.

We report the discovery of Gordonia phage Conley, a siphovirus isolated from Cullowhee Creek in the Fall of 2022. The 60,078bp genome contains 90 predicted protein-coding genes all transcribed in the same direction and has been assigned to genetic cluster DJ based on gene content similarity.

A Spectroscopic Description of Asymmetric Isotopologues of CO2.

A polyad-conserving algebraic model applied to vibrational excitations of asymmetric isotopologues of CO2 is presented. First, the problem of vibrational excitations is studied by taking into account only the minimum subspace of states to characterize the Fermi interaction. This analysis allows an estimation of the force constants as well as the feasibility of describing the system in a local mode scheme, in terms of SU(2) operators associated with Morse ladder operators for the stretches. This description together with the algebraic U(3) for the bends establishes the dynamical group SU1(2) × U(3) × SU2(2) for a series of isotopologues. Six isotopologues are considered, namely, 16O12C18O, 16O12C17O, 16O13C18O, 16O13C17O, 17O13C18O, and 17O12C18O in their electronic ground states. For isotopologues 16O12C18O, 16O12C17O, 17O12C18O, and 16O13C18O, the vibrational description was carried out using a Hamiltonian involving 14 parameters. For this series of isotopologues with a number of energy terms 90, 57, 42, and 40, the deviations obtained were rms = 0.15, 0.10, 0.06, and 0.07 cm-1, respectively. For 16O13C17O, with 28 experimental energies and involving 13 parameters, the deviation was rms = 0.05 cm-1, while for 17O13C18O, a different strategy was proposed since only 12 experimental energy levels. In all cases, the polyad scheme P212 = 2(ν1 + ν3) + ν2 was considered. In addition, a new criterion of locality/normality degree is proposed, embracing the case of molecules with normal mode behavior, in particular, the isotopologues of CO2.

The Role of Acetyl Zingerone and Its Derivatives in Inhibiting UV-Induced, Incident, and Delayed Cyclobutane Pyrimidine Dimers.

Cyclobutane pyrimidine dimers (CPDs) are ultraviolet radiation (UV)-induced carcinogenic DNA photoproducts that lead to UV signature mutations in melanoma. Previously, we discovered that, in addition to their incident formation (iCPDs), UV exposure induces melanin chemiexcitation (MeCh), where UV generates peroxynitrite (ONOO-), which oxidizes melanin into melanin-carbonyls (MCs) in their excited triplet state. Chronic MeCh and energy transfer by MCs to DNA generates CPDs for several hours after UV exposure ends (dark CPD, dCPDs). We hypothesized that MeCh and the resulting dCPDs can be inhibited using MeCh inhibitors, and MC and ONOO- scavengers. Here, we investigated the efficacy of Acetyl Zingerone (AZ), a plant-based phenolic alkanone, and its chemical analogs in inhibiting iCPDs and dCPDs in skin fibroblasts, keratinocytes, and isogenic pigmented and albino melanocytes. While AZ and its methoxy analog, 3-(4-Methoxy-benzyl)-Pentane-2,4-dione (MBPD) completely inhibited the dCPDs, MBPD also inhibited ~50% of iCPDs. This suggests the inhibition of ~80% of total CPDs at any time point post UV exposure by MBPD, which is markedly significant. MBPD downregulated melanin synthesis, which is indispensable for dCPD generation, but this did not occur with AZ. Meanwhile, AZ and MBPD both upregulated the expression of nucleotide excision repair (NER) pathways genes including Xpa, Xpc, and Mitf. AZ and its analogs were non-toxic to the skin cells and did not act as photosensitizers. We propose that AZ and MBPD represent "next-generation skin care additives" that are safe and effective for use not only in sunscreens but also in other specialized clinical applications owing to their extremely high efficacy in blocking both iCPDs and dCPDs.

Developmental Iron Deficiency Dysregulates TET Activity and DNA Hydroxymethylation in the Rat Hippocampus and Cerebellum.

Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification of 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague Dawley rats were fed iron-deficient diet (ID; 4 mg/kg Fe) from gestational day 2 to generate iron-deficient anemic (IDA) offspring. Control dams were fed iron-sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, the hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p = 0.0105), with a corresponding increase in TET activity (p < 0.0001) and Tet3 expression (p < 0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p = 0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

Skeletopy of the intumescentia lumbalis and conus medullaris applied to epidural anaesthesia in Leopardus geoffroyi.

BACKGROUND: Leopardus geoffroyi is a Neotropical wild felid with wide distribution in the south of the South American continent. The objective was to investigate the skeletopy of the intumescentia lumbalis (IL) and conus medullaris (CM) from 11 specimens of L. geoffroyi collected dead on highways. MATERIALS AND METHODS: The cadavers were fixed in formaldehyde solution and dissected to allow the dorsal exposure of IL and CM. The cranial and caudal limits were marked with radiopaque pins and radiographic projections were used to determine the skeletopy. The lengths of IL and CM were measured with a pachymeter. RESULTS: In most specimens, the IL was located at the level of L4 and L5 vertebrae, although in 4 (1 male and 3 females) individuals its cranial limit was L3 and in 3 specimens (2 male and 1 female) the caudal limit was L6. The length of IL was 35.6 ± 6.7 mm. The CM had its base predominantly at the level of the L5 vertebra, although in some specimens the base was in L4 and in others in L6. The apex of the CM can be found since the lumbosacral junction until the level of the Cd2 vertebra. The CM measured 74.4 ± 14.3 mm. CONCLUSIONS: Based on the skeletopy, it can be suggested that epidural anaesthesia procedures in L. geoffroyi are safer with the introduction of the catheter through the sacrocaudal interarcual space, as recommended by some anaesthetists for the domestic cat.

Perinatal Ischemia Alters Global Expression of Synaptosomal Proteins Critical for Neural Plasticity in the Developing Mouse Brain.

Ischemic perinatal stroke (IPS) affects 1 in 2,300-5,000 live births. Despite a survival rate >95%, approximately 60% of IPS infants develop motor and cognitive impairments. Given the importance of axonal growth and synaptic plasticity in neurocognitive development, our objective was to identify the molecular pathways underlying IPS-associated synaptic dysfunction using a mouse model. IPS was induced by unilateral ligation of the common carotid artery of postnatal day 10 (P10) mice. Five days after ischemia, sensorimotor and motor functions were assessed by vibrissae-evoked forepaw placement and the tail suspension test respectively, showing evidence of greater impairments in male pups than in female pups. Twenty-four hours after ischemia, both hemispheres were collected and synaptosomal proteins then prepared for quantification, using isobaric tags for relative and absolute quantitation. Seventy-two of 1,498 qualified proteins were altered in the ischemic hemisphere. Ingenuity Pathway Analysis was used to map these proteins onto molecular networks indicative of reduced neuronal proliferation, survival, and synaptic plasticity, accompanied by reduced PKCα signaling in male, but not female, pups. These effects also occurred in the non-ischemic hemisphere when compared with sham controls. The altered signaling effects may contribute to the sex-specific neurodevelopmental dysfunction following IPS, highlighting potential pathways for targeting during treatment.

Antitumoral activity of quinoxaline derivatives: A systematic review.

Cancer is a leading cause of death and a major health problem worldwide. While many effective anticancer agents are available, the majority of drugs currently on the market are not specific, raising issues like the common side effects of chemotherapy. However, recent research hold promise for the development of more efficient and safer anticancer drugs. Quinoxaline and its derivatives are becoming recognized as a novel class of chemotherapeutic agents with activity against different tumors. The present review compiles and discusses studies concerning the therapeutic potential of the anticancer activity of quinoxaline derivatives, covering articles published between July 2013 and July 2018.

Methods to control anticancer chemotherapy preparations ranked by risk analysis.

The observed increase in cancer led to a continuous rise in anticancer drug preparations in Hospital Centres. The quality and security of these preparations are essential to ensure the efficacy and to limit the risk of iatrogenic toxicity. Several methods have been described to secure the process of preparation (i.e. non-analytical methods for the control during the fabrication; analytical methods for the final product evaluation). These different methods have been presented in many studies, in particular in descriptive studies, but in practice, selecting a method is difficult and related to needs and hospital priorities. Therefore, we decided to conduct this present review focused on various existing methods allowing enhancement in security of anti-cancer drugs preparation process. A proactive hazard analysis method was applied, considering preparation and control steps, to discuss the choice of a method in terms of quality and security and to identify potential risks of failure. The results show that none method is perfect. Methods with the lowest criticality score are the robotization closely followed by Drugcam® in the case of re-labelling of all containers. According to these elements a University Hospital Centre could consider these risk indexesimplementing control methods.

Retrospective study of hypersensitivity reactions to chemotherapeutic agents in a thoracic oncology service.

WHAT IS KNOWN AND OBJECTIVE: With the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered. The allergic clinical symptoms are variable and unpredictable. The aim of this study was to identify the characteristics of hypersensitivity reactions and to assess the value of skin tests for platinum salts and pemetrexed in the treatment of patients with non-small cell lung cancers or malignant pleural mesothelioma. METHODS: A single-centre retrospective study was performed for 2 years. Patients treated with the drugs of interest for an advanced or metastatic non-small cell lung cancers or malignant pleural mesothelioma and who experienced hypersensitivity reactions symptoms were eligible for this study. Clinical symptoms of hypersensitivity reactions, population characteristics and administered chemotherapy regimens were identified. RESULTS: The hypersensitivity reactions frequency was rare (1.2%) and concerned 17 patients in our study. Typical clinical features of immediate hypersensitivity reactions associated with treatment were observed for nine patients (anaphylactic reactions for three cases, angioedema and hypotension associated with asthenia and heat in one case, respectively, and other cutaneous symptoms in the remaining four cases). Skin tests were positive in three patients, but only for platinum salts. The outcome after reintroduction of a negatively tested platinum salt allowed us to calculate a negative predictive value for platinum salt skin tests of 100%. For pemetrexed, skin tests were negative for all patients. WHAT IS NEW AND CONCLUSION: Skin tests could be used to diagnose hypersensitivity reactions with platinum salts or to evaluate the possibility of cross-reactions between two platinum salts. A negative skin test may predict with reasonable reliability the absence of future hypersensitivity reactions in case of reintroduction of drug infusion. Because the IgE-mediated mechanism has never been demonstrated for pemetrexed, skin tests are not valid and have no diagnostic value for this molecule. Because hypersensitivity reactions are potentially fatal adverse events, we recommend that patients who experience a hypersensitivity reactions onset should be monitored closely and clinicians must be aware of hypersensitivity reaction signs.

Erythrocyte deformability and hemorheological profile in multiple myeloma.

The hemorheological profile in multiple myeloma (MM) has been extensively studied. Our investigation regarded the behavior of whole-blood viscosity, plasma viscosity and erythrocyte deformability in MM. We enrolled 24 MM patients; 13 of them had been recently diagnosed and were at the initial stage of therapy, 6 were on consolidation/conservation therapy and 5 had achieved a complete remission. On fasting venous blood we evaluated whole-blood and plasma viscosity at high and low shear rates, haematocrit, the ratios between whole-blood viscosity (at high and low shear rate) and haematocrit×100, the ratio between plasma viscosity at low and high shear rate and the erythrocyte deformability examined by using laser diffractometry and expressed as elongation index. A significant increase in plasma viscosity at low shear rate and a marked decrease in haematocrit were observed in MM patients compared with normal controls. Also the ratio between the high shear rate whole-blood viscosity and haematocrit ×100 and the ratio between the low and high shear rate plasma viscosity were significantly increased in MM patients. A significant decrease in erythrocyte deformability, especially at low shear stresses, was found. We discuss some hypotheses that might explain the behavior of red blood cell deformability in MM, considering that its impairment, in addition to the increase of plasma viscosity, can alter the microcirculatory flow in these patients.

Hemorheological parameters in Monoclonal Gammopathy of Undetermined Significance (MGUS).

There is scarcity of information about the hemorheological pattern in subjects with Monoclonal Gammopathy of Undetermined Significance (MGUS). This preliminary research is focused on the behaviour of whole-blood and plasma viscosity, haematocrit and erythrocyte deformability in the above clinical condition. We enrolled 21 MGUS subjects (10 women and 11 men; mean age 66.4 ± 11.6 years). In fasting venous blood we examined whole-blood and plasma viscosity at high and low shear rates, haematocrit, the ratios between whole-blood viscosity (at high and low shear rate) and haematocrit × 100, the ratio between plasma viscosity at low and high shear rate, and the erythrocyte deformability expressed as elongation index. By comparing normal controls to MGUS subjects a significant increase in whole-blood viscosity at high shear rate and in plasma viscosity at low shear rate were observed. In MGUS subjects the ratios between the high and low shear rate blood viscosity and haematocrit × 100, as well as the ratio between the low and high shear rate plasma viscosity were significantly higher. In MGUS subjects a marked decrease in erythrocyte deformability was also observed. The alteration of the hemorheological profile found in these subjects might be involved in the pathogenesis of thromboembolic events, which occur with a high frequency in MGUS.

Disección aislada de la arteria mesentérica superior: tratamiento endovascular mediante stent y embolización / Isolated dissecting aneurysm of the superior mesenteric artery: Endovascular treatment using stent-assisted coil embolisation

No disponible

Effect of Cu(2+)-complexation on the scavenging ability of chrysin towards photogenerated singlet molecular oxygen (O2((1)Δg)). Possible biological implications.

Visible-light irradiation of aqueous-ethanolic solutions of Riboflavin (Rf) in the individual presence of the flavone chrysin (Chr) and its complex with Cu(2+) ([Chr2Cu]; 2:1 L:M) generates singlet molecular oxygen O2((1)Δg), that concomitantly interact with both flavone derivatives. Overall (kt) and reactive (kr) rate constants in the order of 10(7)M(-1)s(-1) were determined for the process. Metal chelation greatly enhances the scavenging ability of [Chr2Cu] towards O2((1)Δg) through a mechanism dominated, in >80%, by the physical component. In this way, practically all O2((1)Δg) is deactivated by the complex without significant loss of the quencher. The isolated flavone quenches O2((1)Δg) in a prevailing reactive fashion. The very low value exhibited by [Chr2Cu] for the kr/kt ratio constitutes a positive quality for antioxidative protectors in biological media, where elevated local concentration and high reactivity of significant molecules make them initial targets for O2((1)Δg) aggression. Finally, two interesting properties in the field of free radicals scavenging by [Chr2Cu] must be mentioned. In first place metal chelation itself, in the obvious sense of free metal ion withdrawal from the oxidizable medium, prevents the initiation of a free radical-mediated oxidation processes through mechanisms of Fenton or lipid peroxidation. In addition, the incorporation of Cu adds to [Chr2Cu] the ability of a free radical scavenger, already described for similar Cu-chelate compounds. This collection of beneficial properties positions the complex as a remarkably promising bioprotector towards ROS-mediated oxidation. A quantification of the efficiency on the initial anti-oxidative effect exerted by Chr and [Chr2Cu] towards tryptophan was carried out. The amino acid is an archetypal molecular model, commonly employed to monitor oxidative degradation of proteinaceous media. It was efficiently photoprotected against O2((1)Δg)-mediated photooxidation by [Chr2Cu].

Erythrocyte deformability, plasma lipid peroxidation and plasma protein oxidation in a group of OSAS subjects.

Considering that obstructive sleep apnea syndrome (OSAS) is usually associated with endothelial dysfunction, atherosclerosis and cardiovascular disorders, our aim was to examine the erythrocyte deformability and the oxidative status in a group of OSAS subjects. We consecutively enrolled 48 subjects with OSAS defined after a 1-night cardiorespiratory sleep study, subsequently subdivided according to the apnea/hypopnea index (AHI) value in two subgroups: Low (L = 21 subjects with AHI<30) and High (H = 27 subjects with AHI>30). We evaluated the erythrocyte deformability, expressed as elongation index (EI) and the parameters of the oxidative status, such as lipid peroxidation (expressed as thiobarbituric acid-reactive substances - TBARS) and protein oxidation (measured as carbonyl groups - PC). In the entire group and in the two subgroups of OSAS subjects we found a decreased erytrocyte deformability at all shear stresses, not correlated with the plasmatic oxidative stress nor with the polysomnographic parameters. Lipid peroxidation was increased in the whole group and in the H subgroup of OSAS while protein oxidation showed a different trend. As in OSAS the osmotic fragility and the metabolism of the red cells seem to be not impaired, the oxidative damage to the red cell membrane proteins might be responsible for the reduced erythrocyte deformability. This rheological alteration, in addition to the increase in whole blood and plasma viscosity and to the erythrocyte hyperaggregation, could influence the microcircolatory profile in OSAS subjects.

Selection of the appropriate radionuclide source for the efficiency calibration in methods of determining gross alpha activity in water.

Measuring the gross alpha activity in water samples is a rapid, straightforward way of determining whether the water might contain a radionuclide concentration whose consumption would imply a total indicative dose (TID) greater than some reference limit - currently set at 0.1 mSv/y in Europe. There are several methods used for such measurements. Two of them are desiccation with the salts being deposited on a planchet, and coprecipitation. The main advantage of these two methods is their ease of implementation and low cost of preparing the source to measure. However, there is considerable variability in the selection of the most suitable radioactive reference standard against which to calculate the water's gross alpha activity. The goal of this paper is to propose the most appropriate reference radionuclides to use as standards in determining gross alpha activities with these two methods, taking into account the natural radioactive characteristics of a wide range of waters collected at different points in Spain. Thus, the results will be consistent with each other and representative of the sum of alpha activities of all the alpha-emitters contained in a sample.

Scavenging of photogenerated ROS by Oxicams. Possible biological and environmental implications.

The profusely employed drugs Piroxicam (Piro), Tenoxicam (Teno) and Meloxicam (Melo) belonging to the non-steroidal antiinflammatory drug (NSAID) family of the Oxicams (Oxis) were studied in the frame of two specific conditions: (a) their ROS scavenging ability, in relation to a possible biological antioxidant action and (b) their photodegradability under environmental conditions, in the context of Oxi-contaminated waters. Singlet molecular oxygen (O2((1)Δg)) and superoxide radical anion (O2(-)) were photogenerated through Riboflavin (Rf, vitamin B2)-photosensitization in aqueous and aqueous-methanolic solutions in the presence of Oxi concentrations in the range 50-500 µM. The visible-light absorber vitamin is currently present in all types of natural waters and constitutes the most frequent endogenous photosensitizer in mammals. Hence, it was employed in order to mimic both natural sceneries of interest. All three Oxis quench O2((1)Δg) with rate constants in the order of 10(8)M(-1)s(-1) showing a significant photodegradation efficiency given by a dominant reactive fashion for deactivation of the oxidative species. Although this is not a desirable property in the context of photoprotection upon prolonged photoirradiation, constitutes in fact a promissory aspect for the degradation NSAIDs, in waste waters. Indirect evidence indicates that Melo is also oxidized through a O2(-)-mediated component. The simultaneous presence of Piro plus tryptophan or tyrosine under Rf-photosensitizing conditions, which has taken the amino acids as photooxidizable model residues in a proteinaceous environment, indicates that the NSAID induces a protection of the biomolecules against photodynamic degradation.

Meningococcal vaccines: Current state and future outlook.

Neisseria meningitidis infections are a major public health problem worldwide. Although conventional approaches have not led to development of a serogroup B meningococcal vaccine, a new technique based on genome sequencing has created new perspectives. Recently, a universal serogroup B meningococcal vaccine, Bexsero(®), was licensed in Europe, Australia and United States, following several clinical studies demonstrating its immunogenicity and safety. Availability of this vaccine could contribute positively to human health, by significantly reducing the incidence of meningococcal infections. However, unfavorable cost-effectiveness analysis means that routine vaccination is not currently recommended. Another serogroup meningococcal vaccine, Trumemba(®), was also recently licensed in United States. Like any drug, Bexsero(®) and Trumemba(®) will require close observation to assess their impact on meningococcal epidemiology.

Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome is a rare disease, frequently responsible for renal insufficiency in children. Recent findings have led to renewed interest in this pathology. The discovery of new gene mutations in the atypical form of HUS and the experimental data suggesting the involvement of the complement pathway in the typical form, open new perspectives for treatment. This review summarizes the current state of knowledge on both typical and atypical hemolytic uremic syndrome pathophysiology and examines new perspectives for treatment.